I. Pulmonary embolism
Pulmonary embolism (PE) is defined as a condition of blockage of blood flow due to a blood clot of either in main artery of the lung or somewhere else in the body. In most cases, it is in the deep veins of the legs or pelvic. The disease is a common and affect as many as 500,000 persons annually in the United States
A. Symptoms
1. Dyspnoea and pleuritic chest pain
According to the study by Karolinska Institutet, Department of Clinical Science and Education, Initial symptoms in pulmonary embolism, dominated by dyspnoea and/or pleuritic chest pain were significantly different from those in community-acquired pneumonia, dominated by fever, chills and/or cough (P<0.001)(1).
2. Cough or hemoptysis
Pulmonary embolism (PE) is a life-threatening condition that may present as dyspnea, chest pain, cough or hemoptysis, but often occurs without symptom, according to the study by the New York Medical College(2).
3. Hiccups
There is a report of 3 cases of pulmonary embolism presenting as persistent hiccups.
Including a 52-year-old African-American male without significant prior medical or surgical history presented to the emergency department (ED) with a 3-day history of hiccups. Chest radiograph demonstrating a prominent central pulmonary artery (early Fleishner’s Sign, red arrows) and a cut-off of the pulmonary arteries bilaterally. Computed tomography (CT) showing a saddle embolus (black arrow). B. CT showing a large left pulmonary artery embolus (filling defect, red arrow). C. CT showing a left pulmonary artery embolu(3).
4. Other symptoms
Sudden onset dyspnea was the most frequent symptom in both samples (81 and 78%), followed by chest pain (56 and 39%), fainting or syncope (26 and 22%), and hemoptysis (7 and 5%). At least one of the above symptoms was reported by 756 (94%) of 800 patients. Isolated symptoms and signs of deep vein thrombosis occurred in 3% of the cases. Only 7 (1%) of 800 patients had no symptoms before PE was diagnosed, according to the study by the Università degli Studi di Firenze(4).
5. In severe cases, symptoms include persistent hypotension, arterial oxygen desaturation of less than 70%, myocardial ischemia, Acidosis and hypercarbia accompanied death
Experimental massive pulmonary embolism was created in dogs by injecting a standard-sized clot. Certain changes were found to precede death: 1) persistent hypotension, with fall in arterial blood pressure to levels lower than one half base line, 2) arterial oxygen desaturation of less than 70%, and 3) electrocardiographic changes suggestive of myocardial ischemia. Acidosis and hypercarbia accompanied death(5).
B. Causes and Risk factors
B.1. Causes
1. Popliteal venous aneurysm
There is a report of a case of surgical treatment of a 44 years old man, for a popliteal venous aneurysm that was complicated by pulmonary thromboembolism(6).
2. Total hip/knee arthroplasty
Total hip/knee arthroplasty Total hip/knee arthroplasty may cause venous thromboembolism (VTE) as a postoperative complication. There is a report of a patient who developed pulmonary embolism (PE) 6 days after arthroscopic rotator cuff repair but recovered without sequelae. In this case, the possibility of DVT of the lower limbs was denied by contrast-enhanced CT. Most possibly, the source of PE was deep vein thrombosis (DVT) of the upper limb under Desault fixation which showed arthroscopic surgery-related swelling postoperatively(7).
3. Vertebral compression fractures (VCFs)
i n osteoporotic VCFs, pulmonary cement embolism was detected in 23% of PVP sessions, developed in the distal to third-order pulmonary arteries, and was related to leakage into the inferior vena cava, according to the study by Seoul National University Bundang Hospital(8).
4. Medication
Medication such as Heparin , bivalirudin (0.1 mg/kg bolus and 1.75 mg/kg per h infusion) plus warfarin in certain patient can be a potential cause of pulmonary embolism.
A 68-year-old man was referred to the emergency department 6 h after onset of sudden acute dyspnoea. Immediate ECG showed sinus tachycardia with the typical S1-Q3-T3 pattern and incomplete right bundle branch block. The echocardiogram showed the presence of mobile thrombus in the right atrium, a distended right ventricle with free wall hypokinesia and displacement of the interventricular septum towards the left ventricle. Lung spiral computed tomography (CT) showed bilateral pulmonary involvement and confirmed the picture of a thrombotic system in the right atrium and caval vein. Thrombolytic treatment with recombinant tissue plasminogen activator (rt-PA) and heparin (alteplase 10 mg bolus, then 90 mg over 2 h) was administered. Six hours after thrombolysis bleeding gums and significant reduction in platelet count (around 50,000) were observed(9).
B.2. Risk factors
1. Pregnancy
Pregnancy is an important risk factor for venous thrombosis, and venous thromboembolism is a leading cause of preventable death in pregnancy. According to the study by the University of Minnesota Residency Program, physicians should maintain an appropriately high index of suspicion and request diagnostic imaging in a timely manner. Diagnosis of deep venous thrombosis with Doppler ultrasonography of the lower extremity poses no health risk to the fetus, but other radiographic studies pose a low radiation risk to the fetus. Because anticoagulant therapy poses a greater health risk to mother and fetus than does the radiation required for the diagnosis of pulmonary embolism, clinicians should aggressively pursue objective evidence of venous thromboembolism(10)
2. Intracardiac thrombosis
Right intracardiac thrombosis (IT) is a potential cause of pulmonary embolism (PE), according to the study of data Between 1970 and 1982, 23 796 autopsies, representing 84% of all in-hospital deaths in the Malmö city population, were performed, using a standardized procedure by the Uppsala University Hospital(11).
3. Obesity
The number of overweight and obese individuals in the population has increased dramatically in the past few decades, and the rising prevalence of obesity is a major public health concern. The prevalence of pulmonary embolism in hospitalized patients was higher in obese patients than in non-obese patients. Mortality in patients with pulmonary embolism was lower in obese patients than in non-obese patients, with the greatest effects in women, older patients and stable patients(12).
4. Burns
It has been estimated that 26% of Americans are obese. A very small subset of this group can be categorized as morbidly obese, fulfilling the criteria of being 100 pounds, or 100%, over ideal body weight. The clinical records of seven morbidly obese burn patients treated over a 20-year period are reviewed. Particularly notable was a 43% incidence of fatal pulmonary embolism(13).
5. Cancers
Patients with cancer are as increased risk of pulmonary embolism. According to the systematically reviewed Medline, Web of Science, and the Cochrane Library databases and selected 26 studies, by Stony Brook University Medical Center, including 2 randomized controlled trials, and 4 prospective, 18 retrospective cohort, and 2 case-control studies. Overall incidence of PE was 3.6%. Pulmonary embolism abbreviated survival in 2 studies when the diagnosis was synchronous with lung cancer. Venous thromboembolism prophylaxis, treatment, and surveillance are inconsistently reported. Clinical outcome data pertaining to this topic are limited and of overall poor methodologic quality(14).
6. Trauma
Trauma is a leading causes of death and disability in young people. Venous thromboembolism (VTE) is a principal cause of death. Trauma patients are at high risk of deep vein thrombosis (DVT)(15).
7. Heart attack and Heart surgery
Patients with current or previous heat attacked and sugery are associated to the higher risk of pulmonary embolism.
8. Device implanted
There is a report of a case of a 32-year-old woman with a septic pulmonary embolism-related implanted central venous port(16).
9. Childbirth
There is a report of identified 10 specific recurrent errors that account for a disproportionate share of maternal deaths, primarily related to pulmonary embolism, severe preeclampsia, cardiac disease, and postpartum hemorrhage(17).
10. Other risk factors
Body mass index (BMI), estrogen use, family history of PE, (inactive) malignancy, thrombophilia, trauma within 4 weeks, travel, and prior VTE (under treatment) are other risk factors of pulmonary embolism, according to the total of 4,346 patients had D-dimer testing, of whom 2,930 (67%) were women. A total of 2,500 (57%) were white, 1,474 (34%) were black or African American, 238 (6%) were Hispanic, and 144 (3%) were of other race or ethnicity(18).
C. Complications and diseases associated to pulmonary embolism
C.1. Complications
1. Endomyocarditis
Pulmonary embolism (PE) is a significant cause of morbidity and mortality. In a recent study in patients with PE, an increased level of macrophages was found in the right ventricle. In teh study to evaluate the presence of inflammatory cells, myocytolysis and intracavitary thrombi in the left and right ventricle of patients who died because of PE as a putative new source of heart failure, showed that in patients with PE, endomyocarditis and intracavitary thrombi in the left and right ventricle were found. These abnormalities may be an additional new explanation for the observed cardiac enzyme release and functional abnormalities of the heart in these patients and may contribute to the morbidity and mortality of the disease(19).
2. Other complications
In a study by the the University Medical Center Mannheim, of 65 patients with confirmed acute PE, hs-cTnI and D-dimer values were measured. Adverse clinical outcome was defined as cardiogenic shock, cardiopulmonary resuscitation, mechanical ventilation, vasopressor therapy, thrombolysis, catheter intervention or mortality within 60 days of PE. Patients with acute PE and serum hs-cTnI values >0.1 ng/ml showed significantly higher D-dimer concentrations (P= 0.0467) and a 5-fold increased risk of an adverse clinical outcome [odds ratio (OR), 4.9; 95% confidence interval (CI), 1.28-18.66; P=0.0235] compared with patients with acute PE and hs-cTnI values <0.1 ng/ml(20).
C.2. Diseases associated to Pulmonary embolism (PE)
1. Low blood pressure
Massive pulmonary embolism (PE) is characterized by systemic hypotension (defined as a systolic arterial pressure < 90 mm Hg or a drop in systolic arterial pressure of at least 40 mm Hg for at least 15 min which is not caused by new onset arrhythmias) or shock (manifested by evidence of tissue hypoperfusion and hypoxia, including an altered level of consciousness, oliguria, or cool, clammy extremities). Massive pulmonary embolism has a high mortality rate despite advances in diagnosis and therapy, according to teh study by the New York Medical College(21).
2. Deep Vein Thrombosis (DVT)
The average annual incidence of deep vein thrombosis alone was 48 per 100,000, while the incidence of pulmonary embolism with or without deep vein thrombosis was 23 per 100,000. The incidence rates of deep vein thrombosis and pulmonary embolism increased exponentially with age, according to the University of Massachusetts Medical School(22).
3. Congenital heart disease
Long-term complications of congenital heart diseases include rhythm disturbances, pulmonary hypertension, or heart failure are frequent, despite optimal care. Acute complications like arrhythmias, infective endocarditis, cerebral events, cerebral abscesses, aortic dissection, pulmonary embolism, and bleeding(23)
4. Pleural Effusion
Pulmonary embolism (PE) is the fourth cause of pleural effusions, after pneumonia, neoinfiltrates and tuberculosis, according to the study by the Institute of Lung Diseases and Tuberculosis(24).
5. Pulmonary edema
There is a report of a case of severe pulmonary embolism in a 37 years old man admitted to the intensive care unit for severe acute respiratory failure. The presenting signs and symptoms were typical for severe pulmonary oedema(25).
6. Thromboembolic pulmonary hypertension (CTEPH)
Incomplete resolution of acute pulmonary embolism (PE) is frequently observed after acute PE and may rarely result in chronic thromboembolic pulmonary hypertension (CTEPH)(26).
7. Pulmonary hypertension
Incomplete resolution of acute pulmonary embolism (PE) is frequently observed after acute PE and may rarely result in chronic thromboembolic pulmonary hypertension (CTEPH). According to the study by the Leiden University Medical Center, CTEPH is associated with a poor prognosis if left untreated. Therefore, the diagnostic approach of CTEPH aims at assessing the location and extent of the embolic obstruction, establishing the operability and prognosis of the patients and ruling out other variations of pulmonary hypertension with distinct indicated treatment(27).
8. Chronic obstructive pulmonary disease and chronic renal failure
There is a report of a 75-year-old man affected by a chronic obstructive pulmonary disease and chronic renal failure admitted to our emergency department for dyspnea and interscapular stabbing pain. Chest radiography showed diffuse parenchymal consolidation in the lower right lung with bronchiectasis, but the treatment for infection disease did not improve the clinical conditions of the patient. According to Wells score indicating an intermediate risk for pulmonary embolism, chest ultrasonography that showed ultrasonographic patterns of thromboembolism(28).
D. Misdiagnosis and Diagnosis
D.1. Misdiagnosis
1. Congenital absence of the pericardium
There is a report of a case of a 23 year-old-male, who presented to the hospital with complaints of pleuritic chest pain and exertional dyspnea, of a two-week duration. He was physically active and his past history was otherwise insignificant. His chest CT with contrast was interpreted as showing evidence of multiple emboli, predominantly in the left lung, and he was started on a heparin and warfarin therapy. A repeat chest CT with contrast three weeks later showed no significant change from the previous CT scan. Both scans showed that the heart was abnormally rotated to the left side of the chest. An echocardiogram raised the suspicion of congenital absence of the pericardium, with a posteriorly displaced heart. In retrospect, motion artifact on the left lung, attributed to cardiac pulsations and the lack of pericardium, resulted in a CT chest appearance, mimicking findings of pulmonary embolism. The misdiagnosis of pulmonary embolism was attributed to the artifact caused by excessive cardiac motion artifact on the chest CT scan. In non-gated CT angiograms, according to St Francis Medical Center(29).
2. Pulmonary Artery Leiomyosarcoma
There is a report of a 64-year-old woman presented with progressive weakness, fatigue, malaise, and dyspnea, and a marked elevation of pulmonary artery pressure was admitted. She was initially diagnosed with chronic pulmonary thromboembolism and chest computed tomography (CT) scan revealed that lobulated heterogeneous left hilar mass extended to precarinal and subcarinal space. MRI demonstrated a polypoid lesion at trunk with extension to left main pulmonary artery and its first branch(30).
3. Soft tissue sarcomas of the lower limb
Deep venous thrombosis (DVT) or pulmonary embolism (PE) is a rare, but not exceptional presentation of soft tissue sarcomas (STSs). According to the study by the University Hospital Agostino Gemelli, Catholic University of the Sacred Heart School of Medicine, STSs of the lower extremities can rarely present with DVT or PE. This possibility should be considered in the differential diagnosis of painful leg swelling, especially in patients with recurrent or refractory venous thrombosis. When a STS is suspected, MRI should be obtained followed by excisional biopsy of the eventual mass. A delay in diagnosis and treatment of STSs often results in very poor prognosis.Level of evidence(31).
4. Acute anterior myocardial infarction
Pulmonary embolism remains the major malingerer of acute chest disease. There is a report of a case of bilateral pulmonary embolism in a patient of 50 years. The electrocardiogram showed ST elevation in anteroseptal and lateral leads. The diagnosis of acute myocardial infarction was selected and a fibrinolysis achieved. Getting out under beta-blocker therapy, antiplatelet, statin and angiotensin-converting enzyme inhibitors after 10 days hospitalization, the patient was readmitted one month later for a massive pulmonary embolism(32).
5. Acute abdomen
Pulmonary embolisms (PEs) are easily missed both in children and adults because of the varied presentations and subtle clinical findings. There is a report of a series of 2 cases of PE presenting as acute abdomen. Case 1 is a 14-year-old adolescent boy who presented to a pediatric emergency department with abdominal pain, whereas case 2 is a 22-year-old man who presented to the adult emergency department of the same institution with abdominal pain. There was a delay in diagnosis in both cases due to lack of recognition of the unusual presentation. Awareness of the unusual presentations of PE and the risk factors in both adults and children can assist the clinician toward an accurate diagnosis and timely therapeutic intervention(33).
