Biomedical subjects
Publications and source records attributed to A Cohen-Solal.
Studies conducted over recent years have definitively confirmed beta-blockers as the major treatment for heart failure. However, they are difficult to use and, to date, only carvedilol has been granted a Marketing Authorisation for this indication. The practical aspects of treatment with carvedilol in these patients are reviewed.
BACKGROUND: Coprescription of aspirin and ACE inhibitors is frequent in heart failure caused by coronary artery disease. Negative interaction between aspirin and enalapril has been reported, presumably through inhibition by aspirin of ACE inhibitor-induced prostaglandin synthesis. Ticlopidine is a potent antiplatelet agent without interaction with prostaglandin synthesis. METHODS AND RESULTS: The objective of this study was to compare the influence of a coadministration of ticlopidine or aspirin on the hemodynamic effects of an ACE inhibitor (enalapril) in patients with chronic heart failure. Twenty patients with severe heart failure were enrolled in a double-blind comparative trial and allocated to ticlopidine (500 mg daily, 12 patients) or aspirin (325 mg daily, 8 patients). Hemodynamic evaluation was performed after 7 days of treatment, every hour for 4 hours after an oral administration of 10 mg of enalapril. Significant reductions in systemic vascular resistance were observed in the ticlopidine group, in contrast to no significant decrease in the aspirin group. A significant (P=0.03) time-by-treatment interaction indicated significant aspirin-enalapril drug interaction. Total pulmonary resistance decreased significantly in both groups, with no difference between patients assigned to aspirin or ticlopidine. CONCLUSIONS: Enalapril reduced systemic vascular resistance more effectively when given in combination with ticlopidine than with aspirin. In contrast, the reduction in total pulmonary resistance is similar when enalapril is administered in combination with aspirin or ticlopidine. Negative aspirin-enalapril interaction on prostaglandin synthesis presumably alters vasodilatation in systemic vessels, whereas prostaglandin-independent actions of ACE inhibition such as pulmonary arterial vasodilatation are maintained.
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To evaluate the influence of increased right ventricular afterload on radionuclide assessment of the left ventricular ejection fraction (LVEF), we compared the preoperative and postoperative value of isotopic LVEF in 11 patients who underwent lung transplantation and had a preoperative LVEF value below 55% (normal value: 68 +/- 8%). The underlying disease conditions were obstructive lung disease (n = 7) and pulmonary fibrosis (n = 4). The transplantation procedure was unilateral in 10 patients and bilateral in one. The mean value of isotopic LVEF prior to transplantation was 51 +/- 3% (range: 49% to 55%). At 42 +/- 13 mo postoperatively, isotopic LVEF increased significantly, to 65 +/- 10% (p = 0.001), suggesting that intrinsic left ventricular systolic function was in fact normal in these patients. We hypothesize that the low preoperative isotopic LEVF was not related to intrinsic dysfunction of the left ventricle, but rather to right ventricular pressure overload, leading to bulging of the interventricular septum into the left ventricle and to subsequent geometric distortion of the left ventricle. We conclude that isotopic LVEF may underestimate intrinsic left-ventricular systolic function in patients with severe chronic lung disease. Candidates for lung transplantation should not be rejected on the basis of a low isotopic LVEF, provided echocardiographic examination does show apparently normal left ventricular contraction.
We assessed the ventricular-arterial coupling at peak exercise in 20 patients with dilated cardiomyopathy (ejection fraction, 27+/-12%) and 7 normal subjects by radionuclide ventriculography during exercise, coupled with respiratory gas analysis. The end-systolic pressure-volume ratio, taken as an index of contractility, and the effective arterial elastance were calculated at rest and at peak exercise. The end-systolic pressure/volume ratio increased from 3.7+/-2.7 to 6.9+/-4.0 mm Hg/mL at peak exercise in the normal subjects, but did not change significantly (from 0.9+/-0.5 to 1.0+/-0.6 mm Hg/mL) in the patients. Arterial elastance did not change significantly in the patients (+17+/-32%, not significant [NS] vs rest) or in the normal subjects (+22+/-28%, NS vs rest). The change in ejection fraction during exercise correlated both with the end-systolic pressure/volume ratio and with effective arterial elastance changes (r=0.60 and 0.68, respectively). We conclude that ventricular arterial coupling is further altered at peak exercise in these patients because of the lack of increase in contractility and not of altered effective arterial elastance response.
