[Heart failure with preserved ejection fraction: a systemic disorder?]. / L'insuffisance cardiaque à fraction d'éjection préservée : une maladie de système ?

When the syndrome of heart failure (HF) is due to left ventricular (LV) systolic dysfunction the clinical manifestations and natural history of the syndrome depend primarily on the severity of LV systolic dysfunction. In contrast, when the syndrome is attributed to LV diastolic dysfunction multiple comorbidities are responsible for the clinical manifestations and the natural history of the syndrome. The present review underscores the multifactorial pathogenesis of the syndrome of HF associated with LV diastolic dysfunction that nowadays is more properly referred to as HF with preserved LV ejection fraction (HFpEF) than to diastolic HF. The prognosis is similarly poor whether HF is due to systolic dysfunction or associated with diastolic dysfunction. The cause of death that is commonly non-cardiovascular in HFpEF supports the pathogenic importance of comorbidities in this condition. Hypertension, chronic kidney disease (CKD), diabetes, obesity and sleep disorder breathing are among the most frequent comorbidities in HFpEF. These comorbidities account for the multiple clinical presentations of the syndrome of HFpEF. Limited functional capacity is in HFpEF largely related to the downward spiral between CKD mediated fluid accumulation and LV stiffness as well as altered ventricular-vascular coupling. The diagnosis of HFpEF currently relies on 2D-Doppler echocardiography findings of impaired LV relaxation and increased LV stiffness and to a lesser extent on biomarkers. Owing to both lack of stringent inclusion and exclusion enrollment criteria and mistaken therapeutic target, placebo-controlled randomized therapeutic trials have been so far negative in HFpEF.

Progression and management of chronic heart failure.

Current heart failure therapeutic guidelines are based on a new classification of the progression of the syndrome of chronic heart failure (CHF) that was proposed by ad hoc committees of the American College of Cardiology (ACC) and the American Heart Association (AHA). The new ACC/AHA classification depicts the progression of CHF in 4 stages that are labeled A to D. The 4 stages range from risk factors for CHF (A) to the presence of structural heart disease (B) and the development of symptoms (C). The last stage (D) is one of low cardiac output state despite optimal medical therapy. The merit of this new classification is to encourage tailoring of CHF therapy according to the stage of the syndrome. However, except for the final stage D that has clear therapeutic implications, the first 3 stages A, B and C do not have clear therapeutic implications. Moreover, these first 3 stages may inadvertently delay the diagnosis of CHF and fail to identify the important therapeutic target at each stage of CHF. A revised classification consisting of only 3 stages is proposed. These 3 stages are: 1) Left ventricular (LV) remodeling; 2) clinical heart failure and 3) low cardiac output state. These 3 stages have the advantage of delineating precise therapeutic targets at each stage thereby facilitating the management of patients with CHF by non-experts in the field.

Angiotensin II type 1 receptor blockade with 80 and 160 mg valsartan in healthy, normotensive subjects.

BACKGROUND: An 80-mg dose once or twice daily is the dose of valsartan frequently administered for treatment of hypertension. The target dose selected for the Val-HeFT trial in patients with chronic heart failure is 160 mg twice daily. The level and time course of angiotensin II type 1 (AT(1))-receptor blockade achieved by 160 mg valsartan have not been reported. METHODS AND RESULTS: Seven normotensive healthy subjects were assigned in random order to receive a single dose of placebo, 80 mg valsartan, and 160 mg valsartan at 7- to 10-day intervals. AT(1)-receptor blockade level (%) was determined by the pressure response to administration of exogenous angiotensin II. The pressure response to angiotensin II was measured at baseline and 2, 6, 12, and 24 hours after oral administration of placebo, 80 mg valsartan, and 160 mg valsartan. Eighty and 160 mg valsartan resulted in a significant and similar level of AT(1)-receptor blockade at 2 and 6 hours compared with placebo. The 160-mg dose resulted in a significantly greater level of AT(1)-receptor blockade than 80 mg at 12 and 24 hours. CONCLUSIONS: During the first 6 hours after oral administration of 80 and 160 mg valsartan the level of AT(1)-receptor blockade is similar. However, only 160 mg valsartan provides sustained AT(1)-receptor blockade over 24 hours.

