Prognostic significance of right ventricular dysfunction in patients with acute inferior myocardial infarction and right ventricular involvement

Little is known about the influence of right ventricular (RV) dysfunction on prognosis of patients with acute inferior myocardial infarction (IMI) and RV involvement. Therefore, 99 consecutive patients (mean age 56.6 ± 3.4 years) with RV involvement during acute IMI were followed for a 12-month period to clarify the influence of acute RV dysfunction on short- and long-term survivals. Forty-one patients with IMI evolved with severe arterial hypotension due to RV dysfunction, while 58 patients had no hemodynamic impairment due to RV involvement. Basal hemodynamic data (mean ± SD) for patients with RV dysfunction were blood pressure (BP) 92/59 ± 22/20 mmHg, systemic vascular resistance (SVR) 2314 ± 252 dynes·s·cm^?5, and cardiac index (CI) 1.3 ± 0.31/min/m². Patients without RV dysfunction demonstrated BP 113/74 ± 20/16 mmHg (p≤0.05), SVR 1324 ± 354 dynes·s·cm^?5 (p≤0.01), and CI 2.6 ± 0.5 1/min/m² (p≤0.05). Angiographic differences noted were that hemodynamically compromised patients showed lower RV ejection fractions (0.27 ± 0.08) than patients without hemodynamic disturbance [0.41 ± 0.11 (p≤0.05)]; however, left ventricular ejection fractions were 0.48 ± 0.10 and 0.52 ± 0.12, respectively. Short- and long-term mortality rates were assessed during the follow-up period. Patients with hemodynamic impairment due to RV infarction had a higher mortality rate for the first month and for 11 subsequent months post MI than patients without hemodynamic impairment, that is, 24.4 vs. 6.9 and 14.6 (p≤0.05) vs. 3.4% (p≤0.05), respectively. These data suggest that decreased RV ejection fraction possibly is linked with significantly reduced short- and long-term survival in patients with RV involvement during acute IMI.     

Renal circulatory effects of adenosine in patients with chronic heart failure

Objectives. We sought to study the renal circulatory effects of adenosine in patients with chronic congestive heart failure (CHF).Background. Renal blood flow (RBF) is often reduced in patients with chronic CHF and may lead to decreased renal function. The cause of reduced RBF is multifactorial and involves systemic as well as local vasoregulatory mechanisms. Stimulation of renal adenosine A₁receptors in animal models has resulted in a significant vasoconstriction of afferent and efferent glomerular arterioles and deterioration of renal function. Although adenosine serum levels have been shown to be elevated in patients with CHF, their effect on the renal circulation in this patient population has not been studied.Methods. Nine patients with CHF from left ventricular systolic dysfunction were studied. The effects of adenosine at a dose of 10⁻⁵mol/liter infused directly into the main renal artery on heart rate, renal artery blood pressure, renal artery cross-sectional area (measured by intravascular ultrasound), renal Doppler blood flow velocity (measured by a Doppler flow wire in the renal artery), RBF and renal vascular resistance (RVR) were evaluated.Results. Infusion of adenosine resulted in no significant effect on heart rate or renal artery blood pressure but caused a substantial increase in RVR (11,204 ± 1,469 to 31,494 ± 3,911 dynes·s·cm⁻⁵, p = 0.0005), which led to a marked fall in RBF in every patient (mean values 376 ± 36 to 146 ± 22 ml/m², p = 0.0002). These changes in RVR and RBF were associated with no significant change in renal artery cross-sectional area (0.389 ± 0.040 to 0.375 ± 0.033 cm², p = 0.3).Conclusions. Stimulation of renal adenosine receptors in patients with CHF results in marked renal vasoconstriction that leads to an important reduction in RBF. Lack of change in renal artery cross-sectional area suggests that adenosine affects intrarenal resistance blood vessels rather than large conductance vessels. These results may indicate a rationale for investigation of renal adenosine receptor blockade for enhancement of RBF and improvement of renal function in patients with chronic CHF.     

Afterload reduction with nifedipine in aortic insufficiency

The acute hemodynamic effects of nifedipine were assessed In 12 patients with severe isolated aortic Insufficiency during control conditions and 30 minutes after administration of nifedipine (20 mg sublingually). Left ventricular end-diastollc pressure decreased from 19 ± 8 (mean ± standard deviation) to 9 ± 5 mm Hg (probability [p] < 0.0001), mean aortic pressure from 98 ± 12 to 80 ± 9 mm Hg (p < 0.0001), systemic vascular resistance from 1,135 ± 280 to 794 ± 176 dynes·s·cm^?5 (p < 0.0002) and rate-pressure product from 11,732 ± 1,727 to 10,022 ± 1,103 mm Hg⁺ beats/min (p < 0.01). Forward cardiac index increased by 24 percent, from 3.8 ± 1.1 to 4.4 ± 0.8 liters/min per m² (p < 0.04). Left ventricular end-diastolic volume, ejection fraction and total stroke work index did not change significantly. Regurgitant fraction, measured in five patients, changed parallel with systemic vascular resistance. Left ventricular function was maintained while both preload and afterload were decreased. Regurgitant flow was moderated and myocardial oxygen demand decreased. This hemodynamically favorable condition, due to nifedlpine, is clinically important and suggests the need for further therapeutic trials.     