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Heart failure is a major problem of public health, associated with poor outcome in the advanced stage, thus justifying its prevention. Primary prevention is based on the prevention and treatment of its principal etiologic factors, hypertension and coronary artery disease. Broad use of echocardiography or dosage of neurohormonal markers improve detection of asymptomatic left ventricular dysfunction. In ischemic heart disease, coronary recanalisation prevents or limits left ventricular remodeling and dysfunction, even if the "open artery" theory has not been entirely proved. Understanding the deleterous role of neurohormonal stimulation results in a large use of ACE-inhibitors, which beneficial effect has been demonstrated also in case of asymptomatic left ventricular dysfunction. Betablockers, already largely used after myocardial infarction, seem to have also a beneficial effect in heart failure: the same is probably also true for angiotensin II-antagonists. Double blocking of both the sympathetic nervous system and the angiotensin-aldosterone system seems to be recommended. More precisely understanding the pathways signaling the processes of ventricular remodeling and dysfunction points to new potential targets for a preventive treatment: endothelin receptors, apoptosis, oxidative stress, cytokines or even angiogenesis.
Heart failure is defined as the inability of the heart to deliver a cardiac output sufficient for the needs of the periphery. The mechanisms responsible for ventricular failure always correspond for changes in ventricular filling that may have 2 origins: decrease in ventricular systolic function, leading the ventricle to operate on the vertical part of its pressure volume relationship; primary decrease in ventricular distensibility. An increase neurohormonal stimulation participates in sodium retention and in the preservation of blood pressure. The mechanisms leading to the progressive alteration of the haemodynamic status are not perfectly known, but a progressive increase in wall stress and myocyte loss are likely to occur.
BACKGROUND: Congestive heart failure is associated with decreased stimulated myocardial adenylate cyclase activity, increased Gi-binding protein, attenuated parasympathetic tone, and increased modulation of beta-adrenergic inotropic left ventricular stimulation by parasympathetic agonists. Despite these abnormalities, changes in the density or affinity of ventricular muscarinic receptors have not been demonstrated in patients. METHODS AND RESULTS: The density and affinity constants of myocardial muscarinic receptors were evaluated noninvasively by means of positron emission tomography with 11C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, in 20 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (mean left ventricular ejection fraction, 22+/-9%) and compared with values in 12 normal subjects. The mean receptor concentration was significantly higher in patients than in control subjects (B'max, 34.5+/-8.9 versus 25+/-7.7 pmol/mL, P<.005), with no changes in affinity constants. The change in heart rate after injection of 0.6 mg of cold MQNB was lower in patients than in control subjects (34+/-20% versus 55+/-36%, P<.05), and receptor density correlated negatively with maximal heart rate in the patients (r=.45, P<.05). CONCLUSIONS: Congestive heart failure is associated with an upregulation of myocardial muscarinic receptors. This may be an adaptive mechanism to beta-agonist stimulation and should increase the number of potential targets for pharmacological intervention.
Submaximal exercise tests have been advocated to assess exercise capacity in chronic heart failure, but hemodynamic responses have not been characterized. To determine left ventricular (LV) responses during submaximal exercise, the LV ejection fraction (EF) and volumes were evaluated by using an ambulatory radionuclide detector in 13 patients with idiopathic dilated cardiomyopathy during upright maximal graded bicycle exercise, stair climbing and a 6-minute walk test. The 3 tests elicited different responses in volumes and, to a lesser degree, in LVEF. The maximal bicycle exercise led to a decrease in LVEF from 22 +/- 9% to 17 +/- 8% (p <0.05), with marked increases in both end-diastolic volume (EDV) (+15 +/- 10%, p <0.001) and end-systolic volume (ESV) (+23 +/- 18%, p <0.001). Stair climbing tended to reduce LVEF (from 24 +/- 11% to 21 +/- 10%, p = 0.05), with a lesser increase in volumes, which was more marked for ESV (+8 +/- 9%, p <0.01) than for EDV (+4 +/- 4%, p <0.01). The 6-minute walk test did not significantly change LVEF (23 +/- 10% vs 22 +/- 10%), but increased both EDV (+10 +/- 6%, p <0.001) and ESV (+8 +/- 8%, p <0.01) moderately and proportionally. Exercise capacity indexes (peak oxygen consumption, maximal bicycle work rate, stair climbing time, and the distance covered during the 6-minute walk test) correlated significantly with one another. There was no correlation between submaximal exercise tolerance indexes and resting or exercise LVEF. This study shows that (1) LVEF changes are inadequate to report on LV volume changes during exercise; (2) the 3 tests induce different LV volume changes; (3) the 6-minute walk test induces significant changes in LV volumes but no change in LVEF.
