Long-term effects of hydralazine on ventilation and blood gas values in patients with chronic obstructive pulmonary disease and pulmonary hypertension

Hydralazine has been shown to increase minute ventilation, alveolar ventilation, and arterial partial pressure of oxygen (PaO2) after short-term administration in patients with chronic obstructive pulmonary disease and pulmonary hypertension. The effects of orally administered hydralazine on ventilation and blood gas values were evaluated after six to 18 months of treatment in 10 male patients who had demonstrated an increase in minute ventilation after 24 hours of treatment. Hydralazine was administered at a dose of 200 mg per day during the initial 24 hours and in doses ranging from 40 mg per day to 200 mg per day during long-term therapy. Following 24 hours of treatment, a statistically significant increase in minute ventilation, alveolar ventilation, and PaO2, and reduction in arterial partial pressure of carbon dioxide (PaCO2) were seen both at rest and during exercise. After six to 18 months of hydralazine therapy, the increase in minute ventilation at rest persisted when compared with the pre-hydralazine value (15.3 +/- 1.3 liters/minute versus 13.1 +/- 1.1 liters/minute; p less than 0.05). The improvement in PaO2 at rest continued relative to the pre-hydralazine value (70.9 +/- 3.2 mm Hg versus 65.1 +/- 3.0 mm Hg, p less than 0.05) as did the PaO2 during exercise (60.3 +/- 3.5 mm Hg versus 53.3 +/- 2.0 mm Hg; p less than 0.05). The reduction in PaCO2 at rest persisted compared with the pre-hydralazine value (41.2 +/- 2.4 mm Hg versus 47.0 +/- 3.0 mm Hg; p less than 0.05) as did the PaCO2 during exercise (44.0 +/- 2.8 mm Hg versus 48.0 +/- 2.8 mm Hg; p less than 0.05). No significant changes in minute ventilation, PaO2, or PaCO2 were seen at rest or during exercise, when re-measured after six to 18 months in an age- and sex-matched control group of 10 patients who did not receive hydralazine. These results demonstrate that the short-term effects of hydralazine on ventilation and blood gas values persisted after six to 18 months of treatment in this sample of patients, some of whom received doses less than 200 mg per day.     

Effects of six-month afterload reduction therapy with hydralazine in chronic aortic regurgitation

Seventeen patients with chronic asymptomatic aortic regurgitation (AR) were studied to determine whether 6 months of hydralazine therapy can reduce the severity of AR or reverse left ventricular (LV) enlargement and hypertrophy. Echocardiography, radionuclide angiography at rest and during exercise, and maximal treadmill exercise with respiratory gas analysis were performed at intake and after a 6-month double-blind treatment period. After dose titration with hydralazine, patients were randomized to their maximal tolerated hydralazine dose or to placebo. At intake, hydralazine and placebo groups were similar. Six patients taking hydralazine and 8 taking placebo completed the study protocol. One patient taking placebo died and 2 patients taking hydralazine withdrew with drug-related adverse effects. The mean titrated dose of hydralazine was 96 +/- 9 mg, but the mean treatment dose was 63 +/- 21 mg administered 3 times daily because of drug intolerance. After 6 months, mean systolic blood pressure with hydralazine therapy decreased from 136 to 125 mm Hg (p less than 0.02), and end-systolic posterior wall thickness increased from 1.58 to 1.70 cm (p less than 0.05), resulting in a significant reduction in M-mode meridional end-systolic stress (from 104 to 80 kdynes/cm2) (p less than 0.05). M-mode fractional shortening increased from 0.28 to 0.31 (p less than 0.05) with hydralazine, but mean LV echocardiographic dimensions were unchanged. LV mass increased from 383 to 434 g (p less than 0.05) with hydralazine primarily because of an increase in end-diastolic wall thickness. In the placebo group, there was no change in any of the hemodynamic or echocardiographic parameters at 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise responses before and after long-term treatment with oral milrinone in patients with severe heart failure