Acute and chronic effects of nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis

Eleven patients with histologically confirmed fibrosis of the lung were investigated for the effects of the dihydropyridine calcium antagonist nitrendipine on pulmonary hemodynamics. After 5 mg of acute sublingual nitrendipine, mean pulmonary artery pressure was significantly lowered (p≤0.05) from 32 ± 3 to 29 ± 3 mmHg at rest, and significantly lowered (p≤0.05) during exercise from 55 ± 4 to 49 ± 4 mmHg. Short-term oxygen application at rest significantly reduced this parameter to 28 ± 3 mmHg(p≤0.01). Nitrendipine lowered total pulmonary vascular resistance during both rest (from 412 ± 50 to 351 ± 49 dyn?S?cm^-5; p≤0.05) and exercise (from 433 ± 61 to 383 ± 54 dyn?s?cm^-5; p≤0.05), although it did not affect pulmonary arteriolar resistance. Also, oxygen treatment at rest influenced only total pulmonary vascular resistance (reduction from 412 ± 50 to 373 ± 48 dyn?s?cm^-5; p≤0.01), but not pulmonary arteriolar resistance. Pressure-flow curves, which were derived from cardiac output at rest and during exercise and from the corresponding gradient between mean pulmonary artery pressure and pulmonary capillary wedge pressure, remained unchanged by acute medication. Since a change in arterial oxygen partial pressure was not noticed after nitrendipine, arteriovenous shunting or a worsening of ventilation perfusion relationships can be excluded. Long-term (3 weeks) treatment (double-blind parallel design) with 10 mg of nitrendipine (4 patients) once daily showed no advantage in comparison to placebo (6 patients). From these observations we conclude that the reduction of lower circulatory pressures after nitrendipine is not caused by pulmonary arteriolar vasodilation, but rather by indirect effects due to the reduction of total peripheral resistance and left ventricular filling pressure.     

Favorable effects of hydralazine on the hemodynamic response to isometric exercise in chronic severe aortic regurgitation

The hemodynamic effects of isometric exercise and the response to hydralazine therapy were evaluated in 11 patients with chronic, severe aortic regurgitation (AR). Isometric exercise produced a significant increase in heart rate (from 78 ± 11 to 93 ± 19 beats/min [mean ± standard deviation], p < 0.05), mean blood pressure (from 83 ± 8 to 104 ± 20 mm Hg, p < 0.05), mean right atrial pressure (from 3 ± 2 to 7 ± 5 mm Hg, p < 0.05) and mean pulmonary artery wedge pressure (from 12 ± 7 to 18 ± 10 mm Hg, p < 0.05). Small and insignificant changes were seen in cardiac index (from 3.4 ± 0.8 to 3.9 ± 1.0 liters/min/m²), systemic vascular resistance (from 1,097 ± 257 to 1,171 ± 284 dynes s cm^?5), pulmonary vascular resistance (from 120 ± 76 to 130 ± 89 dynes s cm^?5) and stroke volume index (from 44 ± 10 to 43 ± 12 ml/m²). After oral hydralazine administration (100 to 300 mg), hemodynamic values during isometric exercise were: Heart rate increased further, to 105 ± 14 beats/min (p < 0.05), mean blood pressure was 102 ± 16 mm Hg (difference not significant [NS]) cardiac index increased markedly, to 5.2 ± 1.4 liters/min/m² (p < 0.05), stroke volume index increased to 49 ± 12 ml/m² (p < 0.05), right atrial pressure decreased slightly, to 5 ± 5 mm Hg (NS), pulmonary artery wedge pressure decreased to 14 ± 7 mm Hg (p < 0.05), systemic vascular resistance decreased to 903 ± 288 dynes s cm^?5 (p < 0.05), and pulmonary vascular resistance changed to 100 ± 66 dynes s crrr^?5 (NS). Thus, isometric exercise in patients with chronic severe AR is associated with only a slight and insignificant increase in systemic vascular resistance, but a marked increase in pulmonary artery wedge pressure. Direct arteriolar vasodilation with hydralazine results in a significant attenuation of pulmonary artery wedge pressure increase during isometric exercise and leads concomitantly to a significant augmentation of stroke volume and cardiac output. These findings substantiate the value of hydralazine therapy in patients with chronic, severe AR.     

