Primary Arterial Hypertension Research Articles

Primary Pulmonary Arterial Hypertension Presenting as Diffuse Micronodules on CT

Primary pulmonary arterial hypertension is a rare lethal disease that typically presents radiographically with enlarged central pulmonary arteries, pruning of the peripheral vasculature, and cardiomegaly but clear lung fields. Although it is a disease of unknown etiology, primary PAH has been associated with anorexigen use. We present a case of pulmonary arterial hypertension in a woman with a history of fenfluramine and phentermine use who presented with diffuse micronodules on computed tomography scan. Lung biopsy confirmed the micronodules were radiographic manifestations of extensive diffuse plexogenic arterial lesions. This report represents an unusual radiographic presentation of anorexigen related pulmonary arterial hypertension, and to our knowledge, the first case reported as presenting with diffuse micronodules on high resolution computed tomography scan.

Overview of treprostinil sodium for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension is a life-threatening disorder that refers to a group of diseases characterized by an abnormal elevation of the blood pressure within the pulmonary circulation due to a vasculopathy of the pulmonary microcirculation (1). If left untreated, the overall prognosis of pulmonary arterial hypertension is poor, with a 5-year survival rate of 34%. The most common cause of death is progressive right-sided heart failure (2). There is no pharmacologic cure for pulmonary arterial hypertension, and a team approach is required for the proper care of these patients (3). Treatment is directed at improving clinical symptoms, increasing exercise tolerance and extending survival. Until just a few years ago, standard treatment options for the treatment of pulmonary arterial hypertension were limited and included coumarin derivatives, calcium channel blockers, diuretics, digoxin and oxygen supplementation (4). In the last decade, the therapeutic options for pulmonary arterial hypertension have made considerable advances. In at least three major randomized controlled trials, the continuous intravenous infusion of epoprostenol, a synthetic salt of prostacyclin with potent vasodilatory ability, has been shown to improve exercise tolerance, hemodynamics, survival and quality of life in patients with New York Heart Association (NYHA) functional classes III and IV with either primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma (5-9). Epoprostenol has now become a mainstay therapy in the long-term treatment of primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma. Nevertheless, epoprostenol is far from an ideal form of therapy. Issues such as the short half-life of the drug, need for continuous central intravenous access and significant side effects have led to the development of more stable prostacyclin analogues as alternative therapies for primary pulmonary hypertension. These alternative therapies include iloprost (inhaled delivery) and treprostinil (subcutaneous delivery). As a result, the Food and Drug Administration (FDA) recently approved treprostinil for the treatment of pulmonary arterial hypertension in patients with NYHA classes II-IV. This review will offer a discussion of the basic pharmacology of treprostinil, its similarities to and differences from epoprostenol, the animal studies as well as the initial investigational studies leading to its FDA approval, and clinical uses of the drug alone or in combination with newer therapies directed at pulmonary arterial hypertension developed over the last decade.

Primary Pulmonary Arterial Hypertension Presenting as Diffuse Micronodules on CT

Primary Pulmonary Arterial Hypertension Presenting as Diffuse Micronodules on CT

Long-term survival comparison in patients with primary and secondary pulmonary arterial hypertension treated with chronic epoprostenol therapy

Long-term survival comparison in patients with primary and secondary pulmonary arterial hypertension treated with chronic epoprostenol therapy

Increased neutrophil mediator release in patients with pulmonary hypertension--suppression by inhaled iloprost.

Polymorphonuclear neutrophils (PMN) have been implicated in various vascular inflammatory processes. We isolated PMN from venous blood samples of 10 patients with severe primary pulmonary arterial hypertension (PPH), 7 patients with pulmonary hypertension secondary to chronic thromboembolism (CTEPH), and 12 healthy controls. When stimulated with the calcium-ionophore A23187, platelet activating factor (PAF) or the microbial agent n-formyl-Methionyl-Leucyl-Phenylalanine (fMLP), significantly increased release of elastase and superoxide anion was noted in both groups with pulmonary hypertension. Moreover, the neutrophils of CTEPH patients responded with an enhanced liberation of leukotriene (LT) B(4) and 5-hydroxyeicosatetraenoic acid (5-HETE). Inhalation of aerosolized iloprost (5 microg) caused a rapid decline in pulmonary vascular resistance, in both PPH and CTEPH. This hemodynamic response was paralleled by a significant suppression of ionophore- and ligand-induced elastase and superoxide release, as well as LTB(4) and 5-HETE formation. The neutrophil inhibitory effect of the inhalation maneuver was fully reproduced by in vitro incubation of neutrophils with 1-10 pg/ml iloprost for 2 hours. This is the first study to demonstrate that circulating neutrophils from patients with PPH and CTEPH possess an enhanced readiness to respond with inflammatory mediator generation to different stimulatory agents ex-vivo, and that PMN respiratory burst, elastase secretion and leukotriene generation are promptly reduced by an iloprost inhalation maneuver. Neutrophils might participate in the inflammatory processes in pulmonary arterial hypertension.