Dose-dependent blockade of the angiotensin II type 1 receptor with losartan in normal volunteers.

Losartan, an angiotensin II type 1 receptor (AT1) antagonist, was developed as a more specific alternative to angiotensin-converting enzyme (ACE) inhibitors. At a daily dose of 50 mg, losartan is currently evaluated in large outcome trials involving patients with hypertension and postmyocardial infarction. The current study evaluated the level and duration of blockade of a pressor response to angiotensin II by 50 and 150 mg of losartan, compared with 32 mg of candesartan. Eight normotensive volunteers were randomly assigned to a single dose of losartan 50 or 150 mg, candesartan 32 mg, or placebo. Subjects were re-randomized after a 2-week washout period to complete all four study arms. Radial artery systolic pressure response to exogenous angiotensin II was measured at 2, 6, 12, and 24 h after administration of drug. Losartan 50 mg reduced the pressure response to exogenous angiotensin II significantly only at 6 h. In contrast, candesartan and losartan 150 mg produced a greater reduction in the pressure response to angiotensin II throughout the 24-h period. This suppression was not paralleled by a reduction in resting systemic arterial pressure. Higher doses than 50 mg of losartan might be evaluated to elicit optimal clinical effects.

Difficult cases in heart failure: Left ventricular dysfunction related to septic shock masquerading as postpartum cardiomyopathy.

Peripartum cardiomyopathy, an uncommon cause of chronic heart failure, may present during the third trimester of pregnancy, but most often develops within 2 months postpartum. The etiologies of heart failure during pregnancy and postpartum are numerous, however. The authors describe the case of a 25-year-old woman who developed severe, symptomatic heart failure following delivery and discuss their initial consideration of peripartum cardiomyopathy and the differential diagnostic features of this case. (c)2001 CHF, Inc.

Therapeutic implications of escape from angiotensin-converting enzyme inhibition in patients with chronic heart failure.

The level of inhibition of the angiotensin-converting enzyme (ACE) provided by standard doses of ACE inhibitors may only be partial during long-term treatment in patients with severe chronic heart failure (CHF). Partial ACE inhibition with time is often referred to as escape from ACE inhibition and labeled ACE escape. Several lines of evidence suggest that ACE escape occurs in patients with severe CHF. Plasma levels of angiotensin II rise above initial values during long-term ACE inhibition, and the effects of ACE inhibitors on cardiac remodeling and lowering of sympathetic nervous system activity attenuate after 1 year of treatment. Moreover, angiotensin II type I receptor blockade (ARB) produces clinical and hemodynamic benefits in patients with CHF who are already receiving ACE inhibitors. The therapeutic implications of ACE escape include evaluation of higher- than-standard doses of ACE inhibitors and routine addition of ARB to ACE inhibition in patients with severe CHF. Data are reviewed to demonstrate that ACE escape reflects inadequate ACE dosage rather than a decrease in ACE inhibition occurring with time.

Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure.

BACKGROUND: The added benefits of angiotensin II type I receptor (AT(1)) blockers (ARBs) to ACE inhibition suggests that recommended doses of ACE inhibitors provide only partial inhibition of ACE in chronic heart failure (CHF). Accordingly, the level of ACE inhibition was assessed by the pressor response to angiotensin (Ang) I in patients who had been treated with recommended doses of ACE inhibitors. METHODS AND RESULTS: Forty-two patients with CHF receiving 40 mg/d of a long-acting ACE inhibitor or 150 mg of captopril were studied. Radial artery systolic pressure (RASP, mm Hg) was monitored noninvasively. The pressor response to ascending doses of Ang I was evaluated in all patients before and after administration of the ARB valsartan. The pressor response to Ang I before and after valsartan was also reevaluated in 11 patients after the dose of ACE inhibitor was doubled for 1 week. RASP increased linearly with significantly ascending doses of Ang I despite treatment with ACE inhibitors. The pressor response to Ang I was blunted significantly by valsartan. Ang I-induced increase in RASP did not correlate with duration of ACE inhibitor therapy. After the dose of ACE inhibitors was doubled, the pressor response to Ang I was no longer different from that noted after valsartan. CONCLUSIONS: Recommended doses of ACE inhibitors do not fully inhibit ACE in CHF. The level of ACE inhibition achieved is not related to duration of ACE inhibitor therapy. Greater ACE inhibition is also achieved at twice the recommended doses of ACE inhibitors.

Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure.

BACKGROUND: Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown. METHODS AND RESULTS: Thirty-three patients with severe CHF despite treatment with maximally recommended or tolerated doses of ACE inhibitors were randomized 1:1 to receive 50 mg/d losartan or placebo for 6 months in addition to standard therapy in a multicenter, double-blind trial. Peak aerobic capacity (V(O2)) during symptom-limited treadmill exercise and NYHA functional class were determined at baseline and after 3 and 6 months of double-blind therapy. Peak V(O2) at baseline and after 3 and 6 months were 13.5+/-0.6, 15.1+/-1.0, and 15.7+/-1.1 mL. kg-1. min-1, respectively, in patients receiving losartan and 14.1+/-0.6, 14.3+/-0.9, and 13.6+/-1.1 mL. kg-1. min-1, respectively, in patients receiving placebo (P<0.02 for treatment group-by-time interaction). Functional class improved by at least one NYHA class in 9 of 16 patients receiving losartan and 1 of 17 patients receiving placebo. CONCLUSIONS: Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors.

Coronary flow reserve of nonischemic heart failure.

Coronary flow reserve (CFR) provides essential information about the coronary microvascular bed in the absence of narrowing of epicardial coronary arteries. Experimental and human data suggest chronic heart failure is associated with a reduction of CFR in the absence of coronary artery disease. Dipyridamole, papaverine, or adenosine administration intravenously or intracoronary achieve maximal vasodilation of coronary arteries in human studies, however, systemic administration of vasodilator (dipyridamole) resulted in conflicting effects on systemic blood pressure. Various mechanisms including the nitric oxide pathway, neurohumoral alterations, and microvascular spasm among others, may contribute to the decrease in CFR in nonischemic heart failure. Notably, there is no study which describes the correlation between subjective symptoms of heart failure and the severity of the decrease in CFR. Further investigation of this area may be beneficial in determining the appropriate level of exercise training for heart failure patients and understanding mechanisms of the progression of heart failure. (c)1999 by CHF, Inc.

Relationship between Rap1 protein phosphorylation and regulation of Ca2+ transport in platelets: a new approach.

Although the interrelationship between the two messengers Ca2+ and cyclic AMP in platelet function is well documented, its mechanism of action still remains to be established. We investigated here the question of the regulation of platelet Ca(2+)-ATPases by cyclic AMP through the phosphorylation of the Rap1 protein using a pathological model. We first found experimental conditions where Ca(2+)-transport by platelet membrane vesicles appeared to be dependent on the phosphorylation of the Rap1 protein. Then, we studied platelets of patients with congestive heart failure for their expression of the potential 97 kDa Ca(2+)-ATPase target of regulation through the Rap1 protein as well as the phosphorylation of the Rap1 protein using the catalytic subunit of the cyclic AMP-dependent protein kinase (C. Sub.). In the first patients studied, we found no significant modification in the expression of the 97 kDa Ca(2+)-ATPase by Western blotting using the PL/IM 430 monoclonal antibody which specifically recognized this isoform. In contrast, the Rap1 protein was differentially phosphorylated when using 15 micrograms/ml of the C. Sub. These results allowed us to use these pathological platelets to study the relationship between the expression of Rap1 protein and the regulation of Ca2+ transport by selecting a patient with severe heart failure. We could show a decrease in the expression as well as in the phosphorylation of Rap1 protein and demonstrate a lower effect of C. Sub. on Ca2+ transport. Finally, by studying a further series of patients, we could confirm that the decrease in Rap1 protein expression in heart failure, whatever its extent, was variable, and could strictly correlate the expression of Rap1 protein with the stimulatory effect of C. Sub. on Ca2+ transport. Besides the evidence for regulation of the expression of the Rap1 protein in platelets from patients with heart failure, these findings constitute a new approach in favour of the regulation of platelet Ca2+ transport through the phosphorylation of the Rap1 protein.