Hemodynamic effects of supplemental oxygen administration in congestive heart failure

Objectives. This study sought to determine the hemodynamic effects of oxygen therapy in heart failure.Background. High dose oxygen has detrimental hemodynamic effects in normal subjects, yet oxygen is a common therapy for heart failure. Whether oxygen alters hemodynamic variables in heart failure is unknown.Methods. We studied 10 patients with New York Heart Association functional class III and IV congestive heart failure who inhaled room air and 100% oxygen for 20 min. Variables measured included cardiac output, stroke volume, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance, mean arterial pressure and heart rate. Graded oxygen concentrations were also studied (room air, 24%, 40% and 100% oxygen, respectively; n = 7). In five separate patients, muscle sympathetic nerve activity and ventilation were measured during 100% oxygen.Results. The 100% oxygen reduced cardiac output (from 3.7 ± 0.3 to 3.1 ± 0.4 liters/min [mean ± SE], p < 0.01) and stroke volume (from 46 ± 4 to 38 ± 5 ml/beat per min, p < 0.01) and increased pulmonary capillary wedge pressure (from 25 ± 2 to 29 ± 3 mm Hg, p < 0.05) and systemic vascular resistance (from 1,628 ± 154 to 2,203 ± 199 dynes's/cm⁵, p < 0.01). Graded oxygen led to a progressive decline in cardiac output (one-way analysis of variance, p < 0.0001) and stroke volume (p < 0.017) and an increase in systemic vascular resistance (p < 0.005). The 100% oxygen did not alter sympathetic activity or ventilation.Conclusions. In heart failure, oxygen has a detrimental effect on cardiac output, stroke volume, pulmonary capillary wedge pressure and systemic vascular resistance. These changes are independent of sympathetic activity and ventilation.     

Vasodilatory effect of aerosol histamine during pulmonary vasoconstriction in unanesthetized sheep

The effects of aerosol histamine on pulmonary vascular resistance during pulmonary vasoconstriction were studied in 12 unanesthetized sheep. Sheep were chronically instrumented with Silastic catheters in the pulmonary artery and left atrium, thermodilution Swan-Ganz catheter in the main pulmonary artery for measurement of cardiac output, and tracheostomy for delivery of hypoxic gas and/or aerosol histamine. Seven minutes of isocapnic hypoxia (Fl_O2 = 0.12) caused pulmonary artery pressure (P_PA) to increase from 17.2 ± 0.4 to 27.0 ± 1.0 cm H₂O (X¯ ± SEM, P < 0.05) and pulmonary vascular resistance (PVR) to increase from 3.94 ± 0.33 to 4.71 ± 0.38 cm H₂O · L^?1. min (P < 0.05). When sheep breathed a combination of aerosol histamine (5 mg/ml) and 12% O₂, P_PA rose only to 21.3 ± 1.11 cm H₂O and PVR decreased to 3.51 ± 0.31 cm H₂O · L^?1. min. This was a significantly (P < 0.05) smaller response compared to hypoxia alone. Aerosol histamine alone had no significant effect on P_PA or PVR. Meclofenamate did not restore the histamine-induced loss of hypoxic vasoconstriction. Aerosol histamine significantly blunted the pulmonary vasoconstriction caused by intravenous serotonin (8 μg/kg/min) and intravenous prostaglandin H₂-analog (0.74 μg/kg/min). It was concluded that in the awake sheep aerosol histamine acted as a pulmonary vasodilator only in the presence of pulmonary vasoconstriction. Pediatr Pulmonol 1987; 3:94–100 .     

Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: Role of endothelium-derived nitric oxide

Objectives. This study was undertaken to investigate the role of endothelium-derived nitric oxide in the regulation of forearm blood flow during exercise in normal subjects and patients with congestive heart failure.Background. Nitric oxide-mediated vasodilation in response to muscarinic stimulation is impaired in the peripheral circulation of patients with congestive heart failure. Whether nitric oxide-mediated vasodilation during exercise is also impaired in patients with congestive heart failure is unknown.Methods. Forearm blood flows (ml/min per 100 ml) were determined during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction by venous occlusion plethysmography before and after regional inhibition of nitric oxide synthesis with administration of L-N^G-monomethylarginine (L-NMMA) in the brachial artery of 17 patients with congestive heart failure (mean age 49 years, mean left ventricular ejection fraction 0.22) and 10 age-matched normal subjects.Results. Before administration of L-NMMA in the brachial artery, forearm blood flows in patients with congestive heart failure during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction were slightly but not significantly lower than that of normal subjects ([mean ± SE] 6.8 ± 1.0, 8.5 ± 1.0 and 12.9 ± 1.7 ml/min per 100 ml, respectively, in patients with congestive heart failure vs. 6.6 ± 1.2, 11.6 ± 1.9 and 16.2 ± 1.9 ml/min per 100 ml, respectively, in normal subjects, p = NS). After administration of L-NMMA in the brachial artery, forearm blood flows in normal subjects significantly decreased by 10% to 21% during hand grip exercise but did not change during exercise in patients with congestive heart failure.Conclusions. Regional inhibition of nitric oxide synthase with administration of L-NMMA in the brachial artery significantly decreased forearm blood flows during rhythmic hand grip exercise in normal subjects but not in patients with congestive heart failure. These findings suggest that nitric oxide-mediated vasodilation during submaximal exercise is impaired in the forearm circulation of patients with congestive heart failure.     

