Exercise capacity,hemodynamic, and neurohumoral changes following acute and chronic administration of flosequinan in chronic congestive heart failure

Summary We evaluated the responses to 90 minutes and 8 days of therapy with a new long-acting vasodilator flosequinan in ten patients with moderate chronic congestive heart failure in an open, uncontrolled study. Acute administration of 100 mg orally resulted in a decrease of preload, with a reduction of left ventricular end-diastolic volume, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and right atrial pressure. Following the acute administration, we found no significant changes of heart rate, cardiac index, stroke volume, peripheral vascular resistance, ejection fraction, and dp/dt. Chronic application for 8 days (100 mg/day) showed persistent effects on preload, with a significant decrease of pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. After 8 days of treatment, cardiac index was significantly increased from 2.2±0.2 l/min/m² to 2.8±0.2 l/min/m² (p=0.013) and stroke volume from 57±10 ml to 74±9 ml (p=0.022). Peripheral vascular resistance decreased by 28%. After 8 days, bicycle exercise capacity increased significantly from 383±44 sec to 422±43 sec (p=0.01) and the patients were able to increase their walking distance over a 6-minute exercise test from 426±46 m to 477±33 m (p=0.007), with a concomitant decrease of dyspnea (p=0.013). Plasma renin concentration showed only a rise 90 minutes after the acute administration on day 8 of the study, and atrial natriuretic peptide and 6-keto-prostaglandin F₁-alpha decreased significantly. Plasma norepinephrine, epinephrine, dopamine, and prostaglandin E₂ did not change. After 8 days body weight was reduced from 76.5±2.1 kg to 75.1±2.4 kg. These data indicate that flosequinan is effective in patients with heart failure during a relatively short duration of treatment, improving cardiac performance and exercise capacity and acting primarily on preload, and it may have cumulative vasodilator effects on arterial vessels during chronic therapy. We observed no substantial stimulation of neurohumoral factors and no fluid retention.     

Hemodynamic response of a canine model of chronic heart failure to intravenous dobutamine,nitroprusside, enalaprilat,and digoxin

Summary The hemodynamic effects of acute intravenous administration of nitroprusside, dobutamine, enalaprilat, and digoxin was investigated in a canine model of chronic heart failure (CHF) produced by multiple sequential intracoronary microembolizations. Dobutamine (4 µg/kg/min) increased cardiac output (2.4±0.1 vs. 4.0±0.4 l/min; p<.001) and LV ejection fraction (LVEF; 26±1 vs. 30±4%; p<.01), and decreased systemic vascular resistance (SVR; 3620±170 vs. 2470±190 dynes sec cm^–5; p<.001). Nitroprusside (3 µg/kg/min) acted as a venodilator; it decreased pulmonary artery wedge pressure (16±1 vs. 13±1 mmHg; p<.01) and SVR (3730±440 vs. 3210±280 dynes sec cm^–5; NS) but had no effect on cardiac output. Enalaprilat (1.875 mg) produced a significant increase of cardiac output (3.0±0.5 vs. 3.8±0.5 l/min; p<.001) and LVEF (22±1 vs. 30±1%; p<.01), and decreased SVR (3280±400 vs. 2450±250 dynes sec cm^–5; p<.01). Intravenous digoxin at a cumulative dose of 0.75 mg increased LVEF (23±2 vs. 31±2%; p<.01) but had no effect on SVR. These data indicate that this canine model of CHF responds to acute pharmacologic intervention in a manner comparable to that seen in patients with CHF. Accordingly, this model may be a useful tool for the preclinical evaluation of new drugs targeted toward the treatment of CHF and for investigating the mechanisms of action of drugs currently used for the treatment of this disease state.     