6. Pulmonary artery sarcoma
In a Case analysis and literature review by Chinese Academy of Medical Science and Peking Union Medical College, pulmonary artery Sarcoma can be easily misdiagnosed as pulmonary thromboembolism(34).
D.2. Diagnosis
1. Chest X-ray
In the study to investigate if preliminary chest radiograph (CXR) findings can define the optimum role of lung scintigraphy in subjects investigated for pulmonary embolism (PE), showed that In subjects investigated for PE, an abnormal CXR increases the prevalence of non-diagnostic scintigrams. A normal pre-test CXR is more often associated with a definitive (normal or high probability) scintigram result. The chest radiograph may be useful in deciding the optimum sequence of investigations(35).
2. Ventilation-perfusion (V/Q) scan(Lung scan) and Spiral CT scan
Ventilation-perfusion (V/Q) imaging has been used as the screening test for pulmonary embolism (PE) for many years with diagnostic algorithms developed as a result of the Prospective Investigation of Pulmonary Embolism Diagnosis study. With the increasing availability of spiral (helical) computed tomography (CT) and many studies showing a high degree of accuracy for PE, there is much support for the replacement of V/Q by spiral CT. This article reviews the literature concerning V/Q scanning, spiral (helical) CT, and the future potential for magnetic resonance in the diagnosis of PE(36).
3. Pulmonary angiogram
Traditionally, pulmonary angiography has been the gold standard, but over the years computed tomography pulmonary angiography (CTPA) has replaced it and is now the first line imaging test(37).
4. D-dimer blood test
In the study to validate the use of the Wells clinical decision rule combined with a point of care D-dimer test to safely exclude pulmonary embolism of 598 adults with suspected pulmonary embolism in primary care, found that pulmonary embolism was present in 73 patients (prevalence 12.2%). On the basis of a threshold Wells score of ≤ 4 and a negative qualitative D-dimer test result, 272 of 598 patients were classified as low risk (efficiency 45.5%). Four cases of pulmonary embolism were observed in these 272 patients (false negative rate 1.5%, 95% confidence interval 0.4% to 3.7%). The sensitivity and specificity of this combined diagnostic approach was 94.5% (86.6% to 98.5%) and 51.0% (46.7% to 55.4%)respectively(38).
5. Thorax ultrasound (TUS)
In the multicenter study to determine the accuracy of thorax ultrasound (TUS) in the diagnosis of PE (TUSPE) with data from January 2002 through September 2003 of 352 patients with suspected PE, showed that TUS is a noninvasive method to diagnose peripheral PE. In the absence of CTPA, TUS is a suitable tool to demonstrate a PE at the bedside and in the emergency setting(39).
6. Magnetic resonance imaging (MRI)
In the study to assess the individual and combined usefulness of MRI techniques in cases of acute pulmonary embolism and to compare the usefulness of these techniques with that of 16-MDC, showed that MR perfusion imaging had a sensitivity of 93% for subsegmental pulmonary embolism(40).
V. Preventions
A. Diet to prevent pulmonary embolism
Since Pulmonary embolism (PE) is a result of blockage of blood flow due to a blood clot of either in main artery of the lung or somewhere else in the body. Any food containing anti coagulation property is associated to reduced risk of the disease
1. Onion and Garlic
in the testing the effect of dried garlic (Allium sativum) powder on blood lipids, blood pressure and arterial stiffness in a 12-week randomised, double-blind, placebo-controlled trial. Seventy-five healthy, normo-lipidaemic volunteers (men and women aged 40-60 years) were assigned to dried garlic powder tablets (10.8 mg alliin (3-(2-propenylsulfinyl)-L-alanine)/d, corresponding to about three garlic cloves) or placebo, showed that garlic powder was associated with a near-significant decrease (12 %) in triacylglycerol concentration (P=0.07). In conclusion, garlic powder tablets have no clinically relevant lipid-lowering and blood pressure-lowering effects in middle-aged, normo-lipidaemic individuals. The putative anti-atherosclerotic effect of garlic may be linked to risk markers other than blood lipids, according to "Effect of garlic (Allium sativum) powder tablets on serum lipids, blood pressure and arterial stiffness in normo-lipidaemic volunteers: a randomised, double-blind, placebo-controlled trial" by Turner B, Mølgaard C, Marckmann P.(41). Other in a study of "Inhibition of whole blood platelet-aggregation by compounds in garlic clove extracts and commercial garlic products." by Lawson LD, Ransom DK, Hughes BG. posted in US National Library of Medicine National Institutes of Health, researchers found that The best garlic powder tablets were equally as active as clove homogenates whereas steam-distilled oils were 35% as active and oil-macerates (due to low content) only 12% as active. A garlic product aged many months in aqueous alcohol had no activity. For steam-distilled oils, most of the activity was due to diallyl trisulfide. For the oil-macerates, most of the activity was due largely to the vinyl dithiins. Ajoene, an exclusive component of the oil-macerates, had highest specific activity of all the compounds tested but, because of its low concentration, had only 13% of the activity of diallyl trisulfide and 3% of the activity of allicin. Compounds which may be active in vivo are discussed.
2. Ginger
In the identification of key hepatic pathways targeted by anti-obsogenic ginger phytochemicals fed to mice, found that Dietary ginger phytochemicals target cholesterol metabolism and fatty acid oxidation in mice, with consequences, according to "Ginger phytochemicals mitigate the obesogenic effects of a high-fat diet in mice: a proteomic and biomarker network analysis" by Beattie JH, Nicol F, Gordon MJ, Reid MD, Cantlay L, Horgan GW, Kwun IS, Ahn JY, Ha TY.(42). Other In the study of ginger proteases were extracted from fresh ginger rhizome by using phosphate buffer and subsequently purified by ion exchange chromatography, found that the ginger proteases exhibited a similar affinity for κ-casein and higher specificity with increasing temperature. Gel electrophoresis and mass spectra indicated that Ala90-Glu91 and His102-Leu103 of κ-casein were the preferred target bonds of ginger proteases. The milk clotting activity, affinity, and specificity toward κ-casein showed that ginger protease is a promising rennet-like protease that could be used in manufacturing cheese and oriental-style dairy foods, according to "Purification, characterization, and milk coagulating properties of ginger proteases" by Huang XW, Chen LJ, Luo YB, Guo HY, Ren FZ.(43).
3. Red pepper
In a study of Thirty-six participants (22 women and 14 men), aged 46+/-12 (mean+/-s.d.) years; BMI 26.4+/-4.8 kg/m(2), consumed 30 g/day of a chilli blend (55% cayenne chilli) with their normal diet (chilli diet), and a bland diet (chilli-free) for 4 weeks each, researchers found that Four weeks of regular chilli consumption has no obvious beneficial or harmful effects on metabolic parameters but may reduce resting heart rate and increase effective myocardial perfusion pressure time in men, according to" The effect of 4-week chilli supplementation on metabolic and arterial function in humans" by Ahuja KD, Robertson IK, Geraghty DP, Ball MJ.(44). Fermented red pepper paste(FRPP) has caused a modulation of cholesterol levels not seen in the placebo group, causing either no variation or a decrease in low-density lipoprotein and total cholesterol levels, according to the study of "Hypoxanthine levels in human urine serve as a screening indicator for the plasma total cholesterol and low-density lipoprotein modulation activities of fermented red pepper paste" by Kim Y, Park YJ, Yang SO, Kim SH, Hyun SH, Cho S, Kim YS, Kwon DY, Cha YS, Chae S, Choi HK.(45).
B. Phytochemicals and antioxidantsto prevent pulmonary embolism
1. Curcumin
In a study of `Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets.`by Srivastava KC, Bordia A, Verma SK. (Source from Department of Environmental Medicine, Odense University Denmark.) posted in US National Library of Medicine National Institutes of Health, researchers found that this compound inhibited thromboxane B2 (TXB2) production from exogenous [14C] arachidonate in washed platelets with a concomitant increase in the formation of 12-lipoxygenase products. Moreover, curcumin inhibited the incorporation of [14C]AA into platelet phospholipids and inhibited the deacylation of AA-labelled phospholipids (liberation of free AA) on stimulation with calcium ionophore A23187. Curcumin's anti-inflammatory property may, in part, be explained by its effects on eicosanoid biosynthesis.
2. Cinnamic acid
A series of novel ligustrazinyloxy-cinnamic acid derivatives were synthesized and evaluated for their inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation in vitro,
found that compound 2e displayed the highest protective effect on the proliferation of the damaged ECV-304 cells (EC(50) = 0.020 mM), and compound 2f was the most active anti-platelet aggregation agent (EC(50) = 0.054 mM). Structure-activity relationships were briefly discussed, according to "Ligustrazine derivatives. Part 5: design, synthesis and biological evaluation of novel ligustrazinyloxy-cinnamic acid derivatives as potent cardiovascular agents" by Chen H, Li G, Zhan P, Liu X.(46)
3. Aqueous extracts of onion, garlic and ginger
Aqueous extracts of onion, garlic and ginger inhibited platelet aggregation induced by several aggregation agents, including arachidonate (AA), in a dose-dependent manner. While onion and garlic extracts were found to be weak inhibitors of platelet thromboxane synthesis, ginger extract inhibited the platelet cyclooxygenase products and this effect correlated well with its inhibitory effects on the platelet aggregation induced by the above aggregation agents(47).
VI. Treatments
A. In conventional medicine perspective
A. Medication
1. Anticoagulants, including
Heparin,Warfarin (Coumadin) and rivaroxaban (Xarelto). In the study of 256 patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without arterial hypotension or shock. The patients were randomly assigned in double-blind fashion to receive heparin plus 100 mg of alteplase or heparin plus placebo over a period of two hours. found that when given in conjunction with heparin, alteplase can improve the clinical course of stable patients who have acute submassive pulmonary embolism and can prevent clinical deterioration requiring the escalation of treatment during the hospital stay(48).
2. Clot dissolvers
Patients with acute pulmonary embolism are at risk for early death or chronic morbidity. Appropriate therapy can dramatically reduce the incidence of both. Appropriate therapy can dramatically reduce the incidence of both. Oxygen and heparin therapy should be started as soon as the diagnosis is suspected. The condition of a hypotensive patient with right ventricular overload from acute pulmonary embolism usually is made worse by a fluid challenge; hypotension may be relieved by preload reduction or even by gentle diuresis. Norepinephrine (Levophed), isoproterenol hydrochloride (Isuprel), and epinephrine are the pressor agents of choice. Immediate thrombolysis is the standard of care for any patient with significant hypoxemia or hypotension due to proven pulmonary embolism. Beyond this, the potential benefit of using thrombolytic agents should be considered routinely for every patient with proven pulmonary embolism(49).
B. Surgical treatments
1. Clot removal
The aim is to remove the existed large blood clot with a thin flexible tube (catheter) through your blood vessels. According to the study by Harvard Medical School, pulmonary suction thrombectomy can be a successful interventional tool in the treatment of pulmonary thromboembolism. Removal of clot burden typically results in prompt recovery of hemodynamic stability and improved oxygenation. However, in rare cases, clot removal does not sufficiently improve the clinical situation. Herein, two patients with massive pulmonary thromboembolism are presented whose condition improved only after they received nitric oxide as an adjunct to pulmonary suction thrombectomy(50).
2. Vein filter
The aim of placing a filter in the main vein called the inferior vena cava that leads from your legs to the right side of your heart is to filter catches and stops blood clots moving through the blood stream toward your lungs. In the study to investigate clinical experience with the Recovery filter as a retrievable inferior vena cava (IVC) filter, in one hundred seven Recovery filters were placed in 106 patients with an initial clinical indication for temporary caval filtration, found that although all the filters were placed with the intention of being removed, a large percentage of filters were not retrieved. The Recovery filter was safe and effective in preventing PE when used as a retrievable IVC filter(51).
3. Surgery
In case of acute pulmonary embolism, emergency surgery may be the only option to remove as much as clot as possible, specially there is a large clot in your main (central) pulmonary artery, if patients are in shock and thrombolytic medication isn't working quickly enough. In the study to investigate the effectiveness of a comprehensive therapeutic algorithm including extracorporeal life support (ECLS) in high-risk acute pulmonary embolism (aPE) treated with pulmonary embolectomy, indicated that among the 25 patients, 24 had a PAOI≥0.5 and 23 had a RV-to-LV diameter ratio≥1.0. Four patients had right heart thrombi. Sixteen patients developed preoperative instability requiring inotropic and/or mechanical support. Eight in the 16 had a preoperative cardiac arrest (CA) and six of these were bridged to surgery on ECLS. Three in the 6 patients weaned ECLS after surgery and survived to discharge. The overall in-hospital mortality was 20% (n=5). A preoperative CA (Odds ratio [OR]: 16, 95% confidence interval [CI]: 1.4-185.4, p=0.027, c-index: 0.80) and a postoperative requirement of ECLS (OR: 36, 95% CI: 2.1-501.3, p=0.008, c-index: 0.85) was the pre- and postoperative predictor of in-hospital mortality. No late deaths or re-admission for recurrence were found during a median follow-up of 19 months(52).
B. In Herbal medicine perspective
In the study to investigate the effect of aqueous extract of several herbs on human platelet aggregation in vitro of of 28 herbs/nutriceuticals investigated, camomile, nettle alfalfa, garlic and onion exhibited most significant anti-platelet activity (>or=45% inhibition), indicated that queous extracts of alfalfa, fresh nettle, and camomile inhibited ADP induced-platelet aggregation by 73, 65 and 60%, respectively, compared with control (P < 0.05). Camomile and alfalfa inhibited collagen-induced platelet aggregation by 84 and 65%, respectively, but nettle could not inhibit collagen-induced aggregation. In contrast, nettle was the most potent inhibitor (66%) of whole blood aggregation induced by collagen, followed by alfalfa (52%), and camomile (30%) compared with control (P < 0.05). None of these three herbs however could inhibit arachidonic acid or thrombin induced platelet aggregation. Camomile and alfalfa strongly inhibited thromboxane B2 synthesis induced by ADP or collagen, but nettle had no effect. Alfalfa and nettle increased cGMP levels in platelets by 50 and 35%, respectively, compared with the control (1.85 +/- 0.23 nM) (P < 0.005). All these data indicate that camomile, nettle and alfalfa have potent anti-platelet properties, and their inhibitory actions are mediated via different mechanisms(53).
C. In traditional Chinese perspective
According to the China Academy of Traditional Chinese Medicine, in the study of Herbs of activating blood circulation to remove blood stasis, drugs of anti-hyperviscosemia, anti-coagulants, anti-platelet drugs, anti-thrombotics, vasodilators, endothelial cell protectors and anti-arthrosclerosis should be considered as hemorheologicals due to the actions in keeping blood fluidity and in maintaining normal vascular functions. Hemorheologicals are importance for and aging and life-threatening diseases. Blood stasis syndrome is a common pathological syndrome in the elderly. In traditional Chinese medicine, the treatment for the syndrome is by herbs which activates blood circulation to remove blood stasis. The herbs have the efficacy of improving hemorheological events. Therefore, the herbs are the source for developing hemorheologicals. Ligustrazine isolated from Chuangxiong is an example. It showed significant inhibition on shear induced platelet aggregation and on platelet intracellular calcium demonstrated by laser confocal microscope(54).