Peak oxygen uptake (VO2) is attained at peak exercise in normal subjects. Recently, it was shown that the kinetics of the VO2 increase during exercise is slowed in chronic heart failure (CHF). We hypothesized that this may delay maximal VO2 after the end of exercise. We studied 21 patients who attained their peak VO2 15 s or more after cessation of a graded bicycle exercise test with breath-by-breath gas analysis (group 1). They were compared with 21 age- and sex-matched CHF patients who did not do so (group 2) and 21 normal subjects (group 3). Peak VO2 occurred 30 +/- 10 s (15-45) after exercise and was 10 +/- 7% (3-31) higher than end-exercise VO2 (P < 0.001) in group 1. Group 1 patients had poorer functional status (NYHA class 3.0 +/- 0.2 vs. 2.4 +/- 0.5), a smaller ejection fraction (21 +/- 6 vs. 26 +/- 8%), a lower end-exercise VO2 (1156 +/- 251 vs. 1535 +/- 508 ml/min), a lower anaerobic threshold (762 +/- 183 vs. 970 +/- 265 ml/min), and an identical respiratory exchange ratio (1.09 +/- 0.13 vs. 1.06 +/- 0.12) relative to group 2 patients. The delta VO2/delta workrate ratio was lower (9.5 +/- 2.0 vs. 11.2 +/- 1.1 ml/W) and the half-time of VO2 recovery was longer (156 +/- 27 vs. 95 +/- 27 s) in group 1 than in group 2 (P < 0.05, P < 0.01 group 1 vs. group 2). Slow kinetics of the VO2 increase with exercise may delay achievement of peak VO2 beyond the maximal workrate achieved. Gas exchanges should thus be measured also during recovery so as not to underestimate the true peak VO2, especially in severe CHF patients referred for heart transplantation.
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OBJECTIVE: To evaluate the ratio of peak oxygen consumption to peak heart rate (peak oxygen pulse) as a predictor of long term prognosis in chronic heart failure. PATIENTS AND SETTING: 178 consecutive heart failure patients recruited to the cardiology department of a tertiary referral centre between 1986 and 1993. DESIGN: Bicycle ergometry with measurement of respiratory exchange. Mean (SD) follow up was 32 (25) months. RESULTS: Patients who died had a lower peak oxygen consumption (16.0 (5.5) v 18.0 (5.5) ml/min/kg, p = 0.05), lower indexed peak oxygen consumption (52 (14) v 60 (16)%, p = 0.006) but similar peak oxygen pulse (8.4 (2.6) v 8.4 (3.0) ml/beat, NS). The following variables were associated with a good long term prognosis: New York Heart Association class II, non-ischaemic heart failure, peak oxygen consumption > or = 17 ml/min/kg, indexed peak oxygen consumption > 63%. Peak oxygen pulse did not have predictive value. Only indexed peak oxygen consumption remained an independent predictor of survival in multivariate analysis. CONCLUSIONS: Peak oxygen pulse has lower prognostic value than peak oxygen consumption, especially when the latter is indexed to predicted values.
BACKGROUND: The basic physiologic principle underlying cardiomyoplasty is long-term electrostimulation of a latissimus dorsi muscle (LDM) wrapped around the heart to obtain a phasic activity that could be integrated with ventricular kinetics. The aim of cardiomyoplasty is to prolong survival and to improve the quality of life of patients with severe chronic and irreversible myocardial failure by improving systolic contraction and correcting diastolic dysfunction. METHODS: To evaluate the long-term outcome of cardiomyoplasty, we investigated 82 patients electively undergoing this procedure in-our hospital. All patients had severe chronic heart failure that did not respond to optimal medical treatment. Patients had a mean age of 50 +/- 12 years (84% males). The cause of heart failure was ischemic (55%), idiopathic cardiomyopathy (34%), ventricular tumor (6%), and other (5%). The mean follow-up was 4.3 years. RESULTS: The mean New York Heart Association functional class improved after operation from 3.2 to 1.8. Average radioisotopic left ventricular ejection fraction increased from 17% +/- 6% to 28% +/- 3% (p < 0.05). Stroke volume index increased from 35 +/- 9 to 46 +/- 8 ml/beat/m2 (p < 0.05). The heart size remained stable at long term (evaluated by echo and computed tomography scanning). After cardiomyoplasty the number of successive hospitalizations resulting from congestive heart failure was reduced to 0.4 hospitalizations/patient/year (before operation 2.5, p < 0.05). Computed tomography scans showed at long-term a preserved LDM structure in 82% of patients who underwent operation. Survival probability at 7 years was 54% for the totality of patients, and 66% for patients who underwent operation in New York Heart Association functional class 3. Five patients underwent heart transplantation after cardiomyoplasty (mean delay 29 months), principally as a result of the natural evolution of their underlying heart disease, without major technical difficulties. CONCLUSIONS: Our 10-year clinical experience demonstrates that cardiomyoplasty increases ejection fraction, improves functional class, and ameliorates quality of life. Ventricular volumes and diameters remain stable long term. LDM structure is maintained long term if electrostimulation is performed avoiding excessive myostimulation. Patient selection is the most important determinant for early and late outcome. Late death in patients undergoing cardiomyoplasty is principally due to sudden death. Our future aim is to incorporate a cardioverter-defibrillator in the cardiomyostimulator, thus improving long-term results. Cardiomyoplasty may delay or prevent end-stage heart failure and the need for heart transplantation.