The calcium channel blocker nisoldipine delays progression of chronic renal failure in humans (preliminary communication)

Summary Chronic renal failure (CRF) patients with a stable course were asked to participate in a follow-up program in which they were randomized into two groups: 1) the placebo group taking their standard antihypertensive therapy without any calcium ion blocker: and 2) the nisoldipine group, those patients taking the calcium channel blocker nisoldipine as the only antihypertensive drug. The two groups had similar blood pressures on entering the study (151±21.3/90.7±7.4 mmHg in the nisoldipine and 146.7±18/94±9.4 mmHg in the placebo group). Their protein intake was also similar (daily average throughout the follow-up period: 0.83±0.18 g protein per kg body weight in the nisoldipine and 0.9±0.12 g in the placebo group). The patients were checked monthly. The follow-up averaged 11.1±4.8 months in the nisoldipine group and 13.7±4.2 months in the placebo group. The rate of progression of CRF, as expressed by the slope of the regression line of 1/serum creatinine versus time, decreased in the nisoldipine group from the initial (–8.03±4.91)×10^–3 to (–5.57±5)×10^–3) (two-tailed P-test=0.016) after intervention. The slopes tended to become steeper in the placebo group, with an initial slope of (–4.1±3.2)10^–3 changing to (–7.9±5)×10^–3 after intervention. This difference did not reach statistical significance (two-tailed P=0.072). The rate of progression of CRF decreased in 12 of 14 patients in the nisoldipine-treated group versus 3 of 11 patients in the placebo group. The decrease in blood pressure in the two groups was similar and statistically significant but was clinically of marginal importance (mean blood pressure in the nisoldipine-treated group were 111.4±11.7 mmHg before and 105.9±8.6 mmHg after intervention, and in the placebo group mean blood pressure was 110±12.8 mmHg before and 103.8±10.3 mmHg after intervention). The calcium ion blocker nisoldipine may be of benefit in slowing down the progression of CRF in patients who are already on protein restriction and whose blood pressure is adequately treated. However, in view of the different initial severity of renal failure in the two randomized groups with higher initial regression slope in the nisoldipine group, further studies are required to confirm these preliminary findings.     

Acute and chronic effects of a diuretic monotherapy with piretanide in congestive heart failure—A placebo-controlled trial

Summary To evaluate the acute and chronic effects of diuretic monotherapy with 3 mg piretanide bid, 46 patients (pts) with congestive heart failure (NYHA II-III) secondary to coronary artery disease were studied. Within 3 weeks of therapy, the patients lost 1.6 kg body weight. Forty-four patients reported a subjective feeling of improvement. Echocardiographically, a highly significant (p<0.001) reduction of diastolic and systolic diameters was found, as well as an increase of fraction shortening. Chest x-ray indicated a reduction of heart volume from 1012±263 ml to 936±233 ml (p<0.001). The serum potassium level remained unchanged. A subgroup of 26 pts underwent invasive hemodynamic examinations. IV injection of 6 mg piretanide resulted in an acute reduction of pulmonary wedge pressure (pc) from 20.2±5.3 mmHg to 11.9±5.0 mmHg (p<0.001); simultaneously a slight decrease of cardiac index from 3.2±0.6 l/min/m² to 3.0±0.4 l/min/m² was observed. Invasive control after 3 weeks of oral therapy showed no decline of the piretanide effect. The exercise tolerance increased clearly from 135±161 Wmin to 249±268 Wmin (p<0.05). A control group of further 14 pts was treated with placebo only and did not show any significant changes of pc (20.0±6.4 mmHg vs. 22.8±19.2 mmHg), exercise tolerance, or other clinical parameters. Thus, the diuretic monotherapy of congestive heart failure with piretanide is highly effective and shows a significant improvement in all clinical and hemodynamic parameters in the absence of any remarkable side effects.     

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.     