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Pulmonary arterial hypertension
Pulmonary arterial hypertension is a subgroup of a specific subgroup of pulmonary hypertension (PH) defined as a condition of slowly progressive disorder as a result of abnormally high blood pressure in the blood vessel, including pulmonary artery, pulmonary vein, or pulmonary capillaries, that carries blood from the heart to the lungs due to narrowing in diameter of most of the very small arteries throughout the lungs of that increased resistance to blood flow, leading to right heart failure and death. Because the phrase pulmonary arterial hypertension is long and pulmonary hypertension is a bit shorter the phrase pulmonary hypertension is often used in place of pulmonary arterial hypertension(a).According to statistic, approximately over 1,000 new cases of pulmonary arterial hypertension are diagnosed each year, In the United States alone.
I. Symptoms
1. Depressive disorder
In the study to screen Consecutive outpatients with PAH of a A group of 100 patients (88% women, 50% with idiopathic PAH) (idiopathic; or associated with scleroderma, congenital heart disease, or anorexiant use) seen in two university PAH clinics, showed that 5% of subjects had symptoms suggestive of major depressive disorder; 40% had mild-to-moderate depressive symptoms; and 45% had no-to-minimal depressive symptoms(1).
2. Other symptoms
In the study to use cluster analysis to describe the symptom profile in PAH and differences in the health outcomes of health status, health-related quality of life (HRQoL) and psychological states in the cluster groups, by University of Pennsylvania, School of Nursing, found that of the 151 participants, the mean age was 53.5 ± 15.1 with the majority female (n = 128, 85%). Fifty-eight (41%) were disabled and 67 (44%) were Functional Class IV. The most prevalent symptoms were shortness of breath with exertion (n = 149, 99%) and fatigue (n = 144, 93%). Three clusters emerged: Cluster 1 diffuse symptoms (n = 93), Cluster 2 severe cardiopulmonary symptoms (n = 32) and Cluster 3 moderate cardiopulmonary symptoms (n = 26). Overall, on the SF-36 the participants had poor general health, reduced physical function, role physical, vitality, and a low composite score for physical health. On the POMS the sample had limited vigor and increased fatigue. Other study showed that
The most common symptom of PH is breathlessness on exertion. Syncope may be the presenting symptom especially in children. Other PH symptoms include: angina pectoris, palpitations, dry cough, exertional nausea and vomiting(3).
II. Causes of risk factors
A. Causes
1. Mutation of BMPR2 gene
Experimental and clinical studies now converge on the intersection and interactions between a genetic predisposition involving the BMPR2 signaling pathway and an impaired metabolic and chronic inflammatory state in the vessel wall(4). According to the study by the University of Cambridge School of Clinical Medicine, Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II (BMPR-II) receptor underlie the majority (>70%) of cases of familial pulmonary arterial hypertension (FPAH), and dysfunction of BMP signaling has been implicated in other forms of PAH(5).
2. Pulmonary veno-occlusive disease (PVOD)
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. So far some 200 cases have been published worldwide. Since the latest classification, agreed at a meeting in Venice in 2003, PVOD is included in the group of pulmonary arterial hypertension (PAH)(6).
3. Pulmonary endothelial injury and enhanced inflammatory response
In the study to examine the effect of pulmonary endothelial injury in BMPR2(+/-) mice, with mice with two injections of monocrotaline combined with intratracheal instillation of replication-deficient adenovirus expressing 5-lipoxygenase (MCT+Ad5LO), showed that greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension(7).
4. The role of disturbed blood flow
According to the study by University Medical Centre Groningen-GUIDE, In this concept disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e. systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression(7a)
5. Certain Medication
In the late 1960s, an epidemic of primary pulmonary hypertension (PPH) occurred in Europe shortly after the introduction of aminorex fumarate, a potent anorexigen. According to the study by the McGill University Faculty of Medicinethere is a strong association between aminorex and PPH probably led to a 5-fold increase in PPH incidence, and thus a very noticeable epidemic. The association with dexfenfluramine would result in an increase in incidence of only 20%. Based on the available evidence, a repeat PPH epidemic seems unlikely(7b).
B. Risk factors
1. Gender
If you women, you are at increased risk to develop Pulmonary arterial hypertension(8a)
2. Atrial septal defect (ASD)
In the study to analyze risk factors of pulmonary arterial hypertension (PAH) in patients with atrial septal defect (ASD) patients living at above 2000 m high altitude area, found that PAH prevalence was 68.4% (360/526) in ASD patients. The risk factors of developing PAH in these ASD patients were defect size (OR: 1.200, 95%CI: 1.156 - 1.246, P = 0.000), age (OR: 1.027, 95%CI: 1.003 - 1.052, P = 0.025) and altitude (OR: 1.389, 95%CI: 1.001 - 1.637, P = 0.043) while gender and nationality were not risk factors for PAH. The incidence of developing PAH increased with aging (P = 0.000). The standardized ratio of PAH at ≥ 3500 m was 74.8% which was significantly higher than that at 2000 - 2499 m altitude (66.2%, P = 0.005) and at 2500 - 3499 m altitude (66.9%, P = 0.005)(8).
3. Congenital heart disease
Patients with cardiac defects which result in left-to-right shunting are at risk of developing PAH, owing to the increased shear stress and circumferential stretch induced by increased pulmonary blood flow, which leads to endothelial dysfunction and progressive vascular remodelling and, thus, increased pulmonary vascular resistance, according to the study by the Royal Brompton Hospital, Imperial College(9).
4. Other risk factors
In the multicenter study included patients followed at 5 rheumatology units that were systematically assessed using a pretested questionnaire on clinical and immunological variables, focusing on PAH, showed that of a total of 349 patients with SSc, 61 (17%) met the criteria for PAH. Pulmonary fibrosis [adjusted odds ratio (AOR) 7.37, 95% CI 3.67-14.81, p < 0.0001], microstomia (AOR 3.3, 95% CI 1.70-6.28, p < 0.0001), gastroesophageal reflux (AOR 2.41, 95% CI 1.31-4.43, p = 0.005), dysphagia (AOR 2.7, 95% CI 1.49-4.77, p = 0.001), hyperpigmentation (AOR 2.15, 95% CI 1.11-4.16, p = 0.02), and hypopigmentation (AOR 2.4, 95% CI 1.26-4.64, p = 0.008) were the most prevalent clinical characteristics associated with PAH, while anemia (AOR 5.4, 95% CI 1.98-14.93, p = 0.001) was observed as the unique laboratory risk factor(10). Other study showed that increased incidence of the disease in young women, the familial cases, the association with autoimmune disorders, and the recent discovery that mutation of the PPH1 gene may not be restricted to familial PPH support the hypothesis that the development of pulmonary hypertension likely implies an individual susceptibility or predisposition, which is probably genetically determined. It is also now commonly believed that the development of pulmonary hypertension in some of these predisposed individuals could be hastened or precipitated by various expression factors (some of them yet unrecognized), such as ingestion of certain drugs or diets, portal hypertension, or HIV infection(11).
III. Complications and diseases associated to pulmonary arterial hypertension
A. Complications
1. Right-sided heart failure
Pulmonary arterial hypertension (PAH) is a progressive disease in which increased pulmonary arterial pressure and remodelling eventually lead to right heart failure and death. Idiopathic and familial PAH occur far more frequently in women than in men(12).
2. Sudden Cardiac Death
According to the study by the Onassis Cardiac Surgery Center, Pulmonary Arterial Hypertension (PAH) is a disease of small pulmonary arteries, characterized by vascular proliferation and remodeling. Progressive increase in pulmonary vascular resistance ultimately leads to right ventricular heart failure and death(13).
3. Arrhythmia
Cardiac arrhythmias are important contributors to morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Such patients manifest a substrate resulting from altered autonomics, repolarization abnormalities, and ischemia. Supraventricular arrhythmias such as atrial fibrillation and flutter are associated with worsened outcomes, and maintenance of sinus rhythm is a goal(14).
4. Bleeding and thrombosis
According to the study by DRK Kliniken Berlin Köpenick, On one hand, thrombosis is one of the key pathophysiologic features of PAH (besides vasoconstriction, proliferation and inflammation). On the other hand, the incidence of bleeding events is increased in PAH patients(15).
B. Diseases associated to pulmonary arterial hypertension
1. Pulmonary veno-occlusive disease
Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible(16).
2. Primary Sjögren syndrome (pSS)
The present limitations in knowledge of the potential risk factors for PPH undoubtedly are attributable to the facts that PPH is a rare disease with an unknown pathogenesis and lacking large case series. There is a report of report 9 new cases of pSS-associated PAH with a complete assessment including clinical characteristics (of both PAH and pSS), hemodynamic parameters, medical management, and outcome(17).
3. Dyspnea
Dyspnea and PAH disease progression are best assessed by cardiopulmonary exercise testing and the six-minute walk test. Understanding of the molecular pathogenesis of PAH has led to new classes of treatments, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors(18).
4. Systemic sclerosis
Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of CTDs. In patients with SSc, PAH has a dramatic impact on prognosis and survival and is the single most common cause of disease-related death.Yearly echocardiographic screening for PAH is recommended in patients with SSc(19).
IV. Misdiagnosis and Diagnosis
A. Misdiagnosis
1. pulmonary veno-occlusive disease
Misdiagnosis of the disease is common since PVOD presents with clinical and radiographic features mimicking idiopathic pulmonary arterial hypertension or even PH due to interstitial lung disease. Vasodilators may not be efficacious in PVOD and may in fact worsen hemodynamic status with the development of pulmonary edema. According to Aristotle University of Thessaloniki, there is a report of describe the challenging diagnosis of PVOD in a patient with PH referred to our department. Final diagnosis was established by surgical lung biopsy. The patient was offered sequential combination therapy under close monitoring and maintained remarkable clinical stabilization while being on the waiting list for lung transplantation(20).
2. Complication of Arrhythmogenic right ventricular dysplasia
There is a report of a 58-year old Japanese woman who had been diagnosed with and managed for systemic sclerosis (SSc) with pulmonary arterial hypertension died suddenly. However, the autopsy revealed marked right ventricular dilatation, and the myocardium had been replaced by fatty tissue, according to the study by the Dokkyo Medical University School of Medicine(21).
3. Primary pulmonary artery sarcoma
Primary sarcoma of the pulmonary artery (PSPA) is extremely rare. Many cases are misdiagnosed as pulmonary arterial hypertension (PAH) because of chronic thromboembolic disease (CTD). Four cases of PSPA with the initial misdiagnosis are reported, according to the study by Hospital Virgen de la Salud(22).
B. Diagnosis
Diagnosis are depended on the suspected underline-causes of the diseases. If you are experinece certain symptoms of pulmonary arterial hypertension (PAH), after recording the complete physical examination, including signs associated with underlying collagen vascular disease (especially scleroderma), such as skin thickening, Raynaud phenomenon, sclerodactyly, and telangectasia and systematic evaluation including family history, social history, travel history, etc.. The tests which your doctor order may include
1. Echocardiogram with right ventricular systolic pressure measurement
According to the , pulmonary hypertension (PH) is defined by a sustained increase in mean pulmonary arterial pressure > 25 mmHg. Due to its widespread availability, echocardiography (ECHO) is used as the first-line imaging modality to detect pulmonary PH and assess right ventricular (RV) function in daily routine. As such, ECHO is the key examination to detect the presence of PH, to provide valuable prognostic information and to give an orientation to therapeutic strategies(23). Other study indicated that Echocardiogram is the investigation of choice for detecting elevated pulmonary pressures. If the echocardiogram shows signs of PH then the patient should be referred to a designated PH centre if pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension are suspected or if PH is of uncertain cause(24).
2. ECG, a chest radiograph and a full blood count, renal and liver function and thyroid function tests
If patients are experience certain symptoms such as breathlessness on exertion, syncope in children, or other symptoms include: angina pectoris, palpitations, dry cough, exertional nausea and vomiting. Lack of response to conventional treatment for dyspnoea should alert the GP to search for another cause of the patient's symptoms, one of which could be PH. These patients should have an ECG, a chest radiograph and a full blood count, renal and liver function as well as thyroid function tests. When PH is suspected, referral to the local cardiology or respiratory department is recommended(24).
3. Full pulmonary function testing
Pulmonary function tests are a group of tests that measure how well the lungs function, including arterial blood gas analysis, and tests of pulmonary function with an aim to determine severity of pulmonary impairment(25)
4. Multidetector CT scan
The causes of pulmonary arterial hypertension (PAH) are diverse and include multiple congenital and acquired cardiac diseases as well as diseases primarily affecting the pulmonary vasculature, lung, pleura and chest wall. Advances in multidetector CT technology with improved spatial and temporal resolution now permit accurate delineation of cardiac morphology. CT pulmonary angiography (CTPA) is widely utilised in the workup of patients with suspected pulmonary vascular disease and can identify both pulmonary and cardiac causes(26)
.
5. V-Q scan
According to the study by the St Hill Hospital, Yamaguchi, patients with primary PAH and passive PH seem to characteristically have a high prevalence of reverse V-Q mismatch indicative of an inadequate hypoxic vasoconstriction reflex on V/Q SPECT, frequently accompanied with heterogeneous lung attenuations and compressed airways on CT.test (6MWT)(27).
6. Etc.
V. Preventions
A. Diet to prevent pulmonary arterial hypertension
1. Dietary nitrate
According to the study by the Queen Mary University of London, dietary nitrate (vegetables, fruit, and processed meats) and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile depends on endothelial NO synthase and xanthine oxidoreductase -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (ie, dietary nitrate/nitrite supplementation) represents a viable, orally active therapy for PH(28).
2. Fish oil
In the study of the effects of dietary polyunsaturated fats on chronic hypoxic pulmonary hypertension were assessed in rats fed fish oil, corn oil, or a lower fat, "high-carbohydrate" diet (regular) beginning 1 mo before the start of hypoxia (0.4 atm, n = 30 for each), showed that fish oil diet increased lung eicosapentaenoic acid 50-fold and depleted lung arachidonic acid 60% (P less than 0.0001 for each). Lung thromboxane B2 and 6-ketoprostaglandin F1 alpha levels were lower, and platelet aggregation, in response to collagen, was reduced in rats fed fish oil. Chronically hypoxic rats fed fish oil had lower mortality rates than the other hypoxic rats. They also had lower blood viscosity, as well as less right ventricular hypertrophy and less peripheral extension of vascular smooth muscle to intra-acinar pulmonary arteries (P less than 0.05 for each). The mechanism by which dietary fish oil decreases pulmonary hypertension and vascular remodeling during chronic hypoxia remains uncertain(29).
3. Dietary phytoestrogens
In the study totest the hypothesis that phytoestrogenic compounds in the diet contributed to the female cardioprotectionfour groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(-)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats., showed that hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection(30).
B. Phytochemicals and Antioxidants to prevent pulmonary arterial hypertension
Idiopathic pulmonary arterial hypertension (IPAH) is associated with lower levels of the pulmonary vasodilator nitric oxide (NO) and its biochemical reaction products (nitrite [NO(2) (-)], nitrate [NO(3) (-)]), in part, due to the reduction in pulmonary endothelial NO synthesis. According to the study by the Cleveland Clinic Foundation, in the testing of nitrotyrosine and antioxidants glutathione (GSH), glutathione peroxidase (GPx), catalase, and SOD were evaluated in IPAH patients and healthy controls, indicated that SOD and GPx activities were decreased in IPAH lungs (all p < 0.05), while catalase and GSH activities were similar among the groups (all p > 0.2). SOD activity was directly related to exhaled NO (eNO) (R(2)= 0.72, p= 0.002), and inversely related to bronchoalveolar lavage (BAL) NO(3) (-) (R(2)=-0.73, p= 0.04). Pulmonary artery pressure (PAP) could be predicted by a regression model incorporating SOD, GPx, and NO(3) values (R(2)= 0.96, p= 0.01). These findings suggest that SOD and GPx are associated with alterations in NO and PAP in IPAH(31).