Nitric oxide production in arterial vessels of cirrhotic rats

Indirect evidence exists implicating vascular nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. In the current study, a coincubation assay to estimate the vascular nitric oxide production was developed and the nitric oxide production by arterial segments of cirrhotic and control rats was assessed. In the assay, measurement of reporter monolayer cell-associated cGMP levels allows the influence of nitric oxide released by arterial segments to be determined. RFL-6 cells served as reporter cells. Nitric oxide production was determined in thoracic aorta and mesenteric arteries of 22 control rats, 10 cirrhotic rats without ascites, and 12 cirrhotic rats with ascites. Basal and bradykinin-stimulated (10⁻⁶ mol/L) intracellular content of nitric oxide-dependent cGMP was significantly higher in RFL-6 cells coincubated with aortic segments of cirrhotic rats with (21.3 ± 3.6 pmol/10⁵ cells, P < .05 and 44.7 ± 7.0 pmol/10⁵cells, P < .025) and without ascites (15.3 ± 3.0 pmol/10⁵cells, P < .05 and 43.2 ± 7.6 pmol/10⁵cells, P < .05) than in those incubated with aortic segments of control rats (9.7 ±1.3 and 19.5 ± 2.5 pmol/10⁵cells). RFL-6 cells exposed to bradykinin-stimulated mesenteric arterial segments of cirrhotic rats also showed increased cGMP content (ascitic: 2.73 ± 0.31 pmol/10⁵cells, P < .005; nonascitic: 2.58 ± 0.51 pmol/10⁵cells, P < .025) compared with cells exposed to control mesenteric arterial segments (1.28 ± 0.15 pmol/10⁵cells). No differences between cirrhotic and control vessels were observed after endothelium denudation. These results indicate that basal and bradykinin-stimulated vascular nitric oxide production is higher in cirrhotic rats with and without ascites than in control rats in and that the endothelial lining is the site where vascular L-arginine nitric oxide pathway activation takes place in experimental cirrhosis.     

Systemic and pulmonary hemodynamics in patients with non-cirrhotic portal fibrosis (NCPF) is similar to compensated cirrhosis

Background Non-cirrhotic portal fibrosis (NCPF) is an important cause of portal hypertension (PHT) and variceal bleeding, especially in the developing countries. While the hepatic parenchyma and liver functions are normal, the patho-anatomic defect in these patients is pre- and peri-sinusoidal in nature. Aim To study the systemic and pulmonary hemodynamic alterations in patients with NCPF and compare them with compensated cirrhotic patients. Patients and Methods Patients with NCPF (n = 20, mean age 29.3 ± 9.8 year) and matched Child’s A cirrhotic patients (n = 17, age 34.1 ± 9.8 year) who had bled in the past, underwent hemodynamic measurements using a balloon tipped catheter. Results In NCPF patients, the hepatic venous pressure gradient (HVPG) was significantly lower than in the cirrhotic patients (4.9 ± 1.5 mmHg vs. 15.7 ± 4.5 mmHg; P < 0.01). NCPF patients had hyperdynamic circulation and peripheral vasodilatation comparable to cirrhotic patients; cardiac output (8.0 ± 1.2 l/min vs. 8.4 ± 1.9 l/min; P = 0.4), cardiac index (5.4 ± 0.8 l/min/m² vs. 5.5 ± 1.9 l/min/m²; P = 0.86), mean arterial pressure (88.2 ± 14.1 mmHg vs. 89.9 ± 17.3 mmHg; P = 0.73), systemic vascular resistance (852.8 ± 204.3 dynes · s/cm⁵ vs. 854.1 ± 189.9 dynes · s/cm⁵; P = 0.98) and pulmonary vascular resistance (41.6 ± 18.1 dynes · s/cm⁵ vs. 41.3 ± 17.9 dynes · s/cm⁵; P = 0.95) were comparable in the two groups. Conclusions NCPF associated portal hypertension leads to a hyperdynamic state with high cardiac index and low systemic and pulmonary vascular resistance comparable to compensated cirrhosis. These novel observations suggest a primary role of portal hypertension in the development of hyperdynamic state.     