Administration of the positive inotropic vasodilator milrinone results in immediate improvement in the maximal and submaximal metabolic responses to exercise. To determine whether these effects persist during long-term therapy, nine patients with severe congestive heart failure were evaluated by upright maximal exercise testing before therapy (baseline), after 10 +/- 1 weeks of oral therapy, and during double-blind, placebo-controlled readministration of intravenous milrinone after withdrawal of oral drug for 24 hours. During long-term oral therapy, maximal oxygen uptake was unchanged (baseline 792 +/- 72 ml per minute, oral therapy 820 +/- 83 ml per minute), whereas the anaerobic threshold was increased significantly from 570 +/- 53 ml per minute to 681 +/- 61 ml per minute. After withdrawal of milrinone, maximal oxygen uptake and anaerobic threshold decreased significantly; subsequent intravenous administration caused significant increases in maximal oxygen uptake and anaerobic threshold, back to the values measured during oral therapy. After oral milrinone withdrawal, maximal oxygen uptake decreased below baseline values, suggesting progression of the underlying disease. The anaerobic threshold expressed as a percent of maximal oxygen uptake was significantly increased during oral therapy (baseline 73 +/- 2 percent, oral therapy 84 +/- 2 percent) and remained significantly increased after drug withdrawal, suggesting a peripheral circulatory effect. These results indicate that in selected patients with severe congestive heart failure, milrinone exerts persistent effects on the metabolic responses to both maximal and submaximal exercise. Because of progressive deterioration in exercise capacity during long-term oral therapy, the effects of milrinone may not be apparent unless it is withdrawn. The relation of milrinone therapy to disease progression is not known.     

Neurohumoral consequences of vasodilator therapy with hydralazine and nifedipine in severe congestive heart failure

We evaluated the effects of intravenous hydralazine (5 to 30 mg) and oral nifedipine (20 to 80 mg) on plasma catecholamines, renin, and aldosterone in 18 patients with severe chronic heart failure. Both drugs resulted in a significant decrease in systemic vascular resistance and mean systemic blood pressure, and led to an increase in cardiac output. Baseline plasma norepinephrine concentration was elevated in most patients; however, augmentation of cardiac output with both drugs did not decrease the values of this hormone (from 870 +/- 128 to 946 +/- 161 pg/ml with hydralazine and from 1088 +/- 260 to 1106 +/- 187 pg/ml with nifedipine). Plasma epinephrine level was also elevated at baseline and did not change significantly following nifedipine therapy (164 +/- 44 vs 199 +/- 54 pg/ml), but increased in most patients following the administration of hydralazine (from 105 +/- 45 to 153 +/- 27 pg/ml, p less than 0.01). The renin-aldosterone system was activated in our patients and also demonstrated a different response to both drugs. Hydralazine therapy did not change either the plasma renin concentration (30 +/- 7 vs 28 +/- 7 ng/ml/hr) or the aldosterone level (24 +/- 7 vs 22 +/- 5 ng/dl). In contrast, nifedipine increased the plasma renin concentration (22 +/- 7 to 29 +/- 8 ng/ml/hr, p less than 0.05). This change did not correlate with changes in systemic blood pressure (r = 0.03) and was probably the result of previously shown calcium blockade-mediated stimulation of renin release from the juxtaglomerular cells of the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term vasodilator therapy of chronic aortic insufficiency. A randomized double-blinded, placebo-controlled clinical trial

Although vasodilator drugs acutely reduce regurgitation and improve cardiac performance in aortic insufficiency, their long-term effects on left ventricular size and function are uncertain. Consequently, we performed a double-blinded, placebo-controlled trial using hydralazine in 80 minimally symptomatic patients who had clinically stable, moderate-to-severe aortic insufficiency. Patients randomized to hydralazine displayed a progressive reduction in left ventricular end-diastolic volume index (LVEDVI) measured by radionuclide angiography, the predetermined end point of the study. At 24 months, mean LVEDVI had been reduced by 30 +/- 38 ml/m2, an 18% reduction from baseline. In contrast, LVEDVI changed minimally in patients randomized to placebo, and the intergroup differences over time were statistically significant (p less than 0.03). The hydralazine group also experienced reductions in left ventricular end-systolic volume index and increases in ejection fraction that were significantly different (both p less than 0.01) from changes in placebo-treated patients. These findings show that long-term treatment with hydralazine reduces the volume overload in aortic insufficiency and suggest that such therapy may have a beneficial effect on the natural history of the disease.     