1. L-carnitine
In the study of a total of 66 pulmonary arterial hypertension patients (14 idiopathic, 36 congenital heart disease associated and 16 connective-tissue disease associated PAH, WHO heart functional class III, n = 38 or IV, n = 28) to investigate the efficacy of L-carnitine in patients with right-sided heart failure induced by pulmonary arterial hypertension (PAH), found that L-carnitine could improve short-term exercise capacity and WHO heart functional class in right-sided heart failure patients induced by PAH(32).
2. Retinoic acid
Retinoic acid has antimitogenic effects on smooth muscle cells. Studies on the systemic circulation suggest that it may reduce vascular thickening. In the study to study examine retinoid levels in plasma of patients with idiopathic pulmonary arterial hypertension and the effects of retinoic acid on human pulmonary artery smooth muscle cell growth, showed that Idiopathic pulmonary arterial hypertension patients have reduced retinoic acid levels, and retinoic acid treatment can elicit growth-inhibitory signals in pulmonary artery smooth muscle cells in vitro. Thus, retinoic acid may influence pulmonary vascular remodeling in humans(33).
3. Vitamin C
There is areport of 40-year-old female patient who developed severe pulmonary hypertension and life-threatening right-sided heart failure in association with dietary scurvy and iron deficiency. Supplementation with oral vitamin C and iron very likely contributed to her complete cure(34).
4. Genistein
Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early. In the study to examine whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF), found that Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF(35).
5. Resveratrol
Resveratrol, a sirtuin-1 (SIRT1) pathway activator, can prevent the development of PH in a commonly used animal model, but it is unclear whether it can reverse established PH pathophysiology. Furthermore, atrophic ubiquitin ligases, such as atrogin-1 and MuRF-1, are known to be induced by SIRT1 activators but have not been characterized in hypertrophic vascular disease. Therefore, we hypothesized that monocrotaline (MCT)-induced PH would attenuate atrophy pathways in the PA while, conversely, SIRT1 activation (resveratrol) would reverse indices of PH and restore atrophic gene expression, according to the University of New Mexico Health Sciences Center(36).
VI. Treatments
A. In conventional medicine perspective
Treatment of pulmonary arterial hypertension (group 1 of clinical classification) has been recently characterized by important progresses, particularly in pharmacological therapy. According to the study by Azienda Ospedaliero-Universitaria,
1. Only until few years ago, patients with pulmonary arterial hypertension were treated with non-specific drugs, such as diuretics and digoxin for right heart failure and calcium-channel blockers in the minority of cases, responders to the acute vasoreactivity test. In addition, use of oral anticoagulant treatment was supported by uncontrolled studies.
2. In the last 15 years (in particular in the last 8 years) different randomized controlled trials assessing the functional, clinical and hemodynamic efficacy of three classes of targeted drugs (prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors) with pulmonary vascular dilating and antiproliferative effects have been performed.
a. Treatment starts with general measures (physical activity, fertility control, respiratory tract infection, etc.) and supportive therapy (anticoagulant therapy, diuretics, oxygen, digoxin). Patients who respond to the acute vasoreactivity test (10% of idiopathic form) are treated with high doses of calcium-channel blockers, non-responders with targeted therapies either on monotherapy or combination.
b. Usually an oral active drug is initiated and a second compound of a different class is combined in case of non-satisfactory response to the first treatment
c. Combination therapy should be performed only in specialized centers with large experience on use of targeted therapies and their relevant side effects.
d. In case of failure of medical therapy, possible options are balloon atrial septostomy and/or listing for lung or heart-lung transplantation. As available treatments do not constitute a cure for pulmonary arterial hypertension, further progresses are expected in the near future(37).
B. In Herbal medicine perspective
1. Radix Astragali
In the study of Sixty rats divided into three groups: hypoxia group, hypoxia + RA group and normal control group to observe the inhibitory effects of Radix Astragali (RA) on hypoxic structural remodeling of intraacinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT), showe d that compared with the result of hypoxia + RA group, RA could relieve IAPA wall cell injuries and dilate the constricted IAPA induced by hypoxia. RA could also inhibit hypertrophic changes in the tunica media and proliferation of adventitial cells of the IAPA and muscularization of nonmuscular arteries(38).
2. Radix Peucedani
According to the study by the Department of Pathology, Cardiovascular Institute, RP could not only antagonize IAPA contraction caused by hypoxia and lower the resistance of pulmonary circulation, inhibit the cell proliferation and hypertrophy of adventitial cells of pulmonary artery, but also reverse the change in structure and function of pulmonary artery. It suggests that RA plays a key role in inhibiting hypoxic structural remodeling of IAPA and pulmonary hypertension(39).
C. In traditional Chinese perspective
1. Chinese herbs Naofeikang
In the sturdy to evaluate the preventive and therapeutic effect of Chinese herbs Naofeikang on hypoxic pulmonary artery hypertension of elastase-induced emphysema hamsters and its mechanism, by the Department of Pathology, FUWAI Hospital, CAMS, PUMC, indicated that Chinese herbs Naofeikang could lower pulmonary hypertension, preserve vessel endothelial cells and lessen the inflammatory reaction in pulmonary tissue. Thereby, it could hinder the further development of emphysema and inhibit the remodeling of pulmonary small artery(40).
2."Qi-Xue" injection (Panax ginseng, Astragalus monogholicus, Angelica sinensis)
In the study by the Institute of Basic Medical Sciences of the effects of "Qi-Xue" injection (Panax ginseng, Astragalus monogholicus, Angelica sinensis), verapamil (Vp, calcium antagonist) and their combination on pulmonary arterial pressure (PAP) and heart function in rats exposed to chronic hypoxia, indicated that both "Qi-Xue" injection and Vp minimized the increase in PAP due to hypoxia, with the former being more effective than the latter. "Qi-Xue" injection also attenuated IC-R decrease and kept it in the normal range. No appreciable differences were observed between the effect of "Qi-Xue" and its combination with Vp. It is suggested that "Qi-Xue" injection might prevent the development of severe hypoxic pulmonary hypertension by improving heart function(41).
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Pulmonary veno-occlusive disease
Pulmonary veno-occlusive disease (PVOD) is an extremely rare form of pulmonary hypertension, affecting mostly in children and young adults as a result of a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure.
I. Symptoms
1. progressive dyspnea, hypoxemia, and pulmonary hypertension
Some patients may experience symptoms of progressive dyspnea. There is a report of a case of a patient with a long history of progressive dyspnea of over 8 years, who with a diagnosis of chronic cor pulmonale confirmed elsewhere, was ultimately diagnosed as PVOD via histological analysis of a lung biopsy. After treatment with combined bosentan, diuretics and digoxin, his symptoms and function improved, according to the scase reposted by the the Second Affiliated Hospital of Nanchang University(1). Other study also report a case of a case of neuroblastoma with progressive dyspnea, hypoxemia, and pulmonary hypertension and patient was diagnosed as PVOD and successfully treated with low-molecular-weight heparin (LMWH) and corticosteroid(1a)
2. Shortness opf breath
According to the she study by the Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris, Université Paris-Sud, Patients with the diseases are experience to symptoms of Lower arterial oxygen tension and lower diffusing capacityand and lower oxygen saturation nadir during the 6-min walk test(2)
3. Dyspnoea, cough and fatigue
According to the study by the Madigan Army Medical Center, pulmonary veno-occlusive disease (PVOD) is a rare and challenging cause of pulmonary hypertension. Clinical presentation is non-specific, including dyspnoea, cough and fatigue(3).
4. Hemoptysis
There is a report of an extremely unusual case presenting as massive and intractable hemoptysis, in which pulmonary venous occlusion was attributed to granulomatous venulitis in the absence of other pulmonary or systemic inflammatory abnormalities(4).
5. Symptoms of right-sided heart failure
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that mainly affects children and young adults. Its cause is unknown, although viral infections and drugs have been implicated. Patients with PVOD present with symptoms of right-sided heart failure, according ot the study by the University of Southern California School of Medicine(5).
6. Similar to PAH clinical presentation
PVOD has similar clinical presentation, hemodynamic characteristics and genetic background with PAH although main pathology is in venules, According to the study by the Department of Pneumology and Intensive Care, Hôpital Antoine Béclère, Assistance Publique(6).
7. Other symptoms
According to the study by ESS MANDEL, EUGENE J. MARK, and CHARLES A. HALES "Pulmonary Veno-occlusive Disease", American Journal of Respiratory and Critical Care Medicine, Vol. 162, No. 5 (2000), pp. 1964-1973., most patients with PVOD present with nonspecific complaints such as dyspnea on exertion and lethargy, presumed secondary to an inability to adequately increase cardiac output with exercise (23). Many cases present after a respiratory infection and progress despite treatment with antibiotics (4). Chronic cough (either productive or nonproductive) is present in some individuals (57). As pulmonary hypertension becomes more severe, cyanosis, chest pain, right upper quadrant pain secondary to hepatic congestion, and exertional syncope may be noted. Hemoptysis may occur but is rarely massive and life-threatening (58). Orthopnea is reported by patients with PVOD, but is unusual among those with primary pulmonary hypertension (13). Rarer presentations of PVOD include diffuse alveolar hemorrhage and sudden death (58-60)(6a)
II. Causes and Risk factors
A. Causes
Although the cause of Pulmonary veno-occlusive disease (PVOD) is considered unknown, some studies suggested the following
1. Oral contraceptives
According to the study by the University of California San Francisco, there ia 2 cases of PVOD that developed in 2 young women soon after the initiation of oral contraceptives (OCs). The first patient is a 14-year-old girl, with no medical history, who started taking an OC 3 weeks before the onset of symptoms. The second patient is an 18-year-old girl, diagnosed 2 years previously with systemic lupus erythematosus and lupus anticoagulant, who started taking an OC 4 months before the onset of symptoms(7).
2. Idiopathic or complicating other conditions
According to the study by the Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris, Université Paris-Sud, Clamart, France, PVOD has been described as idiopathic or complicating other conditions, including connective tissue diseases, HIV infection, bone marrow transplantation, sarcoidosis and pulmonary Langerhans cell granulomatosis(8).
3. Infections, Toxic Exposures, Thrombotic Diathesis, Autoimmune Disorders may also be the possible causes of PVOD
a. Infection and Toxic Exposures
No convincing data have linked PVOD to a specific infectious insult, although an “influenzalike illness” has preceded the development of PVOD in many cases, and serologic evidence suggestive of recent infection with one of several agents (including Toxoplasma gondii and measles) has been documented around the time when PVOD was diagnosed(8a). According to the study by the Service de Pneumo-Allergologie, there is a report of case of a 27 year old male intravenous drug abuser with HIV infection and pulmonary hypertension. Open lung biopsy led to the diagnosis of pulmonary veno-occlusive disease. This second case of pulmonary veno-occlusive disease raises the question of a relationship between HIV infection and lesions involving the pulmonary veins. However, the pathogenesis of vascular changes remains to be elucidated(9). Other study report a case of a Caucasian female with a long history of progressive dyspnoea ultimately diagnosed as focal granulomatous venulitis leading to a pulmonary veno-occlusive disease-like pathology(10).
b. Thrombotic Diathesis
According to the study by research team lead by Tsou E, there is a report of a 23-year-old woman in her 27th week of gestation presented with clinical findings of progressive pulmonary
hypertension. After cardiac catheterization she went into labor and was
delivered by cesarean section. She died shortly thereafter from right
heart failure. Pulmonary venoocclusive disease was found at autopsy. Hemodynamic changes during pregnancy, labor, delivery, and the
postpartum period may have contributed to her deterioration and death(11).
c. Autoimmune Disorders
There is a report of a 26-year-old woman with systemic lupus erythematosus (SLE) developed
dyspnea and hypoxemia on exertion. She died from rapidly progressive
respiratory failure. Autopsy revealed right ventricular hypertrophy and
occlusion of the pulmonary veins compatible with pulmonary venoocclusive
disease (PVOD), according to the study by Keio University School of Medicine(12).
B. Risk factors
1. Gender
If you are male, you are at increased risk to develop Pulmonary veno-occlusive disease (PVOD), according to the study by research team lead by Wagenvoort CA(13).
2. Genetic abnormality
PVOD is characterized by alterations of circulating cytotoxic cell subpopulations and by epigenetic dysregulation within the GNLY gene, according to the study by the Department of Pneumology and Intensive Care, Hôpital Antoine Béclère, Assistance Publique(14). Other study reported a patient with documented PVOD whose mother had severe pulmonary hypertension. Sequencing of the patient's BMPR2 coding region revealed a del44C mutation in Exon 1 that is predicted to encode for a truncated proteindevelopment of PVOD(14a)
3. Injury
Injury may also have caused the arterialization of the venous walls, a common finding that cannot always be explained by distal narrowing of larger veins. Although the etiology of pulmonary veno-occlusive disease is obscure, it seems increasingly likely that multiple noxious agents may induce this condition(15).
4. Fenfluramine exposure
There is a report of a case of PVOD in a patient with a history of fenfluramine exposure, therefore suggesting a possible association between anorexigen exposure and PVOD(16).
5. Chemotherapy and bone marrow transplantation
PVOD has been reported in association with various chemotherapy regimens including bleomycin, bis-chloronitrosourea and mitomycin(17)
6. After bone marrow transplantation
There is areport of a case of pulmonary veno-occlusive disease (PVOD) following allogeneic bone marrow transplantation (BMT) for the treatment of acute myeloid leukemia (AML) from an HLA mismatched mother using a reduced-intensity conditioning (RIC) regimen including gemtuzumab ozogamicin(18).
III. Complications and diseases associated to pulmonary veno-occlusive disease
A. Complications
1. Pulmonary vascular resistance, right heart failure and premature death
PVOD is characterised by progressive obstruction of small pulmonary veins and venules that leads to increased pulmonary vascular resistance, right heart failure and premature death, according to the study by université Paris-Sud, 94276 Kremlin-Bicêtre(19).
2. Occult alveolar haemorrhage
Occult alveolar haemorrhage is a common feature of pulmonary veno-occlusive disease. Detecting occult alveolar haemorrhage may be of interest in the diagnostic approach of pulmonary veno-occlusive disease, according to the study by Université Paris-Sud, Clamart(20).
3. Other complications
The most frequent CT-findings in pulmonary veno-occlusive disease were the following: ground glass opacity with poorly defined nodular opacities (73%), septal lines (93%), and adenopathy (80%). Pericardial (60%) and pleural effusions (27%) were also noted. Other parenchymal findings were unusual, according to the study by Hôpitaux de Paris, Université Paris Sud(21).