Coronary hemodynamic effects of angiotensin inhibition by captopril and teprotide in patients with congestive heart failure

The coronary hemodynamic effects of vasodilator therapy with angiotensin-converting enzyme inhibitors (captopril arid teprotide) were studied in 11 patients with ischemic heart disease and severe congestive heart failure (CHF). Over 2 hours, systemic vascular resistance was reduced from 2,408 ± 240 to 1,715 ± 170 dynes·s·cm^?5 (p < 0.001), and cardiac output improved 18%, resulting in lower arterial pressure (101 ± 8 to 86 ± 5 mm Hg, p < 0.001) and left ventricular filling pressure (30 ± 2 to 21 ± 2 mm Hg, p < 0.001). Coronary sinus thermodilution blood flow parallelled perfusion pressure but did not significantly vary overall (160 ± 20 to 133 ± 12 ml/min, difference not significant [NS]). Coronary vascular resistance was unchanged. Although the left ventricular stroke work index rose slightly (37.7 ± 8.8 to 41.3 ± 7.9 g·m/m², p < 0.05), there was no change in the coronary arteriovenous oxygen content difference (10.8 ± 1.0 to 10.4 ± 1.0 ml/100 ml, NS) or calculated myocardial oxygen consumption (16.4 ±1.9 to 13.9 ± 1.6 ml/min, NS). The heart rate-systolic blood pressure product declined significantly during this period (8,824 ± 703 to 7,087 ± 514 beats·mm Hg, p < 0.02); this relief of cardiac effort was a function of the pretreatment plasma renin activity. A derived index of external myocardial efficiency improved 37% (19 ± 3 to 26 ± 6, p < 0.05), reflecting greater left ventricular work without increased oxygen demand.Enhancement of myocardial performance after converting enzyme inhibition appears dependent on reduction of angiotensin-mediated ventricular afterload and preload. The lack of coronary vasomotor effects in patients with advanced ischemic cardiomyopathy may reflect limited coronary vascular reserve. Improvement of heart failure in these patients developed without evidence of myocardial ischemia, since balance was maintained between oxygen supply and demand.     

Cardiopulmonary toxicity in patients with breast carcinoma during plasma perfusion over immobilized protein A: Pathophysiology of reaction and attenuating methods

Tumoricidal reactions in dogs with spontaneous breast carcinoma occur after perfusion of plasma over protein A derived from Staphylococcus aureus and immobilized in collodion charcoal. When this treatment was extended to humans with breast cancer, heniodynamic and physiologic changes were noted. The evolution and spectrum of these reactions were evaluated during 47 plasma infusions in five patients. Initial treatment conditions consisting of rapid perfusion of plasma over high quantities of immobilized protein A were employed for 12 treatments in two patients. Within 30 minutes after treatments were begun, mean blood pressure, systemic vascular resistance, and stroke volume increased, as did heart rate, cardiac output, and rectal temperature; however, mean pulmonary artery pressure and total pulmonary resistance did not change. At 90 minutes, hypotension developed (lowest mean blood pressure was 59 ± 14 mm Hg) that was associated with a decrease in systemic vascular resistance and total pulmonary resistance (536 ± 66 and 146 ± 44 dynes·second·cm^?5, respectively). Cardiac output increased, tachycardia developed, stroke volume decreased, and rectal temperature increased. During the hypotensive phase, values of creatinine clearance and fractional excretion of sodium diminished. Noncardiogenic pulmonary edema appeared occasionally, with bronchospasm noted once. No hemodynamic changes were seen when saline solution was passaged over protein A immobilized in collodion charcoal or when autologous plasma was given without passage over protein A immobilized in collodion charcoal. Treatment conditions were modified by diminishing protein A quantity and plasma volume and slowing plasma perfusion rate, which resulted in significant attenuation of all cardiopulmonary responses. This report, then, defines for the first time the physiologic basis of the cardiopulmonary toxicity in humans after plasma perfusion over immobilized protein A.     