Laparoscopic Management of Primary Hyperaldosteronism: Clinical Experience with 212 Cases

Laparoscopy is now widely used to remove benign adrenal tumors. We assessed the value of transperitoneal partial or total adrenalectomy for primary hyperaldosteronism. From September 1994 to October 2001, 212 consecutive patients with a mean age of 48 years who presented with primary hyperaldosteronism and related arterial hypertension underwent transperitoneal laparoscopic adrenalectomy (193) or tumor enucleation (20) performed by a single surgeon, including 1 who underwent bilateral adrenalectomy. In all cases preoperatively high plasma and urine aldosterone was associated with low plasma renin and hypokalemia. Mean followup was 44 months. Conversion to open surgery was necessary in 30 patients (14%) due to bleeding or adhesion and a procedure duration of greater than 3 hours. Mean operative time was 102 minutes (range 30 to 260). Six patients (2.8%) required blood transfusion. No deaths occurred. Postoperatively complications were observed in 10% of patients and the most frequent one was electrical myocardial ischemia without infarction. Mean postoperative pain medication was 17 mg. morphine sulfate equivalents (range 0 to 60). Mean and median hospital stay was 3.6 and 2.9 days, respectively (range 2 to 20). Postoperatively blood pressure was normal in 58% of patients without any drug, while treatment was decreased in the remainder. Kalemia was normalized in all cases. Although some complications can occur, mostly at the beginning of the learning curve, laparoscopic transperitoneal adrenalectomy is effective treatment for primary hyperaldosteronism.

Electrocardiography to Define Clinical Status in Primary Pulmonary Hypertension and Pulmonary Arterial Hypertension Secondary to Collagen Vascular Disease

To determine the utility of the ECG for predicting clinical status in adults with primary pulmonary hypertension (PPH) or pulmonary arterial hypertension (PAH) secondary to collagen vascular disease. Retrospective study. Outpatient clinic in a tertiary referral center. Adult outpatients with PPH or PAH secondary to collagen vascular disease who underwent electrocardiography within 30 days of undergoing right-heart catheterization, echocardiography, and 6-min walk testing. None. The following measurements were recorded from each ECG: P-wave amplitude in lead II; mean frontal QRS axis; QRS duration; R-wave and S-wave deflections in leads I and V6; and the T-wave configurations in the precordial leads. These ECG variables were correlated with hemodynamic variables, RV size, and exercise capacity. Of the 61 patients included in this study, 56 (92%) were women. Eight of 61 patients (13%) had normal findings on ECGs. There was no significant difference in the demographics or hemodynamics when comparing groups with normal vs abnormal ECGs. All ECG parameters had no more than moderate correlation with hemodynamic variables, ventricular size measured by echocardiogram, and exercise capacity as measured by a 6-min walk. The best correlation was between mean the frontal QRS axis and cardiac index (r = -0.46). The ECG is an inadequate screening tool to rule out the presence of clinically relevant pulmonary hypertension, either primary or secondary to collagen vascular disease. The mean frontal QRS axis correlated best with the severity of hemodynamic impairment.

Renovascular and renal parenchymal arterial hypertension: clinical considerations

Parenchymal renal disease (PRD) is the main cause of secondary arterial hypertension (AH) and renovascular (RV) AH is the leading cause of potentially curable hypertension. On the other hand, primary AH is frequently responsible for progressive renal disease, as well as damages in other target organs. When hypertension develops as a result of renal disease, it is the predominant risk factor for accelerated loss of renal function. In Venezuela, the prevalence of AH has been estimated between 8.1% and 23.58% in the general population, but the prevalence of secondary AH due to PRD or RV disease is not known. In this review article that has been made in view of the importance of the subject, we present some clinical and epidemiological considerations about these two forms of AH, based upon current bibliographic data in the field and also in some experience that we have acquired from the management of in-patients with such pathologies, who were attended in a public hospital in Venezuela in the last 20 years.