B. Diseases associated to pulmonary veno-occlusive disease
1. Microangiopathic hemolytic anemia and chemotherapy of gastric adenocarcinoma
There is a report of a 68-year-old man was treated with FAM (5-fluorouracil, doxorubicin [Adriamycin], mitomycin-C) for metastic gastric adenocarcinoma. Twelve months later while in complete clinical remission, pulmonary hypertension and microangiopathic hemolytic anemia were recognized, progressed, and ended in his demise 6 months later. At necropsy, minimal residual cancer and severe pulmonary veno-occlusive disease was found. Pulmonary veno-occlusive disease may occur in association with microangiopathic hemolytic anemia and cancer chemotherapy(22).
2. Primary Sjögren's syndrome
There is a report of a 21-year-old Japanese woman with primary Sjögren's syndrome (pSS) presenting with worsening of dyspnea, palpitation, recurrent parotitis, and arthritis. Chest computed tomography showed diffuse interlobular septal thickening and ground-glass opacities. Right heart catheterization demonstrated pulmonary hypertension, right-sided heart failure, normal pulmonary capillary wedge pressure, and no evidence of arterio-venous shunt. Transbronchial lung biopsy showed luminal obliteration of pulmonary venules by intimal cellular proliferations, without abnormalities in the small pulmonary arteries. These findings were consistent with pulmonary veno-occlusive disease (PVOD), according to the Nagoya City University Graduate School of Medical Sciences(23).
3. Systemic sclerosis sine scleroderma
There is areport of a 77-year-old woman was admitted to the hospital because of an abnormal chest shadow. She complained of shortness of breath on effort. Chest CT showed patchy areas of ground-glass opacity in right S2 and S6. A high titer of antinuclear antibody with a discrete speckled pattern on immunofluorescent staining was disclosed, and she was positive for anticentromere antibodies. Pulmonary arterial hypertension was found by right heart catheterization. Biopsy by video-assisted thoracoscopic surgery was performed. About one month after surgery, she started to need to inhale oxygen due to gradually progressing dyspnea. Continuous PGI2 administration was not very effective, but administration of methylprednisolone and prednisolone induced improvement of her symptoms. Histopathologic examination of biopsy revealed extensive and diffuse occlusion of pulmonary veins. The pathological diagnosis suggested a pulmonary veno-occlusive disease, according to National Hospital Organization Ibarakihigashi National Hospital(24).
4. Granulomatous angiitis
There is a report of a case of a Caucasian female with a long history of progressive dyspnoea ultimately diagnosed as focal granulomatous venulitis leading to a pulmonary veno-occlusive disease-like pathology, according to the Royal Hobart Hospital, according to University of Liege(25).
5. Myeloproliferative disorder
There is a rpeort of a case of biopsy-proven pulmonary veno-occlusive disease as a cause of severe pulmonary hypertension in a patient suffering from a chronic myeloproliferative disorder. The pulmonary disease evolved favourably under treatment with defibrotide, a pro-fibrinolytic medication used in hepatic veno-occlusive disease(26).
6. Recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil
There is a report of a case of PVOD presenting with recurrent episodes of acute non-cardiogenic pulmonary oedema, in the absence of significant pulmonary hypertension. Concern over the risk of precipitating pulmonary oedema led us to use inhaled nitric oxide to predict the safety and efficacy of sildenafil(27).
7. Hashimoto's thyroiditis
There is a report of the occurrence of PVOD in a female patient with Hasimoto's thyroiditis. This report emphasises that PVOD can co-exist with Hashimoto's thyroiditis and a high index of clinical suspicion is required to confirm the diagnosis of PVOD, according to Gazi University(28).
IV. Misdiagnosis and Diagnosis
A. Misdiagnosis
PVOD is an underdiagnosed and commonly misdiagnosed cause of pulmonary hypertension, which may present with a failure to respond to medical therapy. Further studies on PVOD may help confirm whether a change in its classification as a type of PAH is necessary(29). Other study reported a case of a 27-yr-old female with a 6-month diagnosis of idiopathic pulmonary arterial hypertension (PAH) confirmed elsewhere was referred to our centre with worsening dyspnoea. On examination, the patient had low systemic oxygen saturation despite high oxygen flow and reduced exercise capacity. Haemodynamics were indicative of severe pre-capillary PAH. High-resolution computed tomography revealed diffuse ground-glass opacity with thickening interlobular septa, and haemosiderin-laden macrophages were identified by bronchoalveolar lavage. Based on clinical and diagnostic findings, the patient was re-diagnosed with pulmonary veno-occlusive disease (PVOD)(30). Also, there is a review of cases of 14 patients with clinically diagnosed PAH who had failed to respond to medical therapy and had lung tissue available from autopsy or explant. Control samples (n = 6) were obtained from lungs explanted for other causes, and a previous transthoracic echocardiogram excluded pulmonary hypertension(31).
B. Diagnosis
Patients in the early stage with early pulmonary veno-occlusive disease (PVOD) may experience no symptoms at all, but the progression of diseasse may attributable to pulmonary hypertension and right-sided heart failure supervene(32).
B.1. Noninvasive diagnosis to detect PVOD(33)
A noninvasive diagnostic approach may include
1. Chest high-resolution computed tomographymay be helpful for clinical differential diagnosis of PVOD and PCH
In the study to examine chest HRCT images for four patients with idiopathic pulmonary arterial hypertension (IPAH), three patients with PVOD and three patients with PCH, and to evaluate pulmonary vascular casts of lung tissues obtained from those patients at lung transplantation or autopsy, found that
Measurement of the sizes of centrilobular GGOs in HRCT is a simple and useful method for clinical differential diagnosis of PVOD and PCH(34).
2. Arterial blood gas analysis(ABG)
The aim of the blood withdrawn from an artery, involving puncturing an artery with a thin needle and syringe is to determine the pH of the blood, the partial pressure of carbon dioxide and oxygen, the bicarbonate level and gas exchange which reflect gas exchange across the alveolar-capillary membrane(35).
3. Pulmonary function tests (PFT)
It is a complete evaluation of the respiratory system including patient history, physical examinations, chest x-ray examinations, arterial blood gas analysis, and tests of pulmonary function(36).
4. Bronchoalveolar lavage
Bronchoalveolar lavage has a well established role in the diagnosis of pulmonary infections, particularly those due to opportunistic organisms in an immunocompromised host with an aim to assess a number of pulmonary components of whchi may be useful in this regard, particularly if combined with new methods for examining inflammatory responses, such as those utilising the polymerase chain reaction to assess cellular expression for inflammatory cytokines and growth factors.(37).
5. Transthoracic Echocardiography
Transthoracic echocardiography is an important initial non-invasive diagnostic tool with aim to evaluate patients in whom pulmonary hypertension is suspected, according to the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension(38).
6. Flow cytometry
Pulmonary arterial hypertension (PAH) and pulmonary
veno-occlusive disease (PVOD) both display occlusive remodeling of the
pulmonary vasculature responsible for increased pulmonary vascular
resistances. Cytotoxic T (CTL), natural killer (NK), and natural killer T
(NKT) cells play a critical role in vascular remodeling in different
physiological and pathological conditions. According to study, a
decrease in GNLY demethylation in the gDNA extracted
from peripheral blood mononuclear cells and explanted lungs was found
specifically in PVOD but not in PAH. This was associated with a decrease
in populations and subpopulations of CTL and NKT and an increase of NK
populations. Despite the reduced granulysin-containing cells in patients
with PVOD, GNLY serum levels were higher, suggesting these cells were
wasting their content. Furthermore, the increase of GNLY concentration
in the serum of PVOD was significantly higher than in patients with PAH(39).
B.2. Surgical biopsy
Since surgical biopsy represents a high-risk procedure in these patients, it is contraindicated. lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. However, lung biopsy is hazardous in patients with severe pulmonary hypertension, and there is a need for noninvasive diagnostic tools in this patient population. Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible(39).
V. Preventions
Since patients with are at high risk of hemoptysis, using the below preventive diet and phytochemicals and antioxidant should be taken with care and only with the related field specialists
1. Dietary nitrate
According to the study by the Queen Mary University of London, dietary nitrate (vegetables, fruit, and processed meats) and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile depends on endothelial NO synthase and xanthine oxidoreductase -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (ie, dietary nitrate/nitrite supplementation) represents a viable, orally active therapy for PH(40).
2. Fish oil
In the study of the effects of dietary polyunsaturated fats on chronic hypoxic pulmonary hypertension were assessed in rats fed fish oil, corn oil, or a lower fat, "high-carbohydrate" diet (regular) beginning 1 mo before the start of hypoxia (0.4 atm, n = 30 for each), showed that fish oil diet increased lung eicosapentaenoic acid 50-fold and depleted lung arachidonic acid 60% (P less than 0.0001 for each). Lung thromboxane B2 and 6-ketoprostaglandin F1 alpha levels were lower, and platelet aggregation, in response to collagen, was reduced in rats fed fish oil. Chronically hypoxic rats fed fish oil had lower mortality rates than the other hypoxic rats. They also had lower blood viscosity, as well as less right ventricular hypertrophy and less peripheral extension of vascular smooth muscle to intra-acinar pulmonary arteries (P less than 0.05 for each). The mechanism by which dietary fish oil decreases pulmonary hypertension and vascular remodeling during chronic hypoxia remains uncertain(41).
3. Dietary phytoestrogens
In the study totest the hypothesis that phytoestrogenic compounds in the diet contributed to the female cardioprotectionfour groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(-)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats., showed that hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection(42).
VI. Treatments In conventional medicine perspective
A. Non surgical therapy
1. Oxygen therapy
Total correction was performed in a case of complete transposition of the great arteries (TGA) with severe pulmonary vascular obstructive disease (PVOD). Although severe pulmonary hypertension remained after surgery, oxygenation was continued for 15 months, which included a shift to at-home oxygen inhalation therapy (HOT). Cardiac catheterization 15 months after surgery demonstrated that pulmonary hypertension was greatly improved, According to the study by the Nagoya University Graduate School of Medicine(49).
2. Warfarin therapy
In PVOD, one could suggest that caution should be taken in the application of anticoagulation, because of the frequent association with occult alveolar hemorrhage. However, we have reported the same proportion of hemoptysis in idiopathic PAH and PVOD, even with the use of anticoagulation, according to the study by Alice Huertas, MD; Barbara Girerd, MD; Peter Dorfmuller, MD, PhD; Dermot O'Callaghan, MD; Marc Humbert, MD, PhD; David Montani, MD, PhD(50).
3. Immunosuppressive agents
In the study of 14 subjects with PAH, including seven patients with the idiopathic form and seven patients with atrial septal defects, but no other congenital heart abnormalities, indicated that chronic administration of sildenafil improves the physical capacity of PAH patients and may be beneficial in selected cases of veno-occlusive disease(51).
B. Lung Transplantation
According to the study by the, Single living-donor lobar lung transplantation is a unique method of treatment, mostly for small children, and size matching is the most important factor to conduct single living-donor lobar lung transplantation safely. We report a successful single living-donor lobar lung transplantation for a 6-year-old girl with pulmonary venoocclusive disease who received the graft from her mother. Preoperatively, the recipient was intubated under deep sedation because of repeated episodes of pulmonary edema due to rapidly deteriorating pulmonary venoocclusive disease(52).
As the prognosis in PVOD patients is worse than in idiopathic PAH, and due to limited medical therapy, lung transplantation should be considered and discussed early in the course of PVOD or suspected PVOD (HRCT findings, worsening symptoms on treatment or refractoriness to medical therapy, development of worsening hypoxemia or chronic heart failure). In these patients, PAH-specific therapies may serve as a bridge to lung transplantation(50). Other study indicated that patients with PVOD present with symptoms of right-sided heart failure. Radiologic examination shows prominent pulmonary arteries with Kerley B lines, pleural effusion, and mediastinal adenopathy. The definite diagnosis is made by histologic examination. Eccentric intimal fibrosis and recanalized thrombi in pulmonary veins and venules, arterialized veins, alveolar edema, and medial hypertrophy of arteries are seen on lung biopsy. No effective treatment is available; lung transplantation has been tried. The prognosis associated with PVOD is poor(53).
General recommendations include limiting of physical activity to tolerance and avoidance of concomitant medications that can potentially aggravate pulmonary hypertension (such as β-adrenergic receptor blockers) or interfere with the metabolism of vitamin K antagonist anticoagulation therapy. Vaccinations to prevent pneumococcal pneumonia and influenza are advised. Given a possible etiological link between tobacco exposure and PVOD, smoking cessation advice and appropriate pharmacotherapy is particularly important and should routinely be offered to cigarette smokers. Diuretics offer symptomatic benefit in those with right ventricular volume overload that is not controlled by dietary measures alone. The effect of diuretics on mortality in PVOD has not been systemically examined(50).
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Pulmonary edema
Pulmonary edema is defined as a condition of fluid accumulation in the air spaces and parenchyma of the lungs of that can lead to difficult of breathing and respiratory failure.
I. Signs and Symptoms
Acute pulmonary edema can be classified as either cardiogenic or noncardiogenic or both. Cardiogenic pulmonary edema occurs when the pulmonary capillary hydrostatic pressure exceeds plasma oncotic pressure. Noncardiogenic pulmonary edema occurs when pulmonary capillary permeability is increased(a).
1. Shortness of breath, crepitations, high systolic blood pressure, and chest pain
In the study to
1) describe the prehospital clinical presentation and management of patients with a clinical diagnosis of APE and
2) compare the accuracy of coding of APE by paramedics against the emergency department (ED) medical discharge diagnosis, including a retrospective cohort of all patients who had episodes identified as APE by ambulance paramedics and were transported to a metropolitan hospital ED in 2011, found that four hundred ninety-five patients were transported to an ED with APE identified by the paramedics as the primary problem code. Shortness of breath, crepitations, high systolic blood pressure, and chest pain were the most common presenting signs and symptoms. Pink frothy sputum was rare (3% of patient episodes of APE)(1).
2. Severe respiratory distress with evident inability to adequately ventilate and/or oxygenate
According to the study by the University Hospital of Pisa there is a series of study with the use of intravenous atenolol, a short-acting cardioselective beta-adrenergic antagonist, to treat acute pulmonary edema in the prehospital setting. Four patients with a documented history of cardiac disease and one patient with unknown cardiac issues experienced severe respiratory distress and presented with pulmonary edema; the local emergency medical service was utilized. In all of the patients, the saturation of peripheral oxygen (SpO2) was severely low, and the patients were rapidly treated with oxygen, diuretics, morphine, and nitrates(2).
3. According to the article by Jack Hirsh, MD; John Hoak, MD, patients who survive an acute PE are at high risk for recurrent PE and for the development of pulmonary hypertension and chronic cor pulmonale, which occurs in up to 70% of patients and carries its own attendant mortality and morbidity. Massive PE causes hypotension due to acute cor pulmonale, but the physical examination findings early in submassive PE may be completely normal. Initially, abnormal physical findings are absent in most patients with PE. After 24-72 hours, loss of pulmonary surfactant often causes atelectasis and alveolar infiltrates that are indistinguishable from pneumonia on clinical examination and by x-ray. New wheezing may be appreciated. If pleural lung surfaces are affected, a pulmonary rub may be heard.
The spontaneous onset of chest wall tenderness without a good history of trauma is always worrisome, because patients with PE may have chest wall tenderness as the only physical finding.