Worsening of left ventricular diastolic function during long-term correction of anemia with erythropoietin in chronic hemodialysis patients – an assessment by radionuclide ventriculography at rest and exercise

We studied the effect of correction of anemia with erythropoietin on left ventricular systolic and diastolic function at rest and exercise in 17 chronic hemodialysis patients by means of maximum exercise testing and equilibrium gated radionuclide angiocardiography on three occassions: 1) initial–before erythropoietin administration, 2) intermediate–at the time when the target hemoglobin level reached 100 g/l, and 3) long-term–after 12 months of therapy. After correction of anemia, the patients showed a significant improvement in their response to exercise regarding maximal work load achieved, exercise duration and recovery time. Ejection fraction and peak ejection rate remained unchanged during therapy. At rest, peak filling rate was reduced from 2.62 ± 1.0 (baseline) to 2.28 ± 0.9 (intermediate) end-diastolic volume per second, p < 0.01, while no significant difference was observed during exercise. The time to peak filling rate was prolonged significantly during EPO therapy from 157 ± 30 to 177 ± 28 ms at rest, p < 0.05, and from 101 ± 24 to 130 ± 27 ms during exercise, p < 0.01. By the time of the late study, there were no significant differences between the late and intermediate study. In conclusion, amelioration of anemia with erythropoietin in hemodialysis patients produced improvement in exercise capacity, but diastolic function worsened with therapy and this effect was maintained during the long-term treatment, while systolic function at rest and exercise remained unchanged.     

Effect of prostacyclin and prazosin in the treatment of congestive heart failure; with special reference to the sympathetic nervous system

Therapy to decrease the load in congestive heart failure is now classified as acute and chronic vasodilator therapy. In this symposium, we presented prostacyclin (PG I2) as an acute and prazosin as a chronic vasodilator. Their hemodynamic and clinical effectiveness were evaluated and their effect on the sympathetic nervous system was also studied. We studied the effect of intravenous prostacyclin infusion in doses of 22 +/- 11 ng/kg/min in nine patients with severe congestive heart failure refractory to digitalis and diuretic drugs. After prostacyclin infusion, mean pulmonary capillary wedge pressure decreased from 21.0 +/- 7.9 to 15.0 +/- 6.6 mmHg (p less than 0.001), mean arterial pressure from 98.9 +/- 12.8 to 76.2 +/- 7.0 mmHg (p less than 0.001), systemic vascular resistance from 2,574 +/- 384 to 1,368 +/- 283 dynes X sec X cm-5 (p less than 0.001), pulmonary vascular resistance from 1,008 +/- 451 to 443 +/- 135 dynes X sec X cm-5 (p less than 0.001) and pulmonary arteriolar resistance from 330 +/- 111 to 189 +/- 73 dynes X sec X cm-5 (p less than 0.001). The cardiac index increased from 2.0 +/- 0.37 to 3.2 +/- 0.59 l/min/m2 (p less than 0.001), and the stroke index from 27.6 +/- 8.69 to 42.0 +/- 0.62 ml/m2 (p less than 0.001). Moreover, prostacyclin therapy counteracted the sensation of coldness of the limbs and face, and patients felt warmth and mild flushing of the face. The effect of prazosin on the exercise duration time until dyspnea was evaluated by the treadmill test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a low, oral dose of nisoldipine on the systemic and coronary hemodynamics and the prostaglandin metabolism of ischemic heart disease patients

This study investigated the effects of a low dose of nisoldipine (5 mg, p.o.) in 10 patients with ischemic heart disease. The patients were subjected to a 90-min exercise regimen before and after a 5 mg dose of nisoldipine, using a supine bicycle ergometer adjusted to each patient's limitations. The mean blood plasma level of nisoldipine was 3.8 +/- 3.1 (SD) ng/ml. The drug significantly decreased the systolic arterial pressure in patients throughout the experimental session, whereas a change in the diastolic arterial pressure appeared only at the submaximal stage of the exercise. Additionally, at maximal exercise, nisoldipine caused a decrease in the mean coronary sinus pressure from 11.4 +/- 7 mmHg to 6.5 +/- 5 mmHg (p less than 0.01). By contrast, while at rest, nisoldipine decreased the coronary vascular resistance from 1.5 +/- 0.7 mmHg/ml/min to 1.0 +/- 0.7 mmHg/ml/min (p less than 0.05). After exercise, the drug decreased thromboxane B2 levels from 1133 +/- 907 pg/ml to 720 +/- 379 pg/ml (p less than 0.05) in the coronary sinus blood, and increased the 6 keto-prostaglandin F1 alpha levels from 465 +/- 135 pg/ml to 559 +/- 167 pg/ml (p less than 0.05) in brachial artery blood. This suggests that a low, oral dose of nisoldipine can moderately improve the systemic and coronary hemodynamics and afterloads, and may assist in improving the prostaglandin metabolism in ischemic heart disease patients.     