The effects of hydralazine on exercise capacity in pulmonary hypertension secondary to chronic obstructive pulmonary disease

Vasodilator therapy of pulmonary hypertension has been shown to improve hemodynamics in some patients, but the clinical benefits of this therapy have not been evaluated. We studied 14 patients who had pulmonary hypertension secondary to chronic obstructive pulmonary disease to determine the effect of hydralazine treatment on hemodynamics and maximal exercise. Baseline exercise in these subjects showed an abnormal pattern of excessive tachycardia and low stroke volumes, and the stroke volume correlated inversely with the pulmonary vascular resistance during exercise (r = -0.61, p less than 0.05). After 48 h of hydralazine there were decreases in the mean pulmonary artery pressure (43 +/- 8 to 38 +/- 8 mmHg, p less than 0.06) and pulmonary vascular resistance (3.97 +/- 0.97 to 2.88 +/- 1.28 units, p less than 0.05) measured at maximal exercise, and the maximal cardiac output was increased (8.05 +/- 2.57 to 10.13 +/- 2.79 L/min, p less than 0.05), but there was no change in symptom-limited maximal oxygen consumption (747 +/- 266 to 752 +/- 244 ml/min, p = NS). Significant increases in resting and maximal exercise values of minute ventilation and mixed venous oxygen tension were also noted with hydralazine. Repeat exercise testing after 2 to 4 months of chronic hydralazine therapy demonstrated no change in symptom-limited maximal oxygen consumption. We conclude that vasodilator therapy with hydralazine, although hemodynamically efficacious, does not increase exercise capacity in patients with severe chronic obstructive pulmonary disease and secondary pulmonary hypertension.     

Regression of myocardial cellular hypertrophy with vasodilator therapy in chronic congestive heart failure associated with idiopathic dilated cardiomyopathy

Forty-nine patients with idiopathic dilated cardiomyopathy (IDC) were evaluated to determine the hemodynamic and morphologic effects of vasodilator therapy. Hydralazine (225 mg/day, H), isosorbide dinitrate (160 mg/day, I), and combination H + I therapy were compared with placebo (P) at baseline and after 3 months of continuous therapy. Thirty-three randomly assigned patients completed the study. Hemodynamic parameters included the echocardiographic percent change of left ventricular diameter (% delta D), the systolic time intervals ratio of preejection period to left ventricular ejection time (PEP/LVET), the pulmonary capillary wedge pressure, mean pulmonary artery pressure, cardiac index, systemic vascular resistance, and pulmonary vascular resistance. An endomyocardial biopsy was performed at baseline and after 3 months; the myocardial cell diameter of 50 cells per biopsy was measured. During the 3-month study 5 patients died; there was not a significant difference among the groups in the number of deaths. The % delta D and PEP/LVET did not change in the P or I groups but did improve significantly from baseline in the H and H + I groups. The pulmonary capillary wedge and mean pulmonary artery pressures and the pulmonary vascular resistance did not change in the P or H groups but did decrease significantly in the I and H + I groups. The P and I groups did not have improvement in systemic vascular resistance or cardiac index, whereas the H group had a decrease in systemic vascular resistance and an increase in cardiac index from 2.5 +/- 0.4 to 3.1 +/- 0.4 liters/min/m2 (p less than 0.05). The H + I group also had a decrease in systemic vascular resistance; the cardiac index increased from 2.3 +/- 0.4 to 3.1 +/- 0.4 liters/min/m2 (p less than 0.01). Myocardial cell diameter did not change in the P or I group. Cell diameter of the H group decreased from 25.4 +/- 3.1 microns at baseline to 23.1 +/- 3.8 microns (p less than 0.05) after 3 months of continuous therapy. The H + I group decreased its cell diameter from 23.9 +/- 3.7 to 22.2 +/- 2.2 microns (p less than 0.05). Compared with P and H, patients treated with I alone or H + I had a significant reduction of preload. In contrast to P and I, H alone and H + I elicited improvement in parameters of inotropy and afterload, and this improvement was accompanied by a reduction in cell diameter. Chronic therapy of heart failure with H and H + I effects a persistent augmentation of cardiac function and improvement of myocardial cellular morphology.     

Analysis of the mechanisms underlying the changes in left ventricular filling dynamics during oral nisoldipine therapy in patients with anterior myocardial infarction.