The authors compared the clinical and angiographic characteristics of 44 patients with unstable angina according to cardiac Troponine I concentrations (TnIc) during early blood sampling and then tried to determine a threshold value to predic the occurrence of cardiac events during the hospital period and after 12 months. Tnlc, creatinine-kinase (CK), CK-MB activity and CK-MB mass were sampled over 48 hours. Forty-five per cent of patients had TnIc > or = 0.1 microgram/L; CK-MB activity and CK-MB mass were detected in 16 and 32% of patients. Age, gender, classification and recurrence of angina, previous cardiac history, risk factors, coronary angiographic appearances were comparable in patients with and without raised TnIc. No major cardiac events occurred during the hospital period in either group. The number of angioplasties and coronary bypass procedures was also comparable. At one year, the incidence of myocardial infarction (N = 4) and death (N = 5) was significantly different in patients with raised Tnlc (33% versus 0% in patients without increased TnIc). However, betablocker therapy was less prescribed in the group with the poorest outcomes and left ventricular dysfunction was also significantly more common in this group. Early elevation of Tnlc could contribute to the identification of a high risk subgroup of patients with unstable angina.
Cardiomyoplasty is a surgical procedure aimed at assisting the left ventricle during ejection. We describe the long-term effects of cardiomyoplasty on peak exercise capacity, with serial assessments for up to 3 years after operation. Sixteen patients (12 in New York Heart Association class III and 4 in class IV) were enrolled. The mean left ventricular ejection fraction was 18 +/- 8%. Bicycle exercise tests with respiratory gas analysis were performed preoperatively and 6, 12, 18, 24, and 36 months after operation. Mean follow-up was 12 +/- 5 months (range 6 to 24). At 6 months, peak oxygen consumption and the ventilatory threshold were unchanged (from 17.8 +/- 5.8 to 15.8 +/- 5.3 ml/min/kg, and from 12.1 +/- 2.7 to 11.4 +/- 3.4 ml/min/kg, respectively). Ventilation at 50 W, viewed as an index of polypnea at submaximal exercise, was also unchanged. Serial assessment of exercise capacity thereafter showed no changes. However, ejection fraction tended to increase from 18 +/- 8% to 21 +/- 9% (p=0.08) and 14 patients reported an improvement in their functional status, resulting in a significant change in New York Heart Association functional class (3.3 +/- 0.5 to 2.2 +/- 0.4 at 6 months and 2.4 +/- 0.4 at the last visit, p <0.005) and improvement in quality-of-life scores. Thus, cardiomyoplasty does not appear to increase peak exercise capacity in the long term, despite an improvement in the left ventricular ejection fraction. Symptoms and quality of life, however, appear to improve. This may be related in part to an insufficient number of assisted systoles during exercise, persistent deconditioning, or changes in pulmonary mechanics.
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The investigation of left ventricular contractile reserve usually requires the determination of left ventricular volume, but its measurement with radionuclide angiography is difficult. The aim of this study was to determine left ventricular volume directly during exercise by the simultaneous measurement of peak exercise left ventricular ejection fraction (LVEF) and oxygen consumption (VO2max) and to compare the results with another geometric method. In the absence of lung disease, the systemic arteriovenous oxygen difference (DAVmax) during maximal exercise converges to 0.13-0.14 ml O2 per ml blood. The measurement of VO2max allows maximal cardiac output (COmax) to be calculated as VO2max = COmax. DAVmax. By simultaneously determining LVEFex, exercise end-diastolic volume (EDVex) can then be expressed as a linear function of VO2max, maximal heart rate (HRmax), DAVmax and LVEFex. Then, the relationship between end-diastolic counts and true volume can be derived at rest. The two methods were closely correlated (r = 0.91, P < 0.001), despite the geometric method being less accurate when applied to low counting statistic acquisitions. We conclude that rest and exercise left ventricular volume can be determined non-invasively by the simultaneous measurement of VO2max and LVEFex. Furthermore, this method provides additional prognostic information which is clinically relevant in the staging of patients with heart failure.