Effects of bisoprolol on left ventricular hypertrophy in essential hypertension

Summary Previous studies have shown that beta-adrenergic blocking drugs can reverse ventricular hypertrophy in patients with systemic hypertension. Thirty patients with essential hypertension and left ventricular hypertrophy were studied at baseline after withdrawing all previous treatments and after 6 months of treatment with 5–20 mg of bisoprolol, a new beta-selective agent, to assess its possible action on left ventricular mass. Three patients did not finish the study. Blood pressure was reduced to below 160/90 mmHg in 22 of the remaining 27 patients. At the end of follow-up, the left ventricular mass (echocardiography) was reduced from 308.1±89 g to 262.3±51 g (p<0.001) and left ventricular mass index from 165±47.4 g/m² to 141.03±26.7 g/m² (p<0.001). The ratio of E wave/A wave velocity of transmitral blood flow measured by Doppler increased from 0.86±0.44 to 1.07±0.45 (p=0.005). Peak filling rate, derived from nuclear ventriculography, changed from 2.05±0.4 EDV/sec before the treatment to 2.23±0.47 EDV/sec after it (p=0.0046). Serum lipids as well as other biochemical tests were unchanged. Left ventricular volumes and ejection fraction did not change, and treadmill exercise time increased from 343±125 seconds to 420±135 seconds (p=0.002). Maximal systolic blood pressure during exercise decreased from 197.2±19.7 mmHg to 182.9±25.8 mmHg (p=0.011). There were few side effects. We conclude that bisoprolol reduces left ventricular mass, preserves systolic function, and improves diastolic function of the left ventricle in hypertensive subjects with left ventricular hypertrophy.     

The acute effects of intravenous nisoldipine on left ventricular function 24 to 72 hours after uncomplicated acute myocardial infarction

Summary The acute effects on left ventricular function of nisoldipine were studied in six patients 56±12 hours (range 44 to 72 hours) after the onset of uncomplicated acute myocardial infarction. Nisoldipine was administered as a 4.5 g/kg intravenous bolus over 3 minutes followed by an infusion of 0.2 g/kg during 60 minutes. Radionuclide angiography and two-dimensional echocardiography were performed before and during infusien with nisoldipine. The left ventricular ejection fraction increased significantly from 38%±10% to 49%±10% (P=0.028) during nisoldipine infusion. Regional wall motion index was determined both by radionuclide and by two-dimensional echocardiography and showed a significant change during nisoldipine infusion from 1.9±0.3 to 1.5±0.3 (p=0.028, radionuclide angiography) and from 0.7±0.2 to 0.3±0.2 (p=0.043, two dimensional echocardiography). Heart rate increased significantly from 78±12 min^-1 to 92±13 min^-1 (p=0.028), but mean double product did not change significantly during nisoldipine infusion. It is concluded that nisoldipine significantly improves global and regional left ventricular function in patients shortly after acute myocardial infarction. This beneficial effect may, however, be partially offset by an increase in heart rate. Since mean double product did not change, it is suggested that nisoldipine may improve coronary blood flow in patients with acute myocardial infarction.     

Oral OPC-8212 for the treatment of congestive heart failure: Hemodynamic improvement and increased exercise capacity