The aim of this study was to clarify the mechanisms responsible for the increase in early filling rate observed during oral nisoldipine therapy in patients with ischaemic left ventricular (LV) dysfunction. For that purpose, the global and regional LV function was analysed before and after 2 months of double-blind monotherapy with nisoldipine (10 mg twice daily) or a placebo, in 17 patients with a previous anterior myocardial infarction. The baseline LV ejection fraction ranged from 34-51% and no patient had heart failure. Compared to the placebo, nisoldipine significantly lowered LV systolic pressure and end-diastolic pressure (-3 mmHg vs +6 with the placebo; P less than 0.01) and the LV pressure at the time of mitral opening (-2.0 +/- 3.4 mmHg vs +3.5 +/- 3.0; P less than 0.01). Despite this reduction in driving pressure, the global LV early peak filling rate improved with nisoldipine only and this improvement was related to a selective increase in expansion rate of the anterior areas, from 1010 +/- 360 to 1339 +/- 496 mm2.s-1 (P less than 0.001). The time to regional peak filling rate (-8%; P less than 0.01), the asynchrony of diastolic wall motion and the regional ejection fraction (33 +/- 10 to 38 +/- 12%; P less than 0.001) also improved in the anterior areas with nisoldipine but not with the placebo. In contrast, in the inferior, control zones, the regional ejection fraction and filling rate remained unchanged, both when compared to baseline and to the placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of vasodilators and long-term response in heart failure

Hemodynamic responses to vasodilators are commonly assessed when starting long-term vasodilator treatment in patients with chronic left ventricular failure, although the relation between short- and long-term responses is not established. Thus, short- and long-term hemodynamic responses to placebo and vasodilators (isosorbide dinitrate, minoxidil and enalapril or captopril) were measured and long-term clinical efficacy was assessed by changes in exercise capacity after 1 to 5 months of vasodilator administration (plus digitalis and diuretic agents) in 46 patients with New York Heart Association functional class II to IV heart failure caused by cardiomyopathy. There were no significant changes in hemodynamics or exercise capacity during placebo treatment. After initial doses and during long-term administration of vasodilator drugs, hemodynamics were significantly improved. After long-term vasodilator treatment, maximal oxygen uptake during exercise increased by 2.9 +/- 5.7 ml/min per kg from a control value of 14.1 +/- 5.6 ml/min per kg (p less than 0.01), and exercise duration also increased by 1.8 +/- 3.5 minutes (p less than 0.01). Changes in maximal oxygen uptake, however, did not correlate with short-term changes in pulmonary wedge pressure (correlation coefficient [r] = -0.14), cardiac index (r = -0.01) or systemic vascular resistance (r = -0.20). Long-term hemodynamic changes also failed to correlate with changes in exercise capacity. Baseline hemodynamics, cardiac dimensions and left ventricular ejection fraction before vasodilator administration all failed to correlate with baseline exercise capacity or with long-term changes in exercise capacity. Thus, hemodynamic measurements at initiation or during follow-up of vasodilator therapy do not relate to long-term clinical efficacy assessed by exercise capacity in patients with chronic left ventricular failure. Therefore, the rationale for making invasive hemodynamic measurements before initiating long-term vasodilator therapy for heart failure is questioned.     

Raynaud's phenomenon of the lung

To determine if pulmonary vessels develop vasospasm during Raynaud's phenomenon, digital vasospasm was induced by hand immersion in 15 degrees C water (cold pressor test) in 17 subjects, and pulmonary function was measured during the subsequent 120 minutes. Five healthy persons were control subjects, seven subjects had well documented systemic disorders associated with Raynaud's phenomenon (secondary Raynaud's), and five subjects had a history of Raynaud's phenomenon but no evidence of an associated disorder (primary Raynaud's). The only measure of pulmonary function that changed significantly following cold pressor testing was carbon monoxide diffusing capacity. Subjects with primary Raynaud's phenomenon had normal baseline carbon monoxide diffusing capacity (23.7 +/- 4.6 ml/minute/mm Hg) but demonstrated significant decreases (p less than 0.05) at 15 minutes (21.2 +/- 3.5 ml/minute/mm Hg), 45 minutes (19.5 +/- 3.7 ml/minute/mm Hg), and 120 minutes (17.1 +/- 2.1 ml/minute/mm Hg) after cold pressor testing. Subjects with secondary Raynaud's phenomenon had low baseline carbon monoxide diffusing capacity (71 percent predicted) and showed no significant change following cold pressor testing. These findings indicate that digital vasospasm in patients with primary Raynaud's phenomenon is part of a systemic vascular response that includes a decrease in the size of the pulmonary capillary bed.     