In patients with massive PE, the incidence of physical signs has been reported as follows:
96% have tachypnea (respiratory rate >16/min)
58% develop rales 53% have an accentuated second heart sound 44% have tachycardia (heart rate >100/min)
43% have fever (temperature >37.8° C)
36% have diaphoresis
34% have an S3 or S4 gallop
32% have clinical signs and symptoms suggesting thrombophlebitis
24% have lower extremity edema
23% have a cardiac murmur
19% have cyanosis (3)
II. Causes and Risk factors
A. Causes
1. Certain medication
There is a report of a 32-year-old primigravida with spontaneous triplet pregnancy was admitted at 33 3/7 weeks for threatened preterm labour. For tocolysis, atosiban was administered for 48 hours together with betamethasone for foetal lung maturation. One day after treatment with atosiban she developed dyspnoea caused by pulmonary oedema(4).
2. Cardiac disease and one patient with unknown cardiac issues
In case series study, there is a report of the use of intravenous atenolol, a short-acting cardioselective beta-adrenergic antagonist, to treat acute pulmonary edema in the prehospital setting. Four patients with a documented history of cardiac disease and one patient with unknown cardiac issues experienced severe respiratory distress and presented with pulmonary edema(5).
3. Giant left atrial myxoma
There is a report of a case of a huge left atrial myxoma with an unusual clinical presentation characterized by acute pulmonary edema(6). Other study report a case of a 67-year-old female who presented with acute cardiac insufficiency and pulmonary edema. Cardiac murmur was not detected on precordial examination. Urgent echocardiography, however, revealed atrial myxoma causing mitral valve obstruction(7).
4. Congestive heart failureIn the study to prospectively assess the sensitivity and specificity of ultrasonographic assessment of jugular venous distension (US-JVD) for identifying pulmonary oedema on CXR in dyspnoeic patients with suspected congestive heart failure, showed that US-JVD is a sensitive test for identifying pulmonary oedema on CXR in dyspnoeic patients with suspected congestive heart failure(7a). As the pressure in these blood vessels increases, fluid is pushed into the air spaces (alveoli) in the lungs. This fluid reduces normal oxygen movement through the lungs. This and the increased pressure can lead to shortness of breath(7b).
5. Kidney failure
There is a report of a17-year-old male suffered severe noncardiogenic pulmonary edema with arterial hypotension and acute renal insufficiency after withdrawal of a central venous catheter from the subclavian vein(7c).
6. Certain toxic gas
According to the study by the University of Louisville, chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function(7d).
7. Acute lung injury
Pulmonary edema is an under-recognized and potentially serious complication of blood transfusion. Distinct mechanisms include adverse immune reactions and circulatory overload. The former is associated with increased pulmonary vascular permeability and is commonly referred to as transfusion-related acute lung injury (TRALI), according to the study by the Mayo Clinic College of Medicine(7e)
8. After blood transfusion
pulmonary edema frequently occurs after blood transfusion. The association between infusion of plasma and the development of suspected or possible TRALI may have important implications with regards to etiology and prevention of this syndrome, according to the study by ths Mayo Clinic College of Medicine(7f)
9. Hyperbaric oxygen therapy
There is a report of report of three cases of pulmonary edema associated with hyperbaric oxygen therapy, including one fatality. All three patients had cardiac disease and reduced left ventricular (LV) ejection fractions (EFs). Two patients had diabetes, and one patient had severe aortic stenosis. Hyperbaric oxygen therapy may contribute to pulmonary edema by increasing LV afterload, increasing LV filling pressures, increasing oxidative myocardial stress, decreasing LV compliance by oxygen radical-mediated reduction in nitric oxide, altering cardiac output between the right and left hearts, inducing bradycardia with concomitant LV dysfunction, increasing pulmonary capillary permeability, or by causing pulmonary oxygen toxicity(7g).
B. Risk factors
1. High altitude
High altitude pulmonary edema (HAPE) is a noncardiogenic pulmonary edema which typically occurs in lowlanders who ascend rapidly to altitudes greater than 2500-3000 m with early symptoms of HAPE include a nonproductive cough, dyspnoea on exertion and reduced exercise performance(8).
2. Swimming induced pulmonary edema (SIPE)
SIPE can be described as a cardiogenic pulmonary edema, at least in part, since an increased transalveolar pressure gradient has been implicated in the pathogenesis of SIPE. Brain natriuretic peptide (BNP) is used in the clinical setting to differentiate cardiac from pulmonary sources of dyspnea, specifically to diagnose cardiogenic pulmonary edema, according to the study by the Loyola University Medical Center(9).
3. Chronic kidney disease
According to the study by the The VA Medical Center, Chronic kidney disease is often associated with predisposing cardiac risk factors that make patients susceptible to development of flash pulmonary edema(10).
4. Prior history of pulmonary edema
Patients with Prior history of pulmonary edema are at increased risk of recurrent pulmonary edema.
5. Hypertension
Many patients with flash pulmonary edema have preserved systolic left ventricular function and coronary artery disease. Flash pulmonary edema frequently reoccurs in association with marked systolic hypertension, even after coronary revascularization. This suggests that control of hypertension is important and that coronary revascularization may not be adequate to prevent reoccurrence of flash pulmonary edema(10a).
6. History of lung diseases
There is a report of a case of NPE in a middle-aged female patient following a breakthrough seizure in whom an immunological cause for respiratory findings was high on the differential list, based on her past medical history and chronicity of symptoms. Rapid symptomatic and radiological improvement following hospitalization led to the correct diagnosis(10b).
7. Increased vascular permeability
Increased vascular permeability contributes to many diseases, including acute respiratory distress syndrome, cancer and inflammation. studies reveal that pulmonary vascular leakage can be increased by altering extracellular matrix compliance in vitro and by manipulating lysyl oxidase-mediated collagen crosslinking in vivo. Either decreasing or increasing extracellular matrix stiffness relative to normal levels disrupts junctional integrity and increases vascular leakage. The identification of lysyl oxidase and the extracellular matrix as critical regulators of lung vascular leakage might lead to the development of new therapeutic approaches for the treatment of pulmonary oedema and other diseases caused by abnormal vascular permeability, according to the Children's Hospital and Harvard Medical School, Boston(10c).
8. Etc.
III. Complications and diseases associated to Pulmonary edema
A. Complications
1. Acute heart attack (myocardial infarction [MI])
According to the article by American medical network, typical causes of acute cardiogenic pulmonary edema include acute myocardial infarction or severe ischemia, exacerbation of chronic heart failure, acute volume overload of the left ventricle (valvular regurgitation), and mitral stenosis(11).
2. Cardiogenic shock
According to the study to identify the independent predictors of 30-day mortality and to analyse the outcomes of patients with cardiogenic shock (CS) associated with acute myocardial infarction (AMI) and necessitating extracorporeal life support (ECLS), of a total 77 patients who had required ECLS support for AMI with CS, Pulmonary oedema occurred in 24 patients (31.6%)(12).
3. Arrhythmias
In Thirty cases (23 males) of post cardioversion acute pulmonary edema identified with the mean age was 53.8 +/- 13 years (range, 18 to 75 years), underlying arrhythmias were atrial fibrillation (69%), atrial flutter (24%), supraventricular tachycardia (4%), and ventricular tachycardia (4%). The duration of arrhythmia preceding cardioversion varied widely ranging from 1 day to 13 years, according to Beth Israel Medical Cente(13).
4. Electrolyte disturbances
According to the article of Fluid and Electrolyte Regulation by Kathryn E.Roberts, respiratory system examination includes an assessment of thepatient's respiratory effort, an increaseor decrease in respiratory rate and depth, and work of breathing.The presence of rales on auscultation, indicating fluid volume excess, is observed(14).
5. Protein enteropathyIn the differential diagnosis, protein-losing enteropathy (PLE) is a rarely considered explanation of edema. Three such cases are reported in this the study by the Kaohsiung Medical University(15).
6. Death
B. Diseases associated to Pulmonary edema
1. Multiple sclerosis
young woman with multiple sclerosis presented to the Emergency Department in acute respiratory failure. She was cyanotic centrally, hypertensive, and tachycardic. The chest X-ray study suggested pulmonary edema, according to the study by the Centre for Neuroscience and Neurological Research, St Vincent's Hospital(16).
2. Primary cardiac chondroma
Primary chondroma is an exceptionally rare cardiac tumor. There is a report of a case of a patient presenting with acute pulmonary edema with the incidental echocardiographic finding of a large left atrial tumor that was histopathologically diagnosed as primary cardiac chondroma(17).
3. Atrial myxoma
Atrial myxoma is the most common primary cardiac tumor. Its clinical presentation spreads from asymptomatic incidental mass to serious life-threatening cardiovascular complications. There is a report of the case of a 44-year-old man with evening fever and worsening dyspnea in the last weeks, admitted to our hospital for acute pulmonary edema(18).
4. Pleural effusion or pneumothorax
Re-expansion pulmonary edema (RPE) is a rare but potentially fatal complication that can occur following rapid lung expansion while managing patients with pleural effusion or pneumothorax. In this case, fatal outcome occurred due to RPE in a previously healthy young adult male patient subsequent to tube thoracostomy for spontaneous pneumothorax(19),
5. Etc.
IV. Misdiagnosis and Diagnosis
A. Misdiagnosis
1. Pneumonia
Unilateral pulmonary edema can mimic as pneumonia. Clinician should be aware of differential diagnosis of pulmonary edema, otherwise it can lead to unnecessary investigation and delay in starting definitive treatment< according to the study by ths National University Hospital, National University Health System(20).
2. Acute rheumatic fever
Although the diagnostic criteria for acute rheumatic fever (ARF) are well known, a high index of suspicion is necessary in order to assure timely diagnosis and appropriate treatment. We present a case of an 8-year-old child who presented with unilateral pulmonary edema secondary to acute mitral insufficiency due to ARF. ARF should be considered in the differential diagnosis of unilateral pulmonary edema in children(21).
3. Acute mitral regurgitation
Differential diagnosis of unilateral alveolar pulmonary infiltration includes various possibilities. Acutely developing mitral insufficiency, often without any prior cardiac symptoms, may be the cause of pulmonary edema localized exclusively in the right upper lobe(22).
4. Amiodarone pneumonitis
There is a report of a case of the case of a 78-year-old woman with a history of cardiac surgery, who after 2 years of amiodarone therapy for prophylactic treatment of atrial fibrillation developed amiodarone pneumonitis mimicking an acute pulmonary edema(23).
5. Acute myocardial infarction
There is a report of a case of neurogenic pulmonary oedema (NPO) following massive left cerebral infarct, which was initially misdiagnosed as acute myocardial infarction (AMI)(24).
B. Diagnosis
If you are certain symptoms above and suspected to develop, after a complete physical examination, including checking the presence of fluid in your lungs and recorded of your family, the tests which your doctor orders may include
1. Blood test
Blood chemistry tests are a procedure to examine the general health of a patient, but in this case it may be used to test for oxygen levels.
2. Lung ultrasound
Neurogenic pulmonary edema (NPE) is an acute life-threatening complication associated with many forms of central nervous system injury. NPE usually appears within minutes to hours after injury and has a high mortality rate if not recognized and treated appropriately. Lung ultrasound quickly provides at the bedside relevant information on the state of aeration and ventilation of the lung(25).
3. Chest X-ray
The aim of the test is to check for the presence of fluid in the lung. According to the study by the researcher team lead by Liebman PR, the portable chest x-ray technic does not provide quantitative information regarding cardiopulmonary function. It is especially hazardous to accept an x-ray diagnosis of congestive failure as the cause of pulmonary edema(26).
4. Electrocardiogram (ECG)
The aim of the test is to look for heart rhythm problems or signs of a heart attack. There is a report of a case of presented markedly low surface electrocardiographic (ECG) voltage and an infarction pattern are rapidly reversed with renal hemodialysis for pulmonary edema(27).
5. Echocardiogram
The aim of the test is to check for problems of the heart muscle including weakness, thickness, failure to relax properly, leaky or narrow heart valves, or fluid surrounding the heart(28).
V. Preventions
A. Diet to prevent Pulmonary edema
Diet to Prevent cardiovascular disease can be helpful to reduce the risk of pulmonary edema
1. Mediterranean diet
In a study of a random sample of Jewish adults, aged 35+ using a 24-h recall questionnaire. A MD score (scale 0-8) computed reflecting high ratio of monounsaturated to saturated fat; high intake of alcohol, legumes, cereals, vegetables, and fruits; low intakes of meat and it's products, milk and dairy products. Scoring <5 was defined as Low-MD consuming, while 5+ as High-MD consuming, showed that the risk for myocardial infarction, coronary bypass, angioplasty, and any cardiovascular disease in men increased by 1.2 (P = 0.04), 1.6 (P = 0.01), 1.4 (P = 0.003), and 1.3 (P = 0.01), respectively, for each MD score decrease. In women, crude odds ratios ranged from 1.4 to 1.9 but were not statistically significant(29).
2. Wholegrain cereals
In the search of CENTRAL (Issue 4, 2005), MEDLINE (1966 to 2005), EMBASE (1980 to 2005), CINAHL (1982 to 2005), ProQuest Digital Dissertations (2004 to 2005) with no language restrictions applied, found that ten trials met the inclusion criteria. None of the studies found reported the effect of wholegrain diets on CHD mortality or CHD events or morbidity. All 10 included studies reported the effect of wholegrain foods or diets on risk factors for CHD. Studies ranged in duration from 4 to 8 weeks. In eight of the included studies, the wholegrain component was oats. Seven of the eight studies reported lower total and low density lipoproteins (LDL) cholesterol with oatmeal foods than control foods. When the studies were combined in a meta-analysis lower total cholesterol (-0.20 mmol/L, 95% confidence interval (CI) -0.31 to -0.10, P = 0.0001 ) and LDL cholesterol (0.18 mmol/L, 95% CI -0.28 to -0.09, P < 0.0001) were found with oatmeal foods. However, there is a lack of studies on other wholegrains or wholegrain diets(30).