Summary The chronic effects of the oral administration of OPC-8212 (3,4-DIHYDRO-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone) on resting hemodynamics and exercise capacity were assessed in 15 patients with congestive heart failure (NYHA II–IV). Doses of 30 or 60 mg per day were given per os over 3.0 weeks on average (range 2–6 weeks). Multigated radionuclide ventriculography and multistage exercise testing were performed before and during OPC-8212 therapy to assess the changes in left ventricular volume and exercise capacity respectively. Systolic blood pressure showed a slight increase (from 123±3 to 129±4 mmHg) during OPC-8212 therapy, while heart rate was unchanged (69±3 vs 67±3 beats/min). The left ventricular end-diastolic volume index decreased from 127±9 to 107±7 ml/m², and ejection fraction and the P/V index (the ratio of peak systolic pressure to left ventricular end-systolic volume index) increased during OPC-8212 therapy (from 27%±3% to 30%±4% and from 1.5±0.2 to 2.0±0.3 mmHg/ml/m² respectively). NYHA functional class was improved in 9 of 15 patients, and the average peak work load achieved during exercise testing increased from 27±6 to 47±7 W. No significant adverse effect was observed in any patient. These results indicate that OPC-8212 enhances the inotropic state and, hence, reduces heart size with no change in heart rate. Moreover, it increases exercise capacity. Thus, OPC-8212 is an inotropic agent with promise for application in the long-term treatment of congestive heart failure.     

Acute Hemodynamic Effects of Amlodipine 15 Days After a Myocardial Infarction in Normotensive Patients Treated with Atenolol

The acute hemodynamic effects of 20 mg iv amlodipine were evaluated in a placebo-controlled study in 16 normotensive patients 15 ± 1 days after an acute myocardial infarction by covariance analysis. Atenolol was given orally for at least 1 week before the study to maintain the heart rate between 50 and 60 beats/min. All patients were given two doses of 10 mg of amlodipine, or 10 ml of a placebo twice, in iv infusion lasting 2 minutes each. Hemodynamic data were collected during the control period and 15 minutes after each of the two amlodipine or placebo infusions. At the time of the last measurements, 15 minutes after the second amlodipine or placebo infusion, the plasma amlodipine level was 31 ± 16 g/l and the plasma atenolol level was 773 ± 564 /l in the amlodipine group versus 795 ± 916 g/l in the placebo group. There were no chronotropic, dromotropic, or inotropic effects. The main hemodynamic effect was a fall in systemic vascular resistance (1548 ± 591 dynes.sec.cm^-5to 1176 ± 526 dynes.sec.cm^-5, p = 0.045) with decreases in aortic pressure and in the left ventricular stroke work index. The left ventricular ejection fraction was 51 ± 12% in the placebo group and 56 ± 15% in the amlodipine group (ns) during the control period, and did not change after infusion of placebo or amlodipine. Left ventricular compliance seemed to be enhanced by amlodipine, because the end-diastolic left ventricular volume index rose from 82 ± 11 ml/m² to 87 ± 11 ml/m² (p = 0.026) 15 minutes after the beginning of the second infusion of 10 mg of amlodipine, without any change in end-diastolic left ventricular pressure. Intravenous infusion of 20 mg of amlodipine is well tolerated 15 days after acute myocardial infarction in normotensive patients without deeply depressed left ventricular systolic function and chronically treated with atenolol. The main hemodynamic effects observed are potentially useful for such patients.     

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.     

Myocardial,coronary, and peripheral effects of xamoterol (ICI 118,587) in open-chest pigs

Summary The hemodynamic and coronary effects of increasing doses of xamoterol, a beta-adrenoceptor partial agonist, were assessed in an anesthetized pig preparation in which cardiovascular reflexes were abolished and sympathetic tone was modified by infusion of noradrenaline (NA). Xamoterol, in basal conditions, increased heart rate (HR) from 104±12 to 120±13 beats/min (p<.001); systolic, diastolic, and mean blood pressure, respectively, from 77±8 to 103±17 mmHg (p<.01), from 48±7 to 70±12 mmHg (p<.01), and from 58±7 to 84±14 mmHg (p<.01); left ventricular dP/dT max from 2098±564 to 4205±937 mmHg/sec (p<.001); and systemic vascular resistance (SVR) from 1745±564 to 2270±739 dynes sec cm^–5 (p<.01). The increase in HR and dP/dT max brought about by xamoterol was about 37% and 56%, resectively, of the maximum increase produced by NA. At the highest level of sympathetic tone, xamoterol reduced HR from 148±11 to 122±11 beats/min (p<.001) and no significant change was observed in dP/dT max. The increase in blood pressure and SVR induced by xamoterol was maintained at each level of sympathetic tone. On the contrary, SVR did not change after NA, as expected, since receptors were fully blocked. For a given inotropic effect, xamoterol and NA produced a similar increase in coronary blood flow and myocardial O₂ consumption.In conclusion, the results indicate that, in the areflexic pig, xamoterol acts as a partial beta₁-agonist, with a more potent positive inotropic than chronotropic effect in basal conditions. At the highest level of sympathetic tone, it does antagonize the chronotropic, but not the inotropic, effect of NA. Xamoterol increases peripheral resistance and blood pressure possibly through a beta₂ vascular blocking action, and the increase in contractility induced by xamoterol is paralleled by an increase in myocardial O₂ consumption. No direct effects on coronary circulation are observed.     