Renal hemodynamic changes in humans. Response to protein loading in normal and diseased kidneys

This study was undertaken to define the renal hemodynamic changes that mediate the acute response to an oral protein load. Three groups of subjects were studied: (1) disease-free subjects; (2) patients with chronic renal disease of various causes, except for diabetes mellitus, documented by history and/or renal biopsy; and (3) patients with diabetes mellitus, that is, a history of hyperglycemia requiring antihyperglycemic therapy. All subjects were studied before (baseline) and after (test) ingestion of a protein load. Glomerular filtration rate and effective renal plasma flow were evaluated by inulin and para-amino-hippurate, respectively. In the disease-free subjects, the mean baseline glomerular filtration rate and renal plasma flow were 122 +/- 10 ml/minute/1.73 m2 and 644 +/- 64 ml/minute/1.73 m2, whereas test glomerular filtration rate and renal plasma flow were 151 +/- 15 ml/minute/1.73 m2 and 791 +/- 111 ml/minute/1.73 m2, respectively. In patients with chronic renal disease, the test glomerular filtration rate and renal plasma flow were related to the severity of the disease. The more severe the disease, the lower the absolute test values and the smaller the increment from baseline to test values. Patients with diabetes mellitus had a paradoxic response to ingestion of a protein load. Glomerular filtration rate fell while renal plasma flow remained unchanged. This response was observed in all diabetic patients regardless of the type of diabetes or whether clinical evidence of diabetic nephropathy was absent, minimal, or severe.     

Effects of intravenous isradipine on left ventricular performance during rapid atrial pacing in coronary artery disease

The effects of isradipine, a new dihydropyridine calcium antagonist, were evaluated in 24 patients referred for elective cardiac catheterization because of suspected coronary artery disease. Hemodynamics and left ventricular (LV) function (by digital subtraction angiography) were measured at baseline and during rapid atrial pacing (mean peak heart rate 135 beats/min), which induced chest pain or electrocardiographic changes in all patients. After a control pacing period, intravenous isradipine (0.01 mg/kg, n = 16) or placebo (n = 8) was administered in a double-blind fashion and all variables were measured again at baseline and during pacing to the same maximum heart rate. Before isradipine was given, pacing had no effect on systolic blood pressure, while increasing diastolic blood pressure (68 +/- 8 to 87 +/- 11 mm Hg, p less than 0.0001) and LV end-diastolic pressure measured in the immediate postpacing period (13 +/- 5 to 18 +/- 6 mm Hg, p less than 0.03) and decreasing LV end-diastolic volume index (59 +/- 18 to 40 +/- 12 ml/m2, p less than 0.001), stroke volume index (37 +/- 11 to 23 +/- 10 ml/m2, p less than 0.0001), ejection fraction (0.64 +/- 0.07 to 0.53 +/- 0.12, p less than 0.0003) and percent regional shortening in 4 of 5 myocardial wall segments. During pacing after isradipine, systolic and diastolic blood pressures were lower, ejection fraction was higher and percent regional shortening decreased in only 2 of 5 myocardial segments. In comparison to placebo, isradipine increased baseline heart rate, ejection fraction and stroke volume index while it decreased arterial pressure and end-systolic volume index before the second pacing period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term effects of nitrendipine on hemodynamics and oxygen transport in patients with cor pulmonale