Augmentation of right ventricular performance in chronic obstructive pulmonary disease by terbutaline: A combined radionuclide and hemodynamic study

The acute hemodynamic and functional effects of the relatively selective beta₂ adrenoreceptor agonist, terbutaline, was evaluated in a well defined group of eight patients with chronic obstructive pulmonary disease, abnormal right ventricular performance and elevated pulmonary vascular resistance. Radionuclide and hemodynamic data were obtained simultaneously using first pass radionuclide angiocardiography and thermodilution pulmonary arterial catheterization. Terbutaline caused no change in right ventricular end-diastolic volume index but increased right ventricular stroke work index from 13 ±5 to 16 ± 6 g · m/m² (mean ± standard deviation; p < 0.025). Furthermore, pulmonary vascular resistance index decreased in all patients and for the group decreased from 623 ± 279 to 407 ± 204 dynes · s · cm^?5 · m² (p < 0.05). The extent of this decrease correlated linearly with the level of resting pulmonary vascular resistance (r = 0.76). Right ventricular ejection fraction increased significantly from 35 ± 10 to 46 ± 5 percent; terbutaline resulted in normalization (to greater than 45 percent) of the ejection fraction in five of the eight patients. The changes in right ventricular ejection fraction were greatest in patients with the highest level of pulmonary vascular resistance and the lowest baseline ejection fraction. Left ventricular ejection fraction also increased significantly from 62 ± 10 to 71 ± 10 percent; however, there was no correlation between the change in this variable and either systemic vascular resistance or baseline left ventricular ejection fraction. Systemic oxygen delivery increased from 45 ± 16 to 63 ± 19 ml/min per m² (p < 0.005) without any change in arterial oxygen tension. This study demonstrates that terbutaline results in substantial augmentation of right ventricular performance. This effect appears to be mediated predominantly through alterations in pulmonary vascular resistance. Terbutaline may provide significant cardiac benefits in addition to its salutory effects on the tracheobronchial tree.     

Effects of acute and chronic minoxidil administration on rest and exercise hemodynamics and clinical status in patients with severe,chronic heart failure

The effects of acute and chronic oral administration of the vasodilator minoxidil on hemodynamics, oxygen consumption, exercise performance and clinical status were investigated in 10 patients with severe, chronic heart failure refractory to digitalis and diuretic therapy. The cardiac index was 1.99 ±0.38 liters/min/m² at rest and 2.88 ± 0.79 at symptom-limited maximal exercise on conventional therapy, compared with 2.64 ± 0.33 liters/min/m² at rest and 3.55 ± 0.84 at maximal exercise after short-term minoxidil administration (p < 0.02, control versus minoxidil at both rest and exercise). Stroke volume was increased after minoxidil treatment, without significant effect on heart rate. Systemic vascular resistance was decreased by minoxidil from 2,050 ± 722 to 1,325 ± 374 dynes-s/cm^?5 at rest and from 1,500 ± 830 to 1,206 ± 589 dynes· s/cm^?5 at maximal exercise (p = 0.01, control versus minoxidil). No significant effect was observed on left ventricular filling, right atrial, or mean pulmonary arterial pressure, but pulmonary vascular resistance decreased both at rest and on exercise (p < 0.05). Maximal exercise oxygen consumption increased from 8.9 ± 3.2 ml/kg/min on conventional therapy to 10.5 ± 2.4 on minoxidil therapy (p < 0.03), median maximal exercise work load increased from 25 to 50 W and median exercise duration increased from 6.0 to 9.0 minutes. On chronic minoxidil administration all 5 patients who completed a scheduled 6 week follow-up showed symptomatic improvement. However, worsening edema developed in all patients, requiring increased diuretic dosage and close supervision. Symptoms of ischemic heart disease worsened in 2 of 10 patients. We tentatively conclude that minoxidil may be a useful vasoactive agent in the pharmacologic therapy of severe chronic heart failure.     

Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction

The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD₄ boluses on the pulmonary circulation in 6 anesthetized dogs. LTD₄, 1 μg/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41±17% (SD), left atrial pressure rose 3.5±1.5 mmHg, and cardiac output fell 18±8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF₆ infusion, was 25±7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O₂ inhalation, averaged +10.5±3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4±1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26±4%; p=0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9±2.8 mmHg; p<0.05; the increase in PVR was +1.8±1.2 mmHg/L/min, p<0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5±8.1% before and 27.0±7.4% after RG 5901 (p>0.05). The pressor response to hypoxia was + 8.9±2.1 mmHg before and +8.7±3.7 mmHg after RG 5901 (p>0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.     