An analysis of the pulsatile hemodynamic responses of the pulmonary circulation to acute and chronic pulmonary venous hypertension in the awake dog

In this study we measured high fidelity pulsatile pressure and flow waveforms at the inlet to the pulmonary vascular bed to assess the differences in adaptation to acute and chronic pulmonary venous hypertension in awake dogs. Acute elevations in left atrial pressure (P1a) were effected by inflation of left atrial balloons, while chronic elevations were accomplished by placement of aorta to left atrial shunts. Pulmonary artery hydraulic impedance was calculated and analysis of these data revealed marked differences between the responses to acute and chronic elevations of left atrial pressure. The acutely stressed dogs (n = 12) had significantly decreased pulmonary vascular resistance (when P1a = 16.9 +/- 1.0 mm Hg, PVR = 212 +/- 57 dynes sec/cm5; when P1a = 28.6 +/- 1.4 mm Hg PVR = 18 +/- 115 dynes sec/cm5; control P1a = 6.1 +/- 1.5 mm Hg, and PVR = 355 +/- 69 dynes sec/cm5) and normal characteristic impedances (ZO) (210 +/- 36, 227 +/- 39, 178 +/- 14 dynes sec/cm5, respectively), indicating recruitment of arteriolar-capillary perfusion density and no change in proximal pulmonary arterial physical properties. The chronic pulmonary venous hypertension group (n = 11) retained normal PVR (496 +/- 30 dynes sec/cm5) but demonstrated a markedly higher characteristic impedance, ZO = 361 +/- 11 dynes sec/cm5 (P < 0.001). This indicated a measurably different and extremely potent effect of chronic venous hypertension on the physical properties of the pulmonary vessels with an apparently increased arterial stiffness correlating with a 4-fold increase in Young's elastic modulus. These changes were not reversed by alpha-adrenergic blockade or acute lowering of left atrial pressures.     

The effect of isosorbide dinitrate on left ventricular size,wall stress and left ventricular function in chronic refractory heart failure: An echocardiographic study

To determine the effect of a long-acting vasodilator isosorbide dinitrate (ID) on ventricular performance, 16 patients with refractory congestive heart failure underwent echocardiographic studies during control and for a period of 2 hours after the administration of 10 mg of sublingual ID. The effects of ID were seen in 5 to 10 minutes, reached maximum at 30 ± 3 minutes lasted for 60 minutes and dissipated thereafter. At the maximal drug effect, a significant decline in mean blood pressure (74 ± 2 versus 81 ± 3 mm Hg, p < 0.001), left ventricular afterload (228 × 10³ ± 9 × 10³ dynes/cm² versus 273 × 10³ ± 12 × 10³ dynes/cm² p < 0.001), end-diastolic dimension (5.90 ± 0.13 versus 6.40 ± 0.15 cm, p < 0.005) and end-systolic dimension (4.8 ± 0.15 versus 5.50 ± 0.17 cm, p < 0.001) occurred. These changes were associated with a significant increase in per cent fractional shortening (19 ± 2 per cent versus 14.5 ± 1.3 per cent, p < 0.001), mean rate of circumferential fiber shortening (VCF) (0.78 ± 0.06 versus 0.61 ± 0.05 circumferences per second (circ/sec) p < 0.001) and normalized mean posterior wall velocity (VPW) (0.65 ± 0.05 versus 0.47 ± 0.03 sec^?1, p < 0.001) when heart rate was not significantly altered. All 16 patients were maintained on long-term ID therapy. Six of 16 patients (38 per cent) died within 17 to 270 days after the acute study. Nine of 16 patients have been followed for a period of three to 24 months and are clinically improved. These findings suggest that (1) ID reduces left ventricular size, preload and afterload, and improves ventricular performance; and (2) the use of ID might be of value as adjunctive therapy in acute/chronic management of refractory heart failure.     