Recent studies have suggested that vasodilators may acutely improve pulmonary hemodynamics in patients with chronic obstructive pulmonary disease and cor pulmonale, but the effects of long-term therapy have not been assessed. We evaluated the hemodynamic and gas exchange effects of nitrendipine, a calcium channel blocker with a cardiovascular profile similar to nifedipine, acutely and after five days and six weeks of therapy in eight patients with stable COPD and cor pulmonale. After six weeks, nitrendipine significantly decreased both mean pulmonary artery pressure (40.4 +/- 10.3 to 31.2 +/- 6.6 mm Hg, p less than 0.01) and pulmonary vascular resistance (6.8 +/- 3.9 to 3.0 +/- 1.1 units, p less than 0.01), while cardiac index increased (2.4 +/- 0.8 to 3.6 +/- 1.0 L/min/m2, p less than 0.001). Despite a fall in arterial PO2 (53.1 +/- 18.7 to 45.5 +/- 11.3 mm Hg, p = NS), systemic oxygen transport increased by over 30 percent (843 +/- 284 to 1,111 +/- 373 ml/min, p less than 0.05). Systemic arterial pressure, pulmonary capillary wedge pressure, and heart rate were unchanged. Despite these hemodynamic changes, three patients died from complications of their underlying disease while receiving long-term therapy after eight, nine, and ten months. These preliminary findings suggest that long-term vasodilator therapy can result in persistent hemodynamic improvement in some patients with cor pulmonale secondary to COPD, although the impact of this form of therapy on survival remains to be clarified.     

Hydralazine in the management of left ventricular failure.

This study was designed to compare the short and long-term effects of hydralazine when used as a vasodilator in the treatment of left ventricular failure. The hemodynamic changes after the acute intravenous and long-term oral administration of hydralazine were compared in a group of 16 patients with left ventricular failure (14 patients with congestive cardiomyopathy and two with hypertensive heart failure). After 20 mg of hydralazine, administered intravenously there was a 56 percent increase in stroke volume (P < 0.001) and a 27 percent decrease in left ventricular filling pressure (P < 0.001) but no significant change in heart rate despite a 16 percent decrease in mean arterial pressure (P < 0.001).Seven of the patients then took hydralazine, 200 to 300 orally/day for 4 to 6 weeks. They were restudied during therapy with the drug and again 48 to 72 hours after stopping it. After the period of oral treatment there was a 71 percent increase in stroke volume (P < 0.001) and a 25 percent decrease in left ventricular filling pressure (P < 0.05). Forty-eight to 72 hours after discontinuation of drug administration, left ventricular filling pressure had returned to the control value (?3 percent, P < 0.05), but the stroke volume was still slightly elevated (14 percent, P < 0.05). The results show that oral administration of hydralazine can produce sustained benefit with changes similar to those induced by intravenous administration. The second control study after discontinuation of hydralazine therapy confirmed that these changes had been induced by and were dependent on the drug.     

A comparison of the acute hemodynamic effects of prostacyclin and hydralazine in primary pulmonary hypertension

In patients with primary pulmonary hypertension the administration of a vasodilating drug is often used to test pulmonary vasoreactivity. Hydralazine has been employed as a test drug, but because of its long duration of action there is a risk of sustained systemic arterial hypotension in patients with a fixed pulmonary vascular resistance. In this study we compared the acute hemodynamic effects of intravenous prostacyclin, a potent, short-acting vasodilator, with the effects of oral or intravenous hydralazine. Both prostacyclin and hydralazine increased cardiac output and decreased systemic pressure without changing pulmonary arterial pressure in seven patients with primary pulmonary hypertension. The average decrease in total pulmonary resistance with prostacyclin (-46% +/- 5%) was more than that with hydralazine (-32% +/- 6%). The respective decreases in total systemic resistance were -50% +/- 4% vs -43% +/- 6%. The percent changes in individual responses to the two agents were correlated (p less than 0.05) for pulmonary arterial pressure, systemic arterial pressure, total pulmonary resistance, and total systemic resistance. We concluded that the pulmonary hemodynamic effects of prostacyclin resembled those of hydralazine. Prostacyclin may predict the acute pulmonary hemodynamic effects of hydralazine in primary pulmonary hypertension and because of its prompt, brief action may provide greater patient safety.     