Sarcoplasmic reticulum calcium transport and Ca(2+)-ATPase gene expression in thoracic and abdominal aortas of normotensive and spontaneously hypertensive rats.

Increased intracellular Ca2+ concentration has been associated with the elevation of vascular tone in hypertensive animals. The increase in free cytosolic Ca2+ may partially result from a reduced activity of the sarcoplasmic reticulum (SR) calcium pump. Accordingly we investigated the Ca2+ transport function and the expression of the Ca(2+)-ATPase gene in thoracic and abdominal aortas of normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Total SR Ca2+ pump activity was estimated by measuring the oxalate-stimulated Ca2+ transport rate on crude homogenates. Ca2+ transport was also measured on highly active microsomal fractions. Our data indicate that the Ca2+ uptake rate, expressed per mg of protein or per g of muscle, is greater in homogenates from aortas of SHR when compared with that of WKY rats. In microsomal fractions isolated from thoracic aortas of SHR compared with WKY rats, the activity and density of SR Ca2+ pump were only slightly increased. The SR Ca2+ transport rate and the amount of each SR Ca(2+)-ATPase mRNA isoform, i.e. SERCA 2a and SERCA 2b, normalized to 18 S ribosomal RNA, were greater in thoracic than in abdominal aorta in both strains. When compared with WKY rats, the level of each SERCA mRNA isoform is higher in the abdominal aorta of SHR but appears similar in the thoracic aorta. Thus, in contrast to previously published data that documented a depressed SR Ca2+ transport activity in the aorta of SHR, the present data indicate that the SR function is increased. These changes in SR activity are accompanied by quantitative changes in expression of the SR Ca(2+)-ATPase gene without alterations in the SR Ca(2+)-ATPase mRNA isoforms pattern.

Age-related changes in sarcoplasmic reticulum Ca(2+)-ATPase and alpha-smooth muscle actin gene expression in aortas of normotensive and spontaneously hypertensive rats.

The expression of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase gene and the SR Ca2+ pump function were investigated in thoracic aortas of 5- and 17-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The relative level of the two isoforms of SR Ca(2+)-ATPase mRNA expressed in the aorta (i.e., SERCA 2a and SERCA 2b) was determined by quantitative S1 nuclease protection analysis and normalized to the level of alpha-smooth muscle (alpha-Sm) actin mRNA. The level of alpha-Sm actin mRNA itself was normalized to the level of 18S ribosomal RNA using slot-blot hybridization assays. Total SR Ca2+ pump activity was estimated by measuring the rate of oxalate-supported Ca2+ uptake in homogenates. At 5 weeks, the amount of SERCA 2a and SERCA 2b mRNA, normalized to 18S ribosomal RNA, and the ratio of alpha-Sm actin mRNA to 18S RNA were identical in SHR and WKY rats. The Ca2+ pump activity was similar in the two strains of rats at 5 weeks. From 5 to 17 weeks, the amount of SERCA 2a mRNA increased in both strains while the level of SERCA 2b mRNA remained constant. The Ca2+ pump activity was unchanged in SHRs and tended to decrease in WKY rats. Accordingly, the change in the ratio of the SR Ca(2+)-ATPase mRNA isoforms does not appear to influence SR function. The level of alpha-Sm actin mRNA and SERCA 2a mRNA increased in parallel from 5 to 17 weeks in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral circulatory response in cardiac failure.

Derangements of the peripheral circulation play a major role in the pathophysiology of congestive heart failure. Their appearance coincides with that of the symptoms and signs that characterize the full-blown clinical syndrome. Long-term therapy with ACE inhibitors partially reverses these abnormalities, but the pathologic mechanisms are still poorly understood.

Specific phosphodiesterase inhibition and maximal and submaximal exercise performance in patients with congestive heart failure.

The current therapeutic interest in specific phosphodiesterase (PDE) inhibition involves patients