Acute and Chronic Effects of Propionyl-L-Carnitine on the Hemodynamics, Exercise Capacity, and Hormones in Patients with Congestive Heart Failure

Carnitine is an important cofactor in the intermediary metabolism of the heart, and carnitine deficiency is associated with congestive heart failure. We therefore studied the effects of acute (IV bolus, 30 mg/kg body weight) and chronic administration (1.5 mg/d for 1 month) of propionyl-L-carnitine on hemodynamics, hormone levels, ventricular function, exercise capacity, and peak oxygen consumption in 30 patients with chronic congestive heart failure (NYHA II–III, mean EF 29.5 ± 7%) in a phase II, parallel, single-blind, randomized, and placebo-controlled study. Acute administration of propionyl-L-carnitine caused a significant reduction in pulmonary artery and pulmonary wedge pressures at both day 1 (P < 0.001) and day 30 (P < 0.05) of the study but no other hemodynamics changes. Hormone levels did not change following acute administration of the drug. Chronic administration of propionyl-L-carnitine increased peak oxygen consumption by 45% (from 16.0 ± 3 to 23.5 ± 2 mL/kg/min, P ± 0.001), exercise time by 21% (from 8.1 ± 0.5 to 9.8 ± 0.4 minutes, P < 0.01), and peak exercise heart rate by 12% (P < 0.01). These changes were concomitant with a reduction of pulmonary artery pressure. In the treated group, there was a slight, but significant (P < 0.01), reduction in left ventricular dimensions. Hemodynamics and hormones measured after 1 month of oral therapy remained unchanged, except for a fall in pulmonary artery pressures, with a nonsignificant trend towards a fall in filling pressures and plasma norepinephrine. The chronic changes in the propionyl-L-carnitine group were seen at 15 days of treatment, and no further changes in these parameters were seen at 1 month. We conclude that propionyl-L-carnitine increases exercise capacity and reduces ventricular size in patients with congestive heart failure. The drug has no significant effects on hemodynamics or neurohormone levels. The use of a single-blind design reduces the impact of the positive finding on exercise capacity.     

Hemodynamic interactions between diuretics and calcium antagonists in the treatment of hypertensive patients

Summary To investigate the hypotensive and hemodynamic effects of plain and extended-release (ER) formulations of felodipine added to a diuretic in the treatment of moderate essential hypertension, we studied 18 patients in a randomized, double-blind, cross-over study. Blood pressure (BP), heart rate (HR), hemodynamics (bioimpedance), foot volume (Archimedes' principle), and symptoms were evaluated after a 1-month placebo washout, after 1-month's treatment with a fixed combination of hydrochlorothiazide 50 mg plus amiloride 5 mg (HA), and then after felodipine 5 mg twice daily (F) or felodipine ER 10 mg daily (FER) (double-blind phase), each given for 2 weeks in a randomized sequence together with the diuretic. All measurements were performed at the end of the dosing interval. At baseline, supine SBP/DBP was 175.6±12.9/113.4±8.1 mmHg; HR was 77.3±7.0 beats/min; CO was 5.3±1.4 l/min; SVR was 2166±707 dynes sec. cm⁵, and foot volume was 433±195 ml (FV). HA induced a reduction (p<0.05) in BP; one patient had a DBP=90 mmHg and was excluded from the combination study; eight patients had a DBP reduction of 10 mmHg (responders), and their blood pressure was mainly reduced by a fall in SVR. HR, CO, and FV were unchanged. The addition of felodipine to a diuretic induced a further significant (p<0.001) reduction in BP with respect to HA alone, with no differences between F and FER. All patients had a DBP fall >10 mmHg, which had no relationship to their response to the diuretic. The antihypertensive effect of felodipine was due to a reduction in SVR (p<0.05). CO and HR were significantly (p>0.05) increased by felodipine added to HA. FV was increased by felodipine. During felodipine treatment, side effects were significantly decreased in comparison with placebo. Thus, a once-daily administration of 10 mg extended-release felodipine was equieffective with felodipine 5 mg twice daily in hypertensives who were sufficiently controlled by diuretic alone. The antihypertensive effect of felodipine is due to a reduction in SVR and is not prevented by diuretic treatment.     