Beneficial effects of hydralazine in severe mitral regurgitation

The severity of mitral regurgitation is, in part, determined by aortic impedance to left ventricular outflow. Sodium nitroprusside acutely decreases regurgitant flow, but the importance of its dual vasodilating effects, the lowering of peripheral vascular resistance and increasing of venous capacitance, is unclear. We studied the hemodynamic response to intravenous hydralazine, which selectively acts on the arteriolar resistance bed, in 10 patients with severe mitral regurgitation. Hydralazine produced a 50% increase in forward stroke volume (22 +/- 2 to 33 +/- 3 ml/m2, P less than 0.001) and a 33% reduction in regurgitant stroke volume (40 +/- 6 to 27 +/- 6 ml/m2, P less than 0.001), with a resultant fall in pulmonary capillary wedge v wave and mean pressures. Unlike nitroprusside, it did not alter left ventricular end-diastolic volume or pressure. Oral hydralazine maintained this hemodynamic improvement for at least 48 hours and, in three patients, provided more sustained clinical improvement. We conclude that hydralazine, by virtue of its selective lowering of aortic impedance, reduces the amount of mitral regurgitation and thus may be a useful mode of interim or chronic therapy in selected patients.     

Effect of quinapril initiated during progressive remodeling in asymptomatic patients with healed myocardial infarction

Approximately 20% of patients with healed myocardial infarction develop asymptomatic progressive left ventricular (LV) dilation and remodeling and are at increased risk for progression to symptomatic congestive heart failure and premature death. It was the goal of this study to test whether quinapril may interrupt this process and to analyze potential mechanisms. Of 138 patients with an average infarct age of 56 months, 25 had asymptomatic progressive LV dilation and were randomized in a prospective, double-blind study to placebo or quinapril. At baseline (mean +/- SEM) ejection fraction was reduced (35 +/- 3% and 39 +/- 3%) and end-diastolic volume (gated single-photon emission computed tomography) increased (104 +/- 9 and 117 +/- 12 ml/m(2)) with placebo (n = 13) and quinapril (n = 12), respectively. Progressive dilation continued in patients taking placebo (6 months: 9.4 +/- 5.2 ml/m(2), 12 months 24.6 +/- 5. 4 ml/m(2); change from baseline: p <0.05 vs baseline; p <0.05 vs 6 months), but not with quinapril (6 months: -0.9 +/- 4.0 ml/m(2); 12 months: 4.1 +/- 5.2 ml/m(2) [p <0.05] vs placebo). Wedge pressure during bicycle exercise was similar at baseline, but at 12 months tended to be lower with quinapril (17 +/- 1 mm Hg) than with placebo (24 +/- 4 mm Hg, p = 0.1673). Thus, quinapril prevented further progression of asymptomatic LV dilation and remodeling after remote myocardial infarction, possibly due to attenuation of an exercise-induced increase in LV filling pressure.     

Regional blood flow response to orthostasis in patients with congestive heart failure

To investigate the central and regional circulatory response to orthostasis in congestive heart failure, hemodynamic variables and forearm and hepatic blood flow were measured in 22 patients at supine rest and during a 65 degrees head-up tilt. Results were compared with those in nine normal subjects. Heart rate and mean arterial blood pressure increased during tilt in normal subjects, but not in patients with heart failure. Forearm blood flow decreased in normal subjects from 3.7 +/- 1.1 to 2.7 +/- 1.5 ml/min per 100 g (probability [p] less than 0.02), but did not change from a lower baseline (1.65 +/- 0.78 ml/min per 100 g) in patients. Forearm vascular resistance increased in normal subjects but not in patients. Hepatic blood flow did not change during tilt in either group, but hepatic vascular resistance increased in normal subjects from 0.37 +/- 0.13 to 0.47 +/- 0.15 U, (p less than 0.02). The increase was not seen in patients (1.2 +/- 1.1 to 1.4 +/- 1.0 U, p = not significant [NS] ). Total systemic resistance increased in patients from 1,848 +/- 560 to 2,132 +/- 731 dynes.s.cm-5 (p less than 0.005) indicating that resistance did increase in some vascular beds. Plasma norepinephrine also increased modestly in these patients from 665 +/- 377 to 761 +/- 379 pg/ml (p = 0.035), but individual changes in plasma norepinephrine did not correlate with changes in hepatic or forearm resistance. Thus, both the overall hemodynamic response and the regulation of regional blood flow and resistance differ in several respects in patients with congestive heart failure when compared with normal subjects. Changes in heart rate, blood pressure, forearm flow and forearm and hepatic vascular resistance are all blunted in patients. Reasons for the differences are not yet clear, but may be associated with abnormalities in reflex control of the circulation in patients with congestive heart failure.     