Determination of Prostacyclin in Plasma through a Bioluminescent Immunoassay for 6-Keto-prostaglandin F1α: Implication of Dosage in Patients with Primary Pulmonary Hypertension

This work describes a solid-phase immunoassay for 6-keto-prostaglandin F1alpha, the stable hydrolysis product of prostacyclin (prostaglandin I2). Prostacyclin, a potent vasodilator with antiplatelet and antiproliferative properties is an effective treatment for primary pulmonary hypertension and pulmonary arterial hypertension associated with scleroderma and scleroderma-like syndrome. Levels of 6-keto-prostaglandin F1alpha can be directly correlated with levels of prostacyclin. Therefore, 6-keto-prostaglandin F1alpha, has become the indicator of choice to measure prostacyclin levels. The single-step immunoassay for 6-keto-prostaglandin F1alpha reported here was developed using the bioluminescent protein aequorin as a label. Analyte-label conjugates were constructed by linking the carboxyl group of 6-keto-prostaglandin F1alpha and lysine residues of aequorin by chemical conjugation methods. The binding properties of 6-keto-prostaglandin F1alpha toward its antibody and the bioluminescent properties of aequorin were retained in the conjugate, which was then used to generate a dose-response curve for the analyte in a convenient microtiter plate format. The concentration of 6-keto-prostaglandin F1alpha after extraction from plasma showed good correlation with the concentration of 6-ketoprostaglandin F1alpha obtained without prior extraction of the same plasma sample. This measurement demonstrated that the assay allows the measurement of 6-keto-prostaglandin F1alpha directly in plasma without any pretreatment of the samples, which results in a much simpler method with a faster assay time.

Recent advances in pulmonary vascular disease.

There have been remarkable advances in our understanding of the pathobiology of pulmonary hypertension. A region on chromosome 2 encoding bone morphogenetic receptor type 2 has been identified to underlie familial and many cases of sporadic primary pulmonary arterial hypertension. The vasoactive mediators, discovered and defined by vascular biologists, have been translated into promising treatments of human disease. Prostacyclin, endothelin receptor blockers, sildenafil, and nitric oxide have been applied therapeutically to limit, and occasionally reverse, the inexorable damage to the pulmonary circulation initiated by recently identified genetic and environmental triggers of pulmonary arterial hypertension.

Homocysteinemia as a risk factor in primary arterial hypertension

Homocysteinemia as a risk factor in primary arterial hypertension

Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension.

Endothelin (ET) has been identified as playing a fundamental role in many disease processes. Therapeutic efforts at interrupting ET's pathologic effects have focused on endothelin receptor antagonists (ERAs), of which two, bosentan and sitaxsentan, have been evaluated for the treatment of both primary and secondary pulmonary arterial hypertension (PAH). We discuss the multiple actions of ET, its role in various disease states, and the effects of ET receptor stimulation and blockade. Current classification and management of PAH are reviewed, along with the promise of greatly improved treatment generated by recent and ongoing clinical trials using ERAs.

Insulin Resistance and Lipids in Hypertensive Women on Hormone Replacement Therapy

Hypertension, hyperinsulinaemia and dyslipidaemia are strong and independent risk factors for cardiovascular diseases. Their increasing frequency in postmenopausal women suggests that oestrogen deficiency may be a contributing factor. It is well known that oestrogen replacement therapy in postmenopausal women improves carbohydrate and lipid metabolism, but the effect of combined hormone replacement therapy (HRT) remains unclear. The purpose of the present study was to evaluate the effect of HRT on blood pressure, carbohydrate metabolism and lipid profile in postmenopausal women with primary arterial hypertension. The study population consisted of 76 postmenopausal women (mean age 51.1 - 6.8 years). Forty hypertensive women received HRT (17- g -oestradiol, norethisterone acetate, TTS, Estracomb Novartis), whereas 36 women remained without hormonal therapy. One-year combined transdermal HRT did not affect significantly blood pressure and blood pressure variability. HRT was shown to improve lipid profile with a significant decrease in total cholesterol as early as at 3 months. It does not influence carbohydrate metabolism parameters studied by glycaemia and insulinaemia in a standard oral glucose tolerance test. In conclusion, combined percutaneous HRT may reduce the lipid-depended cardiovascular risk in postmenopausal women with arterial hypertension.

Increased prevalence of antiphospholipid antibodies in primary and secondary pulmonary and arterial hypertension

Increased prevalence of antiphospholipid antibodies in primary and secondary pulmonary and arterial hypertension

Secondary Pulmonary Hypertension.