Interaction between cholinergic and nitrergic vasodilation: a novel mechanism of blood pressure control

OBJECTIVE: Cholinergic vasodilation has been thought to play little if any role in the regulation of blood pressure in humans. Autonomic denervation potentiates the vasoconstriction evoked by nitric oxide synthase inhibition in humans, but the mechanism is unclear. We hypothesized that this may be related to loss of neuronal, non-nitric-oxide-dependent vasodilation. METHODS: To test this hypothesis, we examined effects of cholinergic blockade on blood pressure, heart rate and peripheral vascular responses to systemic infusion of the nitric-oxide-dependent vasoconstrictor L-NMMA (0.5 mg/kg/min over 15 min) in eight normal subjects. RESULTS: The L-NMMA-induced increase in mean (+/-S.E.) arterial pressure was roughly three times larger (P=0.002) in the presence than in the absence of cholinergic blockade (38+/-6 vs. 13+/-2 mmHg). Similarly, the increase in systemic and calf vascular resistance was more than twofold larger during L-NMMA-atropine. This potentiation was specific for nitric-oxide-dependent vasoconstriction, because atropine did not alter the responses to phenylephrine infusion. Cholinergic blockade also altered (P=0.004) the heart rate response to nitric oxide synthase inhibition; during L-NMMA alone heart rate decreased by 10+/-2 beats/min, whereas during L-NMMA-atropine infusion it increased by 14+/-4 beats/min. CONCLUSION: Cholinergic mechanisms play an important hitherto unrecognized role in offsetting the hypertension and cardiac sympathetic activation caused by nitric oxide synthase inhibition in humans. Decreased parasympathetic activity and impaired nitric oxide synthesis characterize several cardiovascular disease states, as well as normal aging. The conjunction of these two defects could trigger sudden death and contribute to the hypertension of the elderly.     

Renal and Hormonal Effects of Systemic Nitric Oxide Inhibition in Patients With Congestive Heart Failure and in Healthy Control Subjects

BackgroundThe significance of basal renal nitric oxide (NO) availability in the regulation of renal perfusion and sodium excretion in human congestive heart failure (CHF) has not been described previously.Methods and ResultsWe studied the effects of acute systemic NO synthesis inhibition with N^G-monomethyl-L-arginine (L-NMMA) in 12 patients with CHF and 10 healthy control subjects (CON) in a randomized placebo-controlled study. Effect parameters were renal plasma flow (RPF), renal vascular resistance (RVR), glomerular filtration rate (GFR), urine sodium excretion and plasma levels of vasoactive hormones. L-NMMA was associated with a significant decrease in RPF (CON-LNMMA: ?13 ± 3% [P = .014]; CHF-LNMMA: ?17 ± 7% [P = .017]) and a profound increase in RVR in both CHF and CON (CON-LNMMA: +26 ± 6% [P = .009]; CHF-LNMMA: +37 ± 70% [P = .005]). Significant decreases in sodium excretion were found in both CHF-LNMMA and CON-LNMMA. Relative changes from baseline were not statistically different between CHF-LNMMA and CON-LNMMA. After L-NMMA, RPF values correlated inversely with plasma aldosterone in CHF-LNMMA (P = .01). L-NMMA induced an increase in A-type natriuretic peptide (ANP) only in CHF-LNMMA (+18 ± 8%; P = .035), which correlated significantly with basal ANP levels (P = .034).ConclusionsThere was no difference in the renal response to L-NMMA in CHF vs CON, suggesting that the impact of NO on renal perfusion and sodium excretion is maintained in stable CHF. We suggest that NO influences the release of ANP during high levels of atrial stretch in CHF.     

Intermediate follow-up of pediatric heart transplant recipients with elevated pulmonary vascular resistance index

Objectives. This study examined perioperative and intermediate outcomes in pediatric cardiac transplant recipients who had elevated pulmonary vascular resistance indexes preoperatively.Background. Elevated pulmonary vascular resistance was associated with poor outcome in previous studies and constitutes a relative contraindication to transplantation. Few studies have evaluated this poor outcome risk factor in pediatric patients.Methods. To evaluate outcomes of nonneonatal transplant recipients, records were reviewed and divided into Group I (preoperative pulmonary vascular resistance index ≥6 units·m²) and Group II (pulmonary vascular resistance index <6 units·m²). Donor/recipient weight ratios, ischemic times, length of intensive care unit stay, posttransplantation infection rates, arrhythmia, response to pretransplantation vasodilator infusions and pulmonary vascular resistance indexes at the first and most recent posttransplantation biopsies were analyzed.Results. Group I (8 patients) had a mean (±SEM) pulmonary vascular resistance index of 11.5 ± 3.5 units·m²; Group II (29 patients) had a mean pulmonary vascular resistance index of 2.3 ± 0.4 units·m²(p < 0.002). Pulmonary vascular resistance index decreased from 12.3 ± 3.9 to 3.9 ± 0.9 units·m²(p < 0.05) in 7 Group I patients undergoing vasodilator infusion during pretransplantation catheterization. Thirty-six orthotopic heart transplantations were performed and one heterotopic transplantation. Donor weights exceeded recipient weights by 13% and 31% for Groups I and II, respectively (p > 0.25). Donor ischemic time was 215 min for Group I and 225 min for Group II (p > 0.75). Intensive care unit stay was 11.5 days in Group I and 15.1 days in Group II (p = 0.20). Infection rate was 38% in both groups (p > 0.80). Arrhythmias occurred in 90% of Group I and 42% of Group II (p < 0.03) patients. Pulmonary resistance index in Group I decreased from 11.5 ± 3.5 to 3.3 ± 1.2 units·m²(p < 0.03) by the first posttransplantation biopsy and have not changed subsequently. During 2.3 years (range 0.3 to 8.5) of follow-up, the mortality rate was 25% and 21% for Groups I and II, respectively (p > 0.80).Conclusions. Group I patients did not require significantly oversized donors, restricted donor locations or longer intensive care unit stays or have higher infection rates; however, arrhythmias were more frequent. Pulmonary resistance index normalized early after transplantation. Pulmonary vascular reactivity may be more important for survival than absolute resistance index.     