Coronary flow reserve and ischemic-like electrocardiogram in patients with symptomatic mitral valve prolapse

The purpose of the present study was to determine whether coronary microvascular function is impaired in patients with symptomatic mitral valve prolapse (MVP) and whether ischemia-like ECG, if present, is related to coronary microvascular dysfunction. Twenty chest pain patients with normal coronary angiograms and MVP proven by echocardiogram were included. Both treadmill exercise test (TET) and coronary hemodynamic study were done in each patient. Coronary flow reserve (CFR) was determined by measuring coronary sinus flow (CSF) or great cardiac venous flow (GCVF) both at baseline and after dipyridamole 0.56 mg/kg IV for 4 minutes (maximum). All patients were divided into 2 groups with either negative (TET-) or positive results of TET (TET+). Another 10 subjects with atypical chest pain, normal coronary angiograms, echocardiogram and TET were used as controls. There were no differences in GCVF, either at baseline or after dipyridamole infusion, among the 3 groups. Calculated CFR using GCVF was similar among the 3 groups. However, baseline CSF was higher in the TET+ group (TET- vs TET+ vs control: 77 +/- 24 vs 96 +/- 31 vs 75 +/- 12 ml/min, p < 0.05) and maximum CSF was lower in the TET- group (TET- vs TET+ vs control: 167 +/- 25 vs 219 +/- 85 vs 238 +/- 80 ml/min, p < 0.05). Calculated CFR using CSF was significantly reduced in both the TET- (2.26 +/- 0.4) and TET+ groups (2.31 +/- 0.7) as compared with the control subjects (3.18 +/- 0.95, p < 0.01). There were no differences in any of the hemodynamic parameters between the TET- and TET+ groups. Coronary microvascular function could be impaired in patients with symptomatic MVP. Such impairment, when presented, was probably regional and outside the territory of the left anterior descending coronary artery. However, it was irrelevant to the presence of ischemic-like ECG during exercise.     

Effect of dietary protein restriction on functional renal reserve in diabetic nephropathy

PURPOSE, PATIENTS, AND METHODS: Functional renal reserve in patients with insulin-dependent diabetes mellitus, as determined by the glomerular filtration rate (GFR) response test, is a measure of the capacity of the kidney to increase glomerular filtration in response to the stimulus of a protein meal or amino acid infusion. This 12-month study evaluated the changes in functional renal reserve in eight patients with insulin-dependent diabetes mellitus with nephropathy (micro-albuminuria [greater than or equal to 30 micrograms/minute]) who chronically decreased their dietary protein intake to a mean of 0.6 g/kg/day (Group 1) compared with a group of similar patients (n = 7) who maintained their unusual dietary protein intake (1.0 g/kg/day, Group 2). Patients were evaluated and measurements taken at 3-, 6-, and 12-month intervals. Absolute and percent increases in GFR were calculated from three averaged 1-hour measurements after an 80-g protein test meal. RESULTS: Although the initial absolute mean rise (14 +/- 12 versus 18 +/- 13 mL/minute/1.73 m2) in GFR and maximal percent rise (16% +/- 16% versus 32% +/- 27%) after the meal did not differ significantly between the two groups, at 12 months, values in the lower protein group increased (27.8 +/- 9.5 mL/minute/1.73 m2 and 54.7% +/- 48.8%), whereas those in the normal protein intake group declined significantly (3.7 +/- 3.6 mL/min-ute/1.73 m2 and 6.5% +/- 6.5%) (p less than 0.05). Both urine urea and microalbuminuria decreased significantly (p less than 0.05) in the low protein group. Unstimulated GFR at the end of 12 months was significantly less (p less than 0.05) in Group 2 (47 +/- 2 mL/minute/1.73 m2) than in Group 1 (71 +/- 21 mL/minute/1.73 m2). The rate of decline in GFR was significantly greater (p less than 0.05) in the normal protein intake group than in the low protein intake group (0.68 +/- 0.4 versus 0.28 +/- 0.15 mL/minute/1.73 m2/month). CONCLUSIONS: This study indicates that sustained dietary protein restriction can help to preserve renal function, decrease albuminuria, and lower the baseline GFR while maintaining functional renal reserve in patients with insulin-dependent diabetes mellitus.