The diagnosis of pulmonary hypertension first requires a clinical suspicion, as symptoms are often nonspecific. After the diagnosis is made, appropriate classification into the various categories of pulmonary hypertension is essential in order to manage the patient's disease and symptoms appropriately. Therapy is targeted at the underlying cause of the pulmonary hypertension, as well as its effects on the cardiovascular system. Until recently, the treatment of both primary and secondary pulmonary arterial hypertension was limited to supportive therapy alone. With the advent of novel therapeutic agents, more focused therapies designed to treat the pulmonary vasculopathy have become available. These include pulmonary vasodilators such as continuous intravenous prostacyclin, and experimental agents currently undergoing clinical trials. For patients with pulmonary hypertension secondary to pulmonary venous hypertension, therapies differ. In cases where there is left-sided heart disease leading to pulmonary venous hypertension, treatment is aimed at repairing or ameliorating the underlying heart disease. Patients with pulmonary venous hypertension due to extrinsic compression of the central pulmonary veins, or pulmonary veno-occlusive disease have few options, and treatment is generally palliative. In patients with pulmonary hypertension that is associated with disorders of the respiratory system or hypoxemia, the pulmonary hypertension is due to a reactive pulmonary vasoconstriction. Reversal of this vasoconstriction with pulmonary vasodilators can be harmful because of the risk of increasing perfusion to nonventilated lung units. Pulmonary hypertension due to chronic thrombotic or embolic disease can be treated surgically, if the obstructive thrombi are proximal enough for the surgeon to resect them. More distal pulmonary emboli, however, cannot be resected, but there is emerging evidence that the chronic administration of pulmonary vasodilators can be effective in treating this form of the disease.

Increased Absorption of Zinc from Alimentary Tract in Primary Arterial Hypertension

Zinc absorption from the alimentary tract, as revealed by serum zinc concentration, was studied in a group of 10 patients (age 37.7+/-5.1 yr) with moderate and severe untreated primary arterial hypertension before and after a 30-d treatment with perindopril 4 mg/d. Blood pressure was 177.33+/-16.24/111.33+/-15.26 mm Hg before and 143.41+/-17.34/91.29+/-12.54 mm Hg after treatment (p < 0.05/p < 0.05). Nine persons (age 37+/-6.2 yr) with normal blood pressure (121.33+/-9.9/78+/-5.23 mm Hg) were the control group. Blood samples were taken from the ulnar vein at 8.00 AM (0 h), before taking zinc orally (one tablet of Zincas (zinc aspartate), containing 5 mg Zn2+) and at 1, 3, and 6 h after the dose. Serum zinc concentration in control and hypertensive group (before treatment) were initially 15.47+/-6.26 versus 15.99+/-5.65 (NS), 19.37+/-6.40 versus 20.83+/-4.48 (NS) after 1 h, 17.91+/-4.76 versus 31.32+/-10.49 (p < 0.003) after 3 h, and 15.32+/-5.47 versus 17.87+/-6.56 (NS) after 6 h. Maximal increase of Zn was 4.77+/-2.10 versus 17.53+/-4.13, respectively (p < 0.001). In the hypertensive group, serum Zn before and after perindopril treatment was initially 15.98+/-5.65 versus 14.81+/-3.11 (NS), 20.83+/-4.48 versus 18.17+/-2.50 (NS) after 1 h, 31.32+/-10.49 versus 22.94+/-5.80 (NS) after 3 h, 17.53+/-4.13 (p < 0.001) after 6 h. Maximal increase of Zn before treatment was 17.53+/-4.13 versus 9.17+/-4.67 (p < 0.017) after treatment. The following conclusions were reached: (1) In patients with primary arterial hypertension, an increased zinc absorption from alimentary tract was found; (2) A 30-d perindopril treatment 4 mg/d orally decreased zinc absorption in these patients.

Levels of lipoprotein (a) in pulmonary arterial hypertension.