1. Avocados are a commercially valuable fruit and are cultivated in tropical climates throughout the world, it is a green-skinned, pear-shaped fruit that ripens after harvesting and native to the Caribbean, Mexico, South America and Central America, belonging to the flowering plant family Lauraceae.
a. Cholesterol
In the determination of the atherogenicity of avocado oil relative to saturated (coconut oil), monounsaturated (olive oil) and polyunsaturated (corn oil) fats found that Coconut oil was the most atherogenic fat. Corn oil was only slightly less atherogenic than either olive or avocado oils. Percentage of serum HDL cholesterol was highest in the rabbits fed the two monounsaturated fats, according to "Cholesterol vehicle in experimental atherosclerosis 24: avocado oil" by Kritchevsky D, Tepper SA, Wright S, Czarnecki SK, Wilson TA, Nicolosi RJ.(31)
b. Dietary fiber
Daily intake of right amount of fibers can prevent and treat Diabetes. Increased consumption of vegetables, whole grains, and soluble and insoluble fiber is associated with improved glucose metabolism in both diabetic and nondiabetic individuals. Improvements in insulin sensitivity and glucose homeostasis were more evident in participants following a plant-based diet compared with other commonly used diets, according to the study of "Efficacy of high-fiber diets in the management of type 2 diabetes mellitus" by Wolfram T, Ismail-Beigi F.(32)
c. Heart diseases
c.1.The chemical compound Beta-Sitosterol is found effectively in reducing the bad cholesterol and leaving the good cholesterol untouched by inhibiting the amount our body can absorb, thus reducing the risk of plague building up in the arterial walls, leading to heart diseases, according to the study of "The Effect of Beta Sitosterol on the Serum Lipids of Young Men with Arteriosclerotic Heart Disease" by JOHN W. FARQUHAR M.D.; RALPH E. SMITH M.D.; MARY E. DEMPSEY M.S., posted in Circulation(33)
c.2. It also reduce the risk of autoimmune diseases such as multiple sclerosis, according to the study of "Effect of vitamin D and β-sitosterol on immune function of macrophages" by Alappat L, Valerio M, Awad AB.(34)
2. Almond consists of an outer hull and a hard shell with the seed (nut) inside is native to the Middle East. It is most widely cultivated seed in the world for it economic and health benefit.
a. . Cholesterol
In the research of almond consumption in the improvement of serum lipid profiles found that almond consumption ranging from 25 to 168 g/day significantly lowered total cholesterol [weighted mean difference -6.95 mg/dL (95% confidence interval [CI] -13.12 to -0.772) (-0.18 mmol/L [95% CI -0.34 to -0.02])] and showed a strong trend toward reducing LDL cholesterol [weighted mean difference -5.79 mg/dL (95% CI -11.2 to 0.00) (-0.15 mmol/L [95% CI -0.29 to 0.00])]. No significant effect on HDL cholesterol, triglycerides, or LDL:HDL ratio was found, according to "Almonds have a neutral effect on serum lipid profiles: a meta-analysis of randomized trials" by Phung OJ, Makanji SS, White CM, Coleman CI.(35)
b. Antioxidants
In the evaluation of antioxidant properties of almond green husks (Cvs. Duro Italiano, Ferraduel, Ferranhês, Ferrastar and Orelha de Mula), chestnut skins and chestnut leaves (Cvs. Aveleira, Boa Ventura, Judia and Longal) found that all the assayed by-products revealed good antioxidant properties, with very low EC(50) values (lower than 380 μg/mL), particularly for lipid peroxidation inhibition (lower than 140 μg/mL). The total phenols and flavonoids contents were also determined. The correlation between these bioactive compounds and DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity, reducing power, inhibition of β-carotene bleaching and inhibition of lipid peroxidation in pig brain tissue through formation of thiobarbituric acid reactive substances, was also obtained, according to "Antioxidant potential of chestnut (Castanea sativa L.) and almond (Prunus dulcis L.) by-products" by Barreira JC, Ferreira IC, Oliveira MB, Pereira JA.(36)
c. Cardiovascular diseases
Since it contains high amount of Omega 3 fatty acid, it helps to prevent the risk of cardiovascular diseases by reducing arrhythmias and altering production of prostaglandins, which reduces inflammation and improves platelet and endothelial function, according to "Omega-3 Fatty acids for cardiovascular disease prevention" by Defilippis AP, Blaha MJ, Jacobson TA.(37)
3. Salmon is the common name for Salmonidae. They are anadromous, born in fresh water, migrate to the ocean, then travel thousands of miles in the deep sea cold water throughout their life cycle and within to five years returning to the exacted location where they were born to reproduce and die.
a. Triacylglycerols
In the investigation of Intake of fish and omega-3 (n-3) fatty acids is associated with a reduced concentration of plasma triacylglycerols (TAG) found that intake of cod or salmon when compared with the control group. In conclusion, both lean and fatty fish may lower TAG, possibly by reducing the 18:1n-9/18:0 ratio related to allosteric inhibition of SCD1 activity, rather than by influencing the synthesis of enzyme protein, according to "Daily Intake of Cod or Salmon for 2 Weeks Decreases the 18:1n-9/18:0 Ratio and Serum Triacylglycerols in Healthy Subjects" by Telle-Hansen VH, Larsen LN, Høstmark AT, Molin M, Dahl L, Almendingen K, Ulven SM.(38)
b. Weight loss
In the investigation of supplementation with n3 long-chain polyunsaturated fatty acids (n3-LCPUFA) and its effect in body weight, found that At the end of the 1-month period, 16 children lost weight and 27 children gained weight. Multiple analysis demonstrated that supplementation with n3-LCPUFA decreased HOMA-IR by 15% after adjusting for puberty, treatment adherence, changes in adipokines, and weight loss. Interaction between supplementation and weight loss was significant (p = 0.007), according to "Supplementation of n3 Long-chain Polyunsaturated Fatty Acid Synergistically Decreases Insulin Resistance with Weight Loss of Obese Prepubertal and Pubertal Children" by López-Alarcón M, Martínez-Coronado A, Velarde-Castro O, Rendón-Macías E, Fernández J.(39)
c. Cholesterol
In the assessment of an increasing drive to replace fish oil (FO) in finfish aquaculture diets with vegetable oils (VO), driven by the short supply of FO derived from wild fish stocks,
found that these effects are most likely mediated by SREBP2, which responds to reductions in dietary cholesterol. These changes are sufficient to maintain whole body cholesterol levels but not HUFA levels, according to "Functional genomics reveals increases in cholesterol biosynthetic genes and highly unsaturated fatty acid biosynthesis after dietary substitution of fish oil with vegetable oils in Atlantic salmon (Salmo salar)" by Leaver MJ, Villeneuve LA, Obach A, Jensen L, Bron JE, Tocher DR, Taggart JB.(40)
d. Coronary heart disease
In determination of Omega-3-fatty acids play a protective role in the prevention of CHD,
found that The treatment with salmon oil led to a decrease of triglycerides in patients with hypertriglyceridemia and to an increase of cholesterol in hypercholesterolemia. Following the increase of malondialdehyde as measure of the lipid peroxidation a substitution of antioxidants, like vitamin E and vitamin C, seems to be useful. Further investigations are necessary before wide use of fish-oil capsules, not least to avoid side-effects, according to "[Changes in parameters of lipid metabolism and anti-oxidative potentials in elderly hyperlipoproteinemic patients treated with omega-3 fatty acids].[Article in German]" by Reuter W, Vorberg B, Sauer I, Krumpolt C.(41)
e. Antioxidants
In the research of the antioxidant effect of vitamin E after ingestion of salmon found that that megadoses of vitamin E, far from having pro-oxidative activity, actually increase the anti-oxidative capacity of the liver, especially after ingestion of salmon oil, according to "Effects of megadoses of dietary vitamin E on the antioxidant status of rats fed lard or salmon oil" by Flader D, Brandsch C, Hirche F, Eder K.(42)
4. Soy sauce is a seasoning produced by fermenting soybeans and filamentous fungus, along with water and salt after a period of sometime, it yields a moromi or thick mash of cereal to obtain soy sauce by pressing it to liquid form. Tamari is made by collecting the liquid which was pressed and the liquid drained drains from miso after a certain time of fermentation.
a. Cardiovascular health
In the investigation of dietary proteins and their effect in heart diseases found that a direct cholesterol lowering effect of proteins has not been shown. Despite earlier research indicating that soy protein has cardioprotective effects as compared to other proteins, these observations have not been confirmed by randomized placebo-controlled trials. However, most experts recommend the consumption of foods rich in plant proteins as alternatives to meat and dairy products rich in saturated fat and containing cholesterol, according to "Dietary proteins and atherosclerosis" by Darioli R.(43)
b. Hypolipidemic effect
In the observation of Soy sauce (Shoyu), a traditional Japanese fermented seasoning and its effect on cholesterol level found that in a 4-week randomized, double-blind, placebo-controlled parallel group study, hyperlipidemic men (TG >150 mg/dl) were treated with 600 mg of SPS (n=15) or placebo (n=15) daily. After 4 weeks, serum TG levels in the SPS-treated group were significantly (P<0.05) lower than the baseline (0 week). In conclusion, SPS of soy sauce reduce lipid absorption, and soy sauce is a potentially promising seasoning for the treatment of hyperlipidemia through food, according to "Hypolipidemic effect of Shoyu polysaccharides from soy sauce in animals and humans" by Kobayashi M, Magishi N, Matsushita H, Hashimoto T, Fujimoto M, Suzuki M, Tsuji K, Saito M, Inoue E, Yoshikawa Y, Matsuura T.(44)
5. Pear is Genus Pyrus containg over 30 difference species, belongs to the family Rosaceae and native to western Europe and north Africa east right across Asia. Today, it is cultivation in the cool temperated weather regions all over the world for commercial purposes.
a. AntioxidantsIn the classification of betalains in juices prepared from Moroccan yellow cactus pears and its antioxidant effect found that the pigments tested act as mixed inhibitors. The inhibitive action of the extracts is discussed in term of adsorption and that such adsorption follows a Langmuir adsorption isotherm. The calculated values of the free energy of adsorption indicated that the adsorption process is spontaneous, according to "Betalain: a particular class of antioxidant pigment" by El Gharras H.(45)
b. Stroke
In the assessment of pigmented bioactive compounds, (eg, carotenoids, anthocyanidins, and flavonoids) and theirs effect on stroke found that Higher intake of white fruits and vegetables was inversely associated with incident stroke (Q4, >171 g/d, versus Q1, ≤78 g/d; HR, 0.48; 95% CI, 0.29-0.77). Each 25-g/d increase in white fruit and vegetable consumption was associated with a 9% lower risk of stroke (HR, 0.91; 95% CI, 0.85-0.97). Apples and pears were the most commonly consumed white fruit and vegetables (55%), according to "Colors of fruit and vegetables and 10-year incidence of stroke" by Oude Griep LM, Verschuren WM, Kromhout D, Ocké MC, Geleijnse JM.(46)
c. Dietary fiberDaily intake of right amount of fibers can prvent and treata. Diabetes, as Increased consumption of vegetables, whole grains, and soluble and insoluble fiber is associated with improved glucose metabolism in both diabetic and nondiabetic individuals. Improvements in insulin sensitivity and glucose homeostasis were more evident in participants following a plant-based diet compared with other commonly used diets, according to the study of "Efficacy of high-fiber diets in the management of type 2 diabetes mellitus" by Wolfram T, Ismail-Beigi F.(47)
6. Tomato is a red, edible fruit, genus Solanum, belongs to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose
and often in green house.
a. Cardiovascular diseases
In the review of patents and products within the context of lycopene and CVD prevention and health claims indicated that in vitro data and results from animal experiments partly showed promising preventive mechanisms of lycopene. In contrast, until now, human intervention studies mostly failed to show any CVD prevention. However, there is still an encouraging situation, giving hints for antioxidant as well as anti-inflammatory effects of lycopene. These mechanisms could be the background for cardio-protective effects of tomatoes and tomato products, according to "Lycopene and heart health" by Böhm V.(48)
b. Antioxidative and Cancer Cell-Inhibiting Activities
In the research of Tomato ( Solanum lycopersicum ) plants synthesize nutrients, pigments, and bioactive compounds and their benefit in nutrition and human health found that Tomato extracts promoted growth in normal liver (Chang) cells, had little effect in normal lung (Hel299) cells, mildly inhibited growth of lung cancer (A549) cells, and first promoted and then, at higher concentrations, inhibited growth in lymphoma (U937) cells. The relationship of cell growth to measured constituents was not apparent, according to "Free Amino Acid and Phenolic Contents and Antioxidative and Cancer Cell-Inhibiting Activities of Extracts of 11 Greenhouse-Grown Tomato Varieties and 13 Tomato-Based Foods" by Choi SH, Kim HR, Kim HJ, Lee IS, Kozukue N, Levin CE, Friedman M.(49)
7. Etc.
B. Phytochemicals to prevent Pulmonary edema
1. Resveratrol
Resveratrol is a phytochemical in the class of Stilbenoids, found abundantly in skins and seed of grape wine, nuts, peanuts, etc.
a. Cardiovascular diseasesIn the revie of reviews some of the key studies, and the known mechanisms for these beneficial effects. Evidence from different experimental studies, including from the authors' laboratories, and the beneficial effects of polyphenols found in red wine, especially resveratrol in grape skins.
found that Resveratrol benefits include a reduction in cardiovascular morbidity and mortality, lung cancer and prostate cancer by approximately 30% to 50%, 57% and 50%, respectively. Polyphenols possess antioxidant, superoxide-scavenging, ischemic-preconditioning and angiogenic properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system, as well as other body organs, according to "Significance of wine and resveratrol in cardiovascular disease: French paradox revisited" by Vidavalur R, Otani H, Singal PK, Maulik N.(50).
b. Cardiovascular health
In the review of Resveratrol (3,4',5-trihydroxystilbene), a member of natural, plant-derived chemicals known as polyphenols and is attracting increased attention due to its diverse health benefits especially in case of cardiovascular disease, cancer, diabetes and neurological problems, indicated that Recently, resveratrol was found to induce autophagy and regenerate myocardial ischemic tissue treated with stem cells. Overall observation indicates that resveratrol has a high therapeutic potentials for the treatment of cardiovascular diseases, according to "Resveratrol and cardiovascular health" by Das M, Das DK.(51).
2. Phytosterols Phytosterols are a subgroup of lipids, the steroid compounds similar to cholesterol in plant, Researchers have found more than 200 of them.
1. Cholesterol
Phytosterols are best best known to have a property in lowering the blood cholesterol, according to the study of " Scientific Opinion on the substantiation of health claims related to plant sterols and plant stanols and maintenance of normal blood cholesterol concentrations (ID 549, 550, 567, 713, 1234, 1235, 1466, 1634, 1984, 2909, 3140), and maintenance of normal prostate size and normal urination (ID 714, 1467, 1635) pursuant to Article 13(1) of Regulation (EC) No 1924/2006", posted in EFSA Journak, researchers filed in summary that a cause and effect relationship has been established between the consumption of plant sterols and plant stanols and the reduction of blood cholesterol concentrations.
2. Coronary heart disease
In most case, if a substance have a good effect in lowering blood cholesterol concentration, it may also promote heart health. In a study of " Plant Sterols and Blood Cholesterol Scientific substantiation of a health claim related to plant sterols and lower/reduced blood cholesterol and reduced risk of (coronary) heart disease pursuant to Article 14 of Regulation (EC) No 1924/20061" from Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies Adopted on 11 July 2008, researchers indicated that Elevated low-density lipoprotein (LDL) blood cholesterol is one recognised risk factor for
coronary heart disease (CHD). CHD is an important cause of mortality and morbidity.
Lowering LDL-cholesterol by dietary intervention has been shown to reduce the risk of
coronary heart disease. The Panel considers that the claimed effect of lowering LDLcholesterol
is beneficial to human health.
3. Epigallocatechin
Epigallocatechin, including catechins, is a phytochemical of Flavan-3-ols, in the group of Flavonoids (polyphenols), found abundantly in green tea, St John wort, black Tea, carob flour, Fuji apples, etc.
a Cardiovascular diseases
In the identification of green tea catechins and its lowering the risk of cardiovascular diseases, found that green tea catechins, particularly (-)-epigallocatechin gallate, interfere with the emulsification, digestion, and micellar solubilization of lipids, critical steps involved in the intestinal absorption of dietary fat, cholesterol, and other lipids. Based on the observations, it is likely that green tea or its catechins lower the absorption and tissue accumulation of other lipophilic organic compounds, according to "Green tea as inhibitor of the intestinal absorption of lipids: potential mechanism for its lipid-lowering effect" by Koo SI, Noh SK.(52).
b. Cholesterol
In the examination of the influence of green tea extract, epicatechin (EC), epicatechin galate (ECG) as well as epigallocatechin galate (EGCG) on oxidative modifications of LDL of human blood serum, found that Catechins and green tea abilities to protect lipophilic antioxidant--alpha-tocopherol against oxidation have been also examined. The results reveal that peroxidation of LDL is markedly prevented by green tea extract and in a slightly weaker way by catechins (EGCG in particular), which is manifested by a decrease in concentration of conjugated dienes, lipid hydroperoxides, MDA, dityrosine and by an increase in tryptophan content, according to "The comparison of effect of catechins and green tea extract on oxidative modification of LDL in vitro" by Ostrowska J, Skrzydlewska E.(53)
C. Antioxidants to prevent Pulmonary edema
1. Vitamin D
According to the study by the Boston University Medical Center, Vitamin D deficiency has been associated with increased risks of deadly cancers, cardiovascular disease, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus(54).