Individual responses to transdermal nitrates after chronic administration in angina pectoris

The aim of this study was to investigate whether, and to which extent, sustained treatment with transdermal nitroglycerin plasters may lead to the development of tolerance in patients with effort-induced angina pectoris. Ten patients, all men, mean age 62.7 years, took part in a double-blind, cross-over, acute study, comparing the transdermal therapeutic system of nitroglycerin 10 mg/24 hours with placebo. Patients were then treated for 1 month with the active drug in single-blind condition, and finally they took part in a further acute study identical to the first. Cycloergometric exercise tests were carried out 4 hours after dosing. In comparison with placebo, the active drug significantly (P less than 0.01) increased ischaemic threshold (ST depression = 1 mm) after both acute (from 299 +- 92 to 413 +- 120 sec) and chronic treatment (416 +- 107 sec). The same results were obtained for exercise duration to peak exercise (acute study: from 336 +- 65 to 482 +- 90 sec; chronic treatment: 466 +- 118 sec). The final acute study confirmed the stability of angina, showing that the improvement in exercise tolerance after chronic treatment was entirely due to the pharmacological effect of the drug. In terms of single patient response to the active treatment, 7 of the 10 patients showed an improvement in exercise tolerance after both acute and chronic treatment, while in 3 patients no antianginal effect was observed. These results suggest that nitrate tolerance cannot be considered an inevitable finding in patients chronically treated with transdermal patches.     

Effects of Long-Term Digoxin Therapy on Heart Rate Variability, Baroreceptor Sensitivity, and Exercise Capacity in Patients with Heart Failure

We evaluated the effects of long-term digoxin therapy on exercise capacity and on physiological parameters reflecting autonomic tone in 23 patients with mild to moderate heart failure. Before and after maintenance digoxin treatment, all patients underwent cardiopulmonary exercise testing and indexes of heart rate variability (HRV) and baroreceptor sensitivity (BRS) were measured. Long-term digoxin therapy significantly (P > 0.05) increased time domain indexes (rMSSD, pNN50) which reflect parasympathetic activity (from 30 ± 16 to 37 ± 14 and from 8 ± 9 to 12 ± 7, respectively). High-frequency (HF) and low-frequency (LF) power spectral components also showed a significant increase (from 4.5 ± 1 to 5.1 ± 1 and from 5.4 ± 1 to 5.8 ± 1, respectively), but the ratio LF/HF decreased, indicating a predominance of vagal activity. The magnitude of these changes exhibited a strong negative Pearson correlation coefficient when compared with initial values before treatment. BRS increased from 2.95 ± 1.2 to 5.32 ± 3 ms/mmHg (P > 0.05). Oxygen consumption at peak exercise and at the anerobic threshold increased significantly (from 17 ± 3 to 19 ± 3 mL/kg/min and from 14.7 ± 3 to 16.5 ± 3 mL/kg/min, respectively). A persistent negative correlation was found between initial values of HRV and the magnitude of changes in exercise capacity. These findings show that long-term digoxin therapy increases vagal activity and improves exercise capacity in patients with mild to moderate heart failure and seems to exert a more marked therapeutic effect on patients with poorer initial autonomic function.