We compared the levels of lipoprotein (a) in 48 Caucasian patients with pulmonary arterial hypertension, comprising 32 females and 16 males, aged 28.0 +/- 12.0 years, with a range from 4 through 52 years, with 48 normal Caucasian subjects matched for age and sex. Pulmonary hypertension was secondary in 41 patients with Eisenmenger's syndrome, these comprising 27 females and 14 males aged 27.0 +/- 12.0 years, with a range from 4 through 51 years, and primary in the other 7 patients, 5 females and 2 males, whose age was 30.0 +/- 14.0 years, with a range from 9 through 52 years. Lipoprotein (a) was measured using an immunoprecipitation and turbidimetric assay after a 12 hour fast. Levels of the protein, expressed as the median (% 25; % 75), were higher in those with Eisenmenger's syndrome than in normal controls (p=0.003). In addition, there was a greater prevalence of levels of lipoprotein greater than 30.0 mg/dl in those with secondary pulmonary arterial hypertension patients than in our normal population (p = 0.03). We have found no differences, however, in the levels of lipoprotein(a) in those who had primary pulmonary arterial hypertension when compared with their matched controls, albeit that the number of patients studied was small. We conclude that increased levels of lipoprotein (a) may be secondary to pulmonary arterial hypertension as a marker of tissue damage or may be genetically determined. In either way, the increase in lipoprotein (a) could be an additional factor predisposing to the vascular alterations known to occur in this disease.

Primary hemifacial spasm and arterial hypertension: a multicenter case-control study.

In a case-control study, the authors found that arterial hypertension occurred more frequently among 115 patients with primary hemifacial spasm than among 115 neurologic controls matched for age (+/-5 years), sex, and referral center. The association was not confounded by education level, smoking history, diabetes, or other diseases (adjusted OR 2.64; 95% CI 1.3 to 5.33, p = 0.007). Hypertension was significantly associated with the outcome in the left-sided group (OR 4.0; 95% CI 1.4 to 11.5), but data concerning patients with right-sided spasm were inconclusive (OR 1.05; 95% CI 0.36 to 3.1). In our sample, hypertension either preceded or followed the onset of hemifacial spasm.

Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients.

To describe the demographic, clinical, and laboratory features and natural history of patients with systemic sclerosis sine scleroderma (ssSSc), and to compare them with those of patients with SSc and limited cutaneous involvement (IcSSc). The University of Pittsburgh Scleroderma Databank served as the data source. Patients were divided into those who had no skin thickening (ssSSc) and those who had skin thickening only distal to elbows or knees and/or of the face (IcSSc) during their disease course. These two groups were compared with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. Chi-square and Student's t-test analyses were performed, and Fisher's exact test was used as appropriate. Of 555 consecutive patients without diffuse cutaneous SSc, 48 (9%) had ssSSc and 507 (91%) had IcSSc. The ssSSc patients had a mean total disease duration of 18.6 years (15.1 years before study entry and 3.5 years of followup after study entry), and had not developed IcSSc or another connective tissue disease. Other than the absence of skin thickening, the ssSSc group had no significant differences in individual internal organ involvements, laboratory features, serum autoantibody type, or survival rate compared with patients with IcSSc. Within the category of lung involvement, patients with ssSSc had a significantly greater frequency of dyspnea with mild exertion or at rest, and a tendency toward reduced carbon monoxide diffusing capacity (<70% of predicted normal) and primary pulmonary arterial hypertension. Patients with IcSSc had significantly more frequent individual manifestations of digital pitting scars, digital-tip ulcers, telangiectasia, and calcinosis than those with ssSSc, in part related to increased time of observation. Puffy fingers and finger joint contractures were detected significantly more often in IcSSc patients. Systemic sclerosis sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a distinct or separate disorder.

Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension.

The hypothesis for this study was that increased local expression of vascular angiotensin-converting enzyme (ACE) may contribute to the arterial remodelling which accompanies pulmonary hypertension, since angiotensin II (ANG II) is an important mediator of pulmonary vascular cell growth. The expression of ACE was studied by immunohistochemistry in paraffin-embedded lung sections from adults undergoing heart-lung transplantation for severe primary (n=6) and secondary (n=7) pulmonary arterial hypertension (PH), compared with age-matched controls (n=11). An antigen retrieval technique was used prior to incubating sections with the anti-ACE monoclonal antibody, CG2, or the endothelial marker, monoclonal anti-CD31. In control lungs, the highest level of ACE immunostaining was seen in the alveolar capillary endothelium, with less intense staining in small intra-acinar pulmonary arteries and relatively little staining in larger preacinar arteries. ACE immunostaining was virtually absent in lymphatics and veins. In both primary and secondary PH, there was an increase in ACE immunostaining in the endothelium of intra-acinar peripheral pulmonary arteries compared with control lungs, extending to the level of alveolar ducts, as confirmed by semi-quantitative analysis. The increase in endothelial ACE expression in the intra-acinar arteries of patients with primary and secondary PH is consistent with the hypothesis that locally increased production of ANG II may contribute to the process of pulmonary vascular remodelling.