2. Vitamin C
Vitamin C is an essential dietary nutrient for the biosynthesis of collagen and a co-factor in the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, and some peptide hormones. The lack of vitamin C causes scurvy, a pathological condition leading to blood vessel fragility and connective tissue damage due to failure in producing collagen, and, finally, to death as result of a general collapse. Vitamin C is potentially involved also in cancer and cardiovascular diseases prevention(55).
3. Selenium (Se) and vitamin E (V(E))
In the study to examine the effects of Se and V(E) supplementation on MeHg-mediated systemic oxidative stress, antioxidant defense, inflammation, and endothelial dysfunction in an animal model with male Sprague-Dawley rats fed a starch-based casein diet or the same diet supplemented with 1 or 3 mg Se/kg diet and with or without 250 or 750 mg V(E)/kg diet, found that Se and V(E) supplementation may either alleviate or augment the effects of MeHg, depending on their doses and combinations(56).
4. Pterostilbene
Pterostilbene is a phytochemical in the class of Stilbenoids, found abundantly in grapes, blueberries, etc.
a. Cholesterol
In the investigation of whether resveratrol and its three analogues (pterostilbene, piceatannol, and resveratrol trimethyl ether) would activate the peroxisome proliferator-activated receptor alpha (PPARalpha) isoform, found that the maximal luciferase activity responses to pterostilbene were higher than those obtained with the hypolipidemic drug, ciprofibrate (33910 and 19460 relative luciferase units, respectively), at 100 microM. Hypercholesterolemic hamsters fed with pterostilbene at 25 ppm of the diet showed 29% lower plasma low density lipoprotein (LDL) cholesterol, 7% higher plasma high density lipoprotein (HDL) cholesterol, and 14% lower plasma glucose as compared to the control group. The LDL/HDL ratio was also statistically significantly lower for pterostilbene, as compared to results for the control animals, at this diet concentration, according to "Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters" by Rimando AM, Nagmani R, Feller DR, Yokoyama W.(57).
b. Atherosclerosis
In the determination of the effect of Pterostilbene (PT) on Vascular endothelial cell (VEC) apoptosis, the main event occurring during the development of atherosclerosis, found that Cotreatment with PT and siRNA of LOX-1 synergistically reduced oxLDL-induced apoptosis in HUVECs. Overexpression of LOX-1 attenuated the protection by PT and suppressed the effects of PT on oxLDL-induced oxidative stress. PT may protect HUVECs against oxLDL-induced apoptosis by downregulating LOX-1-mediated activation through a pathway involving oxidative stress, p53, mitochondria, cytochrome c and caspase protease. PT might be a potential natural anti-apoptotic agent for the treatment of atherosclerosis, according to "Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo" by Zhang L, Zhou G, Song W, Tan X, Guo Y, Zhou B, Jing H, Zhao S, Chen L.(58).
5. Astaxanthin
Astaxanthin is a phytochemincal in the class of Xanthophylls, belonging to the group of Carotenoids (tetraterpenoids), found abundantly in yeast, krill, shrimp, salmon, lobsters, etc.
a. Cardiovascular health
In the evualation of the an antioxidant with anti-inflammatory properties effects and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease of Astaxanthin, a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail, found that No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event, according to "Astaxanthin: a potential therapeutic agent in cardiovascular disease" by Fassett RG, Coombes JS.(59)
b. Antithrombotic and antihypertensive effects
In the examination of the hypothesis that astaxanthin, a red pigment carotenoid found in salmonid and crustacean aquaculture, for its protect on stroke-prone spontaneously hypertensive rats (SHRSP) from vascular oxidative damage, hypertension, and cerebral thrombosis, found that the results supported our hypothesis and strongly suggested that the antithrombotic and antihypertensive effects of astaxanthin or vitamin E may be related to an increase in bioavailable NO, possibly mediated by decreased inactivation of NO by reactive oxygen species, according to "Astaxanthin inhibits thrombosis in cerebral vessels of stroke-prone spontaneously hypertensive rats" by Sasaki Y, Kobara N, Higashino S, Giddings JC, Yamamoto J.(60)
c. Cholesterol
In a randomized, double-blind, placebo-controlled study to investigate the effects of astaxanthin on lipid profiles and oxidative stress in overweight and obese adults in Korea, found that all four biomarkers were not significantly different between the two groups. Compared with the placebo group, MDA and ISP were significantly lower, but TAC was significantly higher in the astaxanthin group at 12 weeks. These results suggest that supplementary astaxanthin has positive effects by improving the LDL cholesterol, ApoB, and oxidative stress biomarkers, according to "Positive effects of astaxanthin on lipid profiles and oxidative stress in overweight subjects" by Choi HD, Youn YK, Shin WG.(61).
VI. Treatments
A. In conventional medicine perspective
Treatment of Pulmonary edema is depending to the unlined causes of the diseases. In most cases, the disease is caused by congestive heart failure. According to A.D.A.M. Medical Encyclopedia, most cases of Pulmonary edema are almost always treated in the emergency room or hospital, sometimes in an intensive care unit (ICU), including Oxygen is given through a face mask or tiny plastic tubes are placed in the nose and a breathing tube may be placed into the windpipe (trachea) so you can be connected to a breathing machine (ventilator). The unlined causes of the disease should be diagnosis quickly and treated accordingly. Certain medications may be prescribed such as diuretics to remove excess fluids from the body and medicines to strengthen the heart muscle, control the heartbeat, or relieve pressure on the heart(62).
B. In Herbal medicine perspective
1. Sea buckthorn
Sea buckthorn (Hippophaë rhamnoides L.) is a rich source of flavonols, especially isorhamnetin. Most prospective cohort studies have indicated some degree of inverse association between flavonoid intake and coronary heart disease.
2. Astragalus
Astragalus (Astragalus onobrychis), also known as Huang Qi in traditional Chinese medicine, is a genus of small shrubs, belonging to the legume family Fabaceae. The herb has been used in traditional herbal medicine in boosting and stimulating the immune system, as a diuretic, to treat shortness of breath, general weakness, and lack of appetite, colds, flu, stomach ulcers, diabetes, etc.
a. Congestive heart failure
In a study of Sixty-two in-patients with CHF (congestive heart failure), whose heart function belonged to NYHA grade II-IV with Astragalus Injection (AI),conducted by Huazhong University of Science and Technology, posted in PubMed(63), researchers found that astragalus Injection could improve the immune function of CHF patients, and can be taken as an important auxiliary treatment for CHF.
b. Atherosclerosis
Extract of Astragalus, Radix Codonopsis and Cortex Lycii, reduces the risk of Atherosclerosis by suppressing the low-density lipoprotein (LDL) oxidation and inhibiting vascular smooth muscle cell migration, according to the study of "Suppression of low-density lipoprotein oxidation, vascular smooth muscle cell proliferation and migration by a herbal extract of Radix Astragali, Radix Codonopsis and Cortex Lycii" by Chan JY, Koon JC, Leung PC, Che CT, Fung KP., posted in PubMed(64).
c. Heart diseases
One optimal dose of DHEA or Astragalus can reduce the condition of heart disease? according to the study of "Organ representation areas of different internal organs localized on the eyebrows & eyelids by the Bi-Digital O-Ring Test electromagnetic resonance phenomenon between 2 identical molecules--Part I: Detection of increased markers for cancer & heart disease from white hairs on the eyebrows and marked decrease in the markers after taking one optimal dose of DHEA" by Omura Y., posted in PubMed(65)
d. Hypertension
flavonoid (TF), extracted from the seed of Astragalus have shown the properties of lowering blood pressure in both in both renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR) according to the study of "Antihypertensive effect of total flavonoid fraction of Astragalus complanatus in hypertensive rats" by Li JX, Xue B, Chai Q, Liu ZX, Zhao AP, Chen LB., posted in PubMed(66)
3. Bromelain
Bromelain, a proteolytic enzymes found in pineapples (Ananas comosus) has been used in traditional medicine as inflammatory agent and to treat pains, strains, and muscle aches and pains and ease back pain and chronic joint pain, skin diseases, etc.
a. Bromelain in cardiovascular diseases
In the review out of Out of 223 papers retrieved, 6 papers met the inclusion criteria(Randomised controlled trials (RCTs), human studies, animal studies and experimental studies related to bromelain for CVDs. Data extraction and analysis: The quality assessment of all the selected studies was conducted by the authors. Data from 3 animal trials and 3 human trials were included in the review. Data collected included: type of trial, drug dosage, duration, outcome measures, characteristics of bromelain used, significance of results and conclusion), bromelain could be used for treating acute thrombophlebitis, as it decreases aggregation of blood platelets, has a cardio-protective effect, ameliorates rejection-induced arterial wall remodelling, prevents thrombin-induced human platelet aggregation as well as reduces thrombus formation, according to the study of "A review of the use of bromelain in cardiovascular diseases" by Ley CM, Tsiami A, Ni Q, Robinson N., posted in PubMed(67)
b. Renal diseases
Bromelain proteolytic enzymes has improved proteinuria and urinary TGF-beta 1 excretion, as well as the severity of tubulointerstitial fibrosis without signs of toxicity, according to the study of "The effect of oral protease administration in the rat remnant kidney model" Sebeková K, Dämmrich J, Krivosíková Z, Heidland A." by posted in PubMed(68).
4. Garlic
Garlic (Allium sativum) is a species in the onion genus, belonging to family Amaryllidaceae, native to central Asia. It has been used popularly in traditional and Chinese medicine in treating common cold and flu to the Plague, blood pressure cholesterol levels, natural antibiotic, etc.
a. Blood pressure
In the assessment of garlic extract and its effect of hypertension. found that Aged garlic extract was generally well tolerated and acceptability of trial treatment was high (92%) and aged garlic extract is superior to placebo in lowering systolic blood pressure similarly to current first line medications in patients with treated but uncontrolled hypertension, according to "Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: a randomised controlled trial" by Ried K, Frank OR, Stocks NP.(69)
b. Atherosclerosis
In the demonstration of aged garlic extract therapy with supplements (AGE+S) and theirs effect on cardiovascular diseases found that CAC progression was significantly lower and TR significantly higher in the AGE+S compared to the placebo group after adjustment of cardiovascular risk factors (p<0.05). Total cholesterol, LDL-C, homocysteine, IgG and IgM autoantibodies to MDA-LDL and apoB-immune complexes were decreased, whereas HDL, OxPL/apoB, and Lp (a) were significantly increased in AGE+S to placebo and concluded that AGE+S is associated with a favorable improvement in oxidative biomarkers, vascular function, and reduced progression of atherosclerosis., according to "Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial" by Budoff MJ, Ahmadi N, Gul KM, Liu ST, Flores FR, Tiano J, Takasu J, Miller E, Tsimikas S.(70).
c. . Cardiovascular diseases
In the review of the experimental and clinical studies confirm that the ancient experience with beneficial effects of garlic holds validity even in prevention of cardiovascular disorders and other metabolic ills, indicated that Garlic-derived organic polysulfides are converted by erythrocytes into hydrogen sulfide which relaxes vascular smooth muscle, induces vasodilation of blood vessels, and significantly reduces blood pressure. There are data on potential ability of garlic to inhibit the rate of progression of coronary calcification. Garlic as a dietary component appears to hold promise to reduce the risk of cardiovascular disease (Fig. 2, Ref. 46), according to "Garlic (Allium sativum L.) and cardiovascular diseases" by Ginter E, Simko V.(71)
C. In traditional Chinese medicine
1. Ligusticum chuanxiong Hort., Dalbergia odorifera T. Chen and Corydalis yanhusuo WT Wang
In the study of incorporating the chemical predictors, target predictors and network construction approaches, an integrated system of TCM has been constructed to systematically uncover the underlying action mechanisms of TCM. From three representative Chinese herbs, i.e., Ligusticum chuanxiong Hort., Dalbergia odorifera T. Chen and Corydalis yanhusuo WT Wang which have been widely used in CVD treatment, by combinational use of drug absorption, distribution, metabolism and excretion (ADME) screening and network pharmacology techniques, showed that the result provides new information on the efficiency of the Chinese herbs for the treatment of CVD and also explains one of the basic theories of TCM, i.e., "multiple herbal drugs can treat one disease". The predicted potential targets were then mapped to target-disease and target-signal pathway connections, which revealed the relationships of the active ingredients with their potential targets, diseases and signal systems. This means that for the first time, the action mechanism of these three important Chinese herbs for the treatment of CVD is uncovered, by generating and identifying both their active ingredients and novel targets specifically related to CVD, which clarifies some of the common conceptions in TCM, and thus provides clues to modernize such specific herbal medicines(72).
2. Wind dispelling and dampness removing herbs
In the study to observe the clinical efficiency and safety of Benazepril and wind dispelling and dampness removing Chinese herbs were singly or combined used in patients with stage 3 chronic kidney disease (CKD 3), and to provide effective integrative medicine methods for treatment of CKD 3, showed that
for CGN CKD 3 patients, treatment by Benazepril combined with wind dispelling and dampness removing Chinese herbs showed favorable renal protective effects. It delayed the progress of renal failure, significantly improve the overall clinical efficacy. It was an effective treatment method for CGN CKD 3 patients with good patient tolerance and less adverse reactions(73).
3. Cao Gou
Cao Gou also Known as Cardamom. The acrid, warm, aromic herb has been used in TCM to stomach pain, flatulence, belching, indigestion, vomiting, malarial disorders, etc. as it dries Dampness, warms the Middle Burner, etc., by enhancing the functions of spleen and stomach channels.
a. Blood pressure, fibrinolysis and antioxidant
In the investigation of Elettaria cardamomum (L.) Maton. (Small cardamom) fruit powder and its effects in cardiovascular desieases found that the fruit powder antioxidant significantly (p<0.05) increased by 90% at the end of 3 months and effectively reduces blood pressure, enhances fibrinolysis, according to the study of "Blood pressure lowering, fibrinolysis enhancing and antioxidant activities of cardamom (Elettaria cardamomum)" by Verma SK, Jain V, Katewa SS.(74).
b. Platelet aggregation and lipid peroxidation
In the study of cardamom extract and it effects in platelet aggregation and lipid peroxidation found that an increase in concentration of cardamom has decreased the MDA formation significantly. Hence, it may be said that aqueous extract of cardamom may have component(s), which protect platelets from aggregation and lipid peroxidation, according to the study of "Cardamom extract as inhibitor of human platelet aggregation" by Suneetha WJ, Krishnakantha TP.(75).
c. Diuretic
In the observation of and it diuretic and sedative activities effects found that cardamom exhibits gut excitatory and inhibitory effects mediated through cholinergic and Ca++ antagonist mechanisms respectively and lowers BP via combination of both pathways. The diuretic and sedative effects may offer added value in its use in hypertension and epilepsy, according to the study of "Gut modulatory, blood pressure lowering, diuretic and sedative activities of cardamom" by Gilani AH, Jabeen Q, Khan AU, Shah AJ.(76).
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