Muscle mass,strength, bone mineral density and vascular function in middle-aged people living with HIV vs. age-matched and older controls

IntroductionCombination antiretroviral therapy (cART) substantially extended the life of people living with HIV (PLHIV). However, prolonged HIV infection and cART increase the risk of comorbidities accelerating age-related muscle, bone, and vascular disorders. This cross-sectional study compared muscle mass and strength, bone mineral density (BMD), and vascular function in middle-aged PLHIV treated with cART vs. non-infected age-matched and older controls.MethodsAfter careful screening for secondary diseases and medications, body composition, muscular and vascular function were assessed in 12 PLHIV (43.9±8.7 yrs old; HIV-infection for 16.2±8.6 yrs; on cART for 11.6±9.2 yrs), 12 age-matched (CONT, 43.2±8.5 yrs old), and 12 older (OLDER, 74.4±8.3 yrs old) controls through dual x-ray absorptiometry, isokinetic dynamometry, and venous occlusion plethysmography, respectively.ResultsPLHIV and CONT showed similar relative muscle mass (65.3±8.0 vs. 66.9±7.3%, respectively; P= 0.88) and strength (160.7±53.9 vs. 152.0±52.9 N.m⁻¹, respectively; P= 0.90), which were greater than OLDER (80.6±18.8 N.m^−1; P= 0.001). Total BMD was similar in PLHIV (1.04±0.13 g.cm⁻²) and OLDER (1.00±0.15 g.cm⁻², P= 0.86), and both groups presented lower values than CONT (1.20±0.13 g.cm⁻², P< 0.01). No significant difference across groups was detected for macrovascular reactivity (P= 0.32).ConclusionAge-related osteopenia might be accelerated in middle-aged PLHIV on prolonged cART, as their BMD approached values found in older adults. On the other hand, muscle mass, isokinetic strength, and vasodilation capacity were similar in PLHIV and age-matched uninfected controls.     

Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients

Aim: In liver cirrhosis, the increased production of nitric oxide (NO) contributes to increased systemic and splanchnic vasodilatation. The inhibition of phosphodiesterase-5 (PDE-5), an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP), is widely used in the treatment of erectile dysfunction. The aim of our study is to evaluate the overall effects of PDE-5 inhibitor administration on splanchnic, pulmonary and systemic hemodynamics in cirrhotic patients. Methods: Sildenafil, a specific PDE-5 inhibitor, was administrated orally to cirrhotic patients (n = 7) to see the hemodynamic changes. A control group receiving a placebo was used as a point of comparison (n = 6). Results: Compared to the control group, the hepatic vein NO and cGMP levels were significantly increased after sildenafil administration in the sildenafil group (NO from 112.3 ± 43.5 to 325.3 ± 117.5 nM, P = 0.018; cGMP from 7.3 ± 0.4 to 19.2 ± 4.2 pmol, P = 0.018). The hepatic venous pressure gradient in the sildenafil group did not differ from that of the control group. However, a significantly decreased hepatic sinusoidal resistance in the sildenafil group (1999 ± 1243 vs. 1563 ± 1014 dyne/s/cm⁻⁵, P < 0.05) was noted. The study also found that the right arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure were reduced at 60 min after administration, compared with the basal parameters in cirrhotic patients receiving sildenafil (RAP1.3 ± 2.0 vs −0.6 ± 1.3 mmHg, MPAP 14.1 ± 11.3 vs 11.7 ± 9.5 mmHg, PCWP 4.6 ± 1.7 vs 2.9 ± 1.6 mmHg, P < 0.05 respectively). Conclusions: An oral administration of 50 mg of sildenafil significantly decreased the mean pulmonary arterial pressure and hepatic sinusoid resistance with a significant increase in hepatic NO and cGMP production, and did not worsen portal hypertension in cirrhotic patients.