Effects of vasodilator treatment with felodipine on haemodynamic responses to treadmill exercise in congestive heart failure.

Treatment with vasodilators in heart failure has not always produced a useful improvement in the haemodynamic responses to exercise, and in many cases early drug tolerance has further limited the potential of this type of treatment. In a study to evaluate the efficacy of felodipine, a new calcium antagonist with selective vasodilator properties, in the management of congestive heart failure 10 patients with congestive heart failure underwent treadmill exercise testing before and during oral treatment with felodipine 30 mg daily. At every level of exercise felodipine lowered the pulmonary capillary wedge pressure, whereas cardiac index and stroke index increased considerably. The haemodynamic improvement was associated with an increase in the duration of exercise to exhaustion. Importantly, these beneficial effects were sustained throughout four weeks of treatment without evidence of drug tolerance. These observations suggest a useful role for felodipine in the long term management of congestive heart failure.     

Acute haemodynamic and metabolic effects of felodipine in congestive heart failure.

Felodipine is a new calcium antagonist with a high degree of vascular selectivity. To examine its potential value as an afterload reducing agent in congestive heart failure 11 patients were studied. Substantial increments in cardiac index were associated with a fall in systemic vascular resistance. Left ventricular end diastolic pressure was also significantly reduced. Although left ventricular maximum dP/dt remained unchanged, maximum dP/dt/P increased. Left ventricular unloading was reflected by a reduction in cavity dimensions and a shift in the relation between end systolic pressure and dimension downwards and to the left. The myocardial oxygen supply to demand ratio was also improved: coronary sinus flow increased significantly despite a decline in myocardial oxygen consumption. These beneficial haemodynamic and metabolic effects suggest that felodipine may extend the clinical application of calcium antagonists to include the treatment of congestive heart failure.     

Efficacy of felodipine in congestive heart failure

The efficacy of felodipine, a vasodilating calcium antagonist, was analysed in 23 patients with congestive heart failure, New York Heart Association class III, during an 8-week, double-blind, randomized, placebo-controlled, parallel study. After felodipine, exercise duration increased significantly without changes in oxygen consumption. Heart rate, arterial pressures and rate pressure product decreased at similar submaximal exercise levels. Invasive haemodynamics before and after 8 weeks of therapy revealed arterial vasodilation without reflex tachycardia and no significant reduction in right atrial, pulmonary and capillary wedge pressures. Subjective symptom scores improved and side-effects were minor. Fluid retention, as assessed by body weight and ankle circumference did not occur. Felodipine has a beneficial effect in patients with moderately severe heart failure. Further research is necessary to demonstrate its long-term efficacy and safety.     

Cardiovascular and neurohumoral postural responses and baroreceptor abnormalities during a course of adjunctive vasodilator therapy with felodipine for congestive heart failure

Studies in patients with congestive heart failure (CHF) have demonstrated an abnormal beta-adrenergic reflex vasodilation during orthostatic tilt. Baroreflex modulation of vascular resistance in patients with CHF was investigated during therapy with a vasoselective calcium antagonist, felodipine. Eight patients on conventional therapy for severe CHF were studied after a 3 week course of additional felodipine or placebo treatment under randomized, double-blind, and crossover conditions. Forearm subcutaneous vascular resistance (FSVR) was estimated with use of the local 133Xe washout. Aortic pulsatile stretch, expressed as the systolic distension in percent of diastolic diameter, was calculated from echocardiographic measurements of aortic root diameters. At 3 weeks, felodipine reduced the arterial pressure, systemic vascular resistance, and FSVR, preserved cardiac filling pressures and heart rate, and increased cardiac output, stroke volume, and aortic pulsatile stretch. Upright tilt (45 degrees) was used to study baroreflex-mediated cardiovascular responses. The unloading of cardiopulmonary baroreceptors during upright tilt was substantial and about equal during both treatment courses, but the pulse pressure was maintained during the placebo and decreased during the felodipine period. During tilt, the patients on placebo failed to increase heart rate and their FSVR, systemic vascular resistance, and arterial mean pressure were decreased, whereas during tilt after felodipine, heart rate and systemic vascular resistance increased to maintain arterial mean pressure and FSVR also tended to increase. Both the stroke volume and aortic pulsatile stretch increased during tilt in patients on placebo but they decreased in those on felodipine. The tilt caused increments in circulating norepinephrine and epinephrine levels during both treatment regimens. Regulation of FSVR during the sympathetic stimulation of orthostatic stress was further elucidated. Proximal neural blockade caused an increase in FSVR during tilt in patients on placebo and a decrease in FSVR during tilt in those on felodipine. Local beta-adrenoceptor blockade caused similar increments in FSVR during tilt in patients on both treatments. Combined proximal and local blockade still increased FSVR during tilt in those on placebo, but caused no change in FSVR during tilt in those on felodipine. This study demonstrates that felodipine normalizes baroreflex control of vascular resistance in patients with CHF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of active muscle mass size on cardiopulmonary responses to exercise in congestive heart failure

Previous studies from this laboratory demonstrated that in healthy young men, cardiac output is closely coupled to oxygen uptake during dynamic exercise, regardless of its mode or relative intensity, whereas other physiologic responses such as heart rate, blood pressure and ventilation are inversely related to the size of the active muscle mass when expressed as functions of oxygen uptake. The purpose of the current investigation was to determine whether congestive heart failure alters the pattern of physiologic responses to various modes of arm and leg exercise in proportion to the size of the active muscle mass. Cardiopulmonary responses to four modes of dynamic work (one arm curl, one arm cycle ergometry, one leg cycle ergometry and two leg cycle ergometry) were characterized in terms of absolute and relative intensities (oxygen uptake and mode-specific percent of peak oxygen uptake, respectively) in middle-aged men with congestive heart failure and control groups of healthy subjects and patients after myocardial infarction without heart failure. Peak oxygen uptake was reduced to the greatest extent in patients with heart failure for large muscle mass work (-13% for curl, -32% for one arm and one leg cycle ergometry and -37% for two leg cycle ergometry; p less than 0.05 versus the normal group for the three modes of ergometry). This finding was paralleled by a markedly blunted slope for the cardiac output-oxygen uptake relation for leg but not arm exercise that was only partially compensated for by a widened arteriovenous oxygen difference. Blood pressure expressed as a function of oxygen uptake remained inversely related to active muscle mass size in all groups of subjects despite attenuation of systolic pressure for heavy large muscle mass effort in the group with heart failure. Pulmonary ventilation at a given metabolic rate was not influenced by active muscle mass size. Thus, saturation of capacity for systemic oxygen transport occurs in conjunction with blunted cardiac output reserve in patients with heart failure during exercise involving a smaller muscle mass than in healthy subjects. The basic inverse relation between size of the active muscle mass and blood pressure at a given metabolic rate is not altered by aging or reduced cardiac reserve. The muscle mass effect on ventilation seen in young healthy subjects disappears with aging.     

Hemodynamic effects of felodipine in congestive heart failure

Summary The hemodynamic effects of increasing dosages of felodipine, a new calcium antagonist with selective vasodilator properties, were studied in 13 patients with chronic cardiac failure. A Swan-Ganz thermodilution catheter was positioned in the pulmonary artery and hemodynamic parameters were monitored from 9 am to 6 pm for five days. On the first and the fifth day patients received placebo (P) and on the second, third, and fourth day patients received felodipine 5, 10, and 20 mg, respectively. Symptom-limited exercise tests with a bicycle ergometer were performed on both days of P and on the fourth day. A marked reduction of systemic vascular resistance (SVR) and a significant increase of cardiac index without increments of heart rate (HR) were observed after felodipine at rest. A dose response effect could be demonstrated. During exercise a significant increment of cardiac index and decrease of pulmonary wedge pressure was observed after felodipine. Felodipine showed a potent vasodilator action on systemic circulation with significant changes on both stroke volume and filling pressures at rest and during exercise without side effects.Part of the data in this paper was presented at the Cardiovascular Pharmacotherapy International Symposium in Geneva, Switzerland, April 1985     

Restoration of normal reflex responses to orthostatic stress during felodipine therapy in congestive heart failure

The mechanisms underlying the abnormal responses to orthostatic stress in congestive heart failure are ill defined and little is known about the effects of specific therapy. In the present study intravascular pressures and plasma noradrenaline levels were measured in nine patients with heart failure subjected to 45 degrees and 90 degrees upright tilt. Studies were repeated during 4 weeks of vasodilator therapy with felodipine and again after felodipine withdrawal. Before the introduction of vasodilator therapy, tilt did not activate orthostatic reflexes despite significant reductions in left ventricular filling pressure and cardiac output. Thus, plasma noradrenaline, heart rate and systemic vascular resistance were unaffected and blood pressure fell. Felodipine resulted in a rapid and sustained improvement in left ventricular function but restoration of orthostatic reflexes was delayed and could be detected only after 48 h therapy. At this time, and during the subsequent 4 weeks, tilt-induced reductions in ventricular filling and cardiac output produced a normal rise in plasma noradrenaline and heart rate. A postural drop in blood pressure, however, was not averted because the direct action of felodipine on vascular smooth muscle prevented adrenergically-mediated increments in systemic vascular resistance. Felodipine withdrawal led to a prompt deterioration in left ventricular function. Orthostatic reflexes, however, were still intact 48 h later when tilt elicited a completely normal pattern of responses. These observations confirm that the abnormal responses to orthostatic stress in congestive heart failure are due principally to impairment of autonomic control mechanisms and are not related to the absence of venous pooling. Importantly the autonomic dysfunction is reversible with felodipine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different results in cardiopulmonary exercise tests after long-term treatment with felodipine and enalapril in patients with congestive heart failure due to ischaemic heart disease

We evaluated the cardiopulmonary exercise test results before and after long-term (16 weeks) treatment with the dihydropyridine calcium antagonist, felodipine (10 mg b.i.d., n = 9), and the ACE inhibitor, enalapril (10 mg b.i.d., n = 11), in 20 patients with New York Heart Association class III congestive heart failure. There were no significant differences at baseline. After 16 weeks patients in the enalapril group showed a significant increase in exercise duration and VO2max, without changes in arterial pressures and heart rate. In the felodipine group, exercise duration and VO2max did not change significantly, but arterial pressures and heart rate were significantly reduced at all exercise levels. Between group analysis showed a significant reduction in arterial pressures and heart rate in the felodipine group compared with enalapril, but no differences in aerobic capacity and exercise duration. These results demonstrate that felodipine and enalapril have essentially different effects on cardiopulmonary exercise results in patients with congestive heart failure.     

Chronic vasodilator therapy with flosequinan in congestive heart failure

This study was conducted to determine the long-term effect of flosequinan, a new orally administered arterial and venous dilator, on the clinical course of patients with moderate to severe congestive heart failure. Seventeen patients on chronic digitalis and diuretic therapy were randomized to receive either flosequinan (n = 9) or placebo (n = 8) in a double-blind fashion. Changes in symptomatology, exercise performance, and left ventricular function were assessed serially during the two-month treatment period. During the course of therapy, a modest improvement in the symptom scores and functional classification of the flosequinan-treated patients was observed. Flosequinan evoked a significant increase in maximal exercise capacity. While long-term flosequinan administration also effected a progressive increase in resting heart rate, it did not consistently improve indices of left ventricular systolic function. The addition of chronic vasodilator therapy with flosequinan to standard digitalis-diuretic regimens is capable of inducing clinical improvement in patients with moderate to severe chronic heart failure. Trials involving larger patient populations will be necessary to confirm the results of this preliminary study and to determine the extent of clinical improvement, subpopulations benefited, role in heart failure therapeutics, and so forth.     

Efficacy of felodipine in chronic congestive heart failure: a placebo controlled haemodynamic study at rest and during exercise and orthostatic stress

A vascular selective calcium antagonist, felodipine, was evaluated in a randomised, double blind, crossover trial in 18 patients with chronic congestive heart failure of ischaemic cause. Felodipine (10 mg twice daily) or a corresponding placebo was added to conventional treatment. After three weeks haemodynamic function was assessed at rest, during a standard supine leg exercise, and during 45 degrees passive upright tilt. In patients in the supine resting position, felodipine reduced the mean arterial pressure (9%) and systemic vascular resistance (24%) and increased the stroke volume (25%) and cardiac index (23%). The heart rate and right and left ventricular filling pressures were unchanged. During felodipine treatment the standard exercise was accomplished at a similar cardiac index but at a substantially lower heart rate (7%), arterial pressure (10%), systemic vascular resistance (17%), and left ventricular filling pressure (19%), and a higher stroke volume (13%). During both placebo and felodipine administration there were substantial reductions in cardiac filling pressure during upright tilting. Upright tilting during the placebo phase did not increase the heart rate. It also caused a greater fall in systemic vascular resistance while the arterial pulse pressure but not the mean pressure was maintained and the cardiac index and stroke volume increased. The reduced cardiac filling pressures during the felodipine upright tilt were accompanied by reductions in arterial pulse pressure and stroke volume and the patients were able to maintain the mean arterial pressure by an increase in both the heart rate and systemic vascular resistance. Thus three weeks treatment with felodipine improved haemodynamic function at rest and during standard exercise and normalised the baroreflex mediated haemodynamic response in patients with congestive heart failure. The haemodynamic efficacy of the drug in such patients may be associated with a baroreceptor mediated effect as well as direct vasodilatation.     

Efficacy of felodipine in chronic congestive heart failure: a placebo controlled haemodynamic study at rest and during exercise and orthostatic stress.

A vascular selective calcium antagonist, felodipine, was evaluated in a randomised, double blind, crossover trial in 18 patients with chronic congestive heart failure of ischaemic cause. Felodipine (10 mg twice daily) or a corresponding placebo was added to conventional treatment. After three weeks haemodynamic function was assessed at rest, during a standard supine leg exercise, and during 45 degrees passive upright tilt. In patients in the supine resting position, felodipine reduced the mean arterial pressure (9%) and systemic vascular resistance (24%) and increased the stroke volume (25%) and cardiac index (23%). The heart rate and right and left ventricular filling pressures were unchanged. During felodipine treatment the standard exercise was accomplished at a similar cardiac index but at a substantially lower heart rate (7%), arterial pressure (10%), systemic vascular resistance (17%), and left ventricular filling pressure (19%), and a higher stroke volume (13%). During both placebo and felodipine administration there were substantial reductions in cardiac filling pressure during upright tilting. Upright tilting during the placebo phase did not increase the heart rate. It also caused a greater fall in systemic vascular resistance while the arterial pulse pressure but not the mean pressure was maintained and the cardiac index and stroke volume increased. The reduced cardiac filling pressures during the felodipine upright tilt were accompanied by reductions in arterial pulse pressure and stroke volume and the patients were able to maintain the mean arterial pressure by an increase in both the heart rate and systemic vascular resistance. Thus three weeks treatment with felodipine improved haemodynamic function at rest and during standard exercise and normalised the baroreflex mediated haemodynamic response in patients with congestive heart failure. The haemodynamic efficacy of the drug in such patients may be associated with a baroreceptor mediated effect as well as direct vasodilatation.     

Hemodynamic responses to sublingual nifedipine during exercise and recovery in congestive heart failure

To elucidate the hemodynamic responses to sublingual nifedipine administration during exercise and recovery in congestive heart failure, 16 patients with dilated cardiomyopathy (DCM) and 11 controls were studied using supine bicycle exercise testing. The cardiac index (CI) was measured at rest, at peak exercise and successively during recovery by the thermodilution method. The heart rate (HR), mean blood pressure (mBP) and mean pulmonary arterial pressure (mPAP) were measured every minute. The same exercise load and hemodynamic measurements were repeated about 30 min after the sublingual administration of 10 mg nifedipine. The recovery slope in each parameter was analyzed using an exponential function (Cp = C1ekt). The regression coefficient in each parameter was defined as a CI slope, an HR slope, an mBP slope and an mPAP slope. Before the administration of nifedipine, CI at peak exercise was lower, mPAP during recovery was persistently higher and the CI slope was more blunt in DCM patients, compared with those of the controls. With the administration of nifedipine, CI and HR increased or tended to increase, mBP decreased throughout the exercise and recovery, and mPAP decreased at rest, at peak exercise and one min after exercise in the controls. In DCM patients, however, the CI increased, mBP and mPAP decreased nearly throughout the exercise and recovery, while HR increased throughout the exercise and recovery, except at peak exercise. The CI, HR and mPAP slopes were blunted in the controls; whereas, each slope showed no change in DCM patients. These results suggest that sublingual nifedipine administration can reduce both the preload and afterload, and increase CI throughout exercise and recovery without significant alteration in the recovery course.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute and chronic efficacy of felodipine in congestive heart failure

In 13 patients with congestive heart failure we tested the acute hemodynamic effects of 5 vs. 10 mg felodipine tablets, in a double-blind, cross-over study. One hour after felodipine 5 mg, echocardiographic ejection fraction (%), cardiac index (thermodilution-ml/min/m2), and pulmonary wedge pressure (mm Hg) significantly changed (from 21 +/- 2 to 26 +/- 2, 2350 +/- 150 to 2790 +/- 160, 24 +/- 4 to 17 +/- 4) while they remained steady after felodipine 10 mg. The greatest stroke index increases were associated with felodipine 5 mg in 12 patients and 10 mg in 1 patient. Therefore we evaluated (open study) the long-term (2 months- 1 year) clinical and hemodynamic efficacy following the treatment with the acutely most effective dose (twice daily). After 2 months ejection fraction, cardiac index and pulmonary wedge pressure were respectively 24 +/- 2, 2550 +/- 150, and 18 +/- 4 (12 hours after the last drug administration, n = 11, P less than 0.02 from baseline). These parameters further increased one to two hours after the following administration of felodipine. Clinical improvement (reduction of 1 functional class, according to the New York Heart Association) was observed in 8/13 patients. These 8 patients participated to the one year follow-up. In 5 patients follow-up was interrupted because of acute cardiovascular events. However, before study interruption (5 patients) or ending (3 patients) clinical status did not worsen and ejection fraction remained higher than in the pretreatment period. Therefore, low dose felodipine might be used in the treatment of congestive heart failure.     

Combined vasodilator therapy for chronic congestive heart failure

There are few data to support the potential efficacy of combined vasodilator therapy for severe congestive heart failure. For documentation of the feasibility of such an approach, a short-term hemodynamic study utilizing captopril, an oral converting enzyme inhibitor, followed by the addition of nitroprusside infusion, was made of 11 patients with severe chronic congestive heart failure. Captopril alone resulted in reduction of mean arterial pressure (84 +/- 7 to 70 +/- 3 mm Hg), associated with increase of cardiac index and stroke index. There was also a significant reduction of systemic resistance and pulmonary wedge pressure. The initial hemodynamic response to captopril was correlated with initial plasma renin activity (all values at least p less than 0.05). The addition of nitroprusside to captopril resulted in further hemodynamic improvement. Reduction of mean arterial pressure, systemic vascular resistance, and pulmonary wedge pressure were all significant, as were increases of cardiac index and stroke index. The degree of hemodynamic improvement with this sequence of vasodilator therapy was linearly related to the reduction of mean arterial pressure. Therefore vasodilators with dissimilar mechanisms of action may have an additive effect. These data support the potential feasibility of combined, long-term oral vasodilator therapy in selected subgroups of patients with congestive heart failure.     

Mechanisms and implications of vasodilator tolerance in the treatment of congestive heart failure

Vasodilators play an important role in the treatment of the patient with severe heart failure and increased systemic vascular resistance. However, there are both clinical data and theoretic reasons to anticipate that some degree of tolerance may develop during the long-term use of most agents. The cause of the increased vascular resistance of heart failure is not completely understood, but it appears to be related to a number of neuroendocrine, molecular and physical mechanisms including increased activity of the sympathetic nervous and renin-angiotensin systems, and increased vascular stiffness due to intra- and extracellular sodium and fluid accumulation. Not surprisingly, a lowering of systemic vascular resistance either by direct smooth muscle relaxers or by blockade of specific neuroendocrine systems may result in a number of compensatory responses at the neuroendocrine and/or molecular level. The over-all effectiveness of a particular vasodilator is the net sum of its direct pharmacologic action, and the neuroendocrine and molecular responses to the drug. The specific compensatory mechanisms activated depend on several factors including the type of vasodilator used, the dose employed, the baseline neuroendocrine status of the patient, the severity of heart failure and the functional integrity of various reflex systems. Although not directly applicable to patients with heart failure, much information derived from the use of these agents to treat patients with hypertension and angina pectoris suggests several potential mechanisms by which tolerance may develop to virtually all classes of vasodilators. The major types of vasodilators are discussed with regard to their potential mechanisms of tolerance. Finally, the evidence currently available from long-term studies is reviewed in order to assess the potential relevance of vasodilator tolerance to the clinical management of the patient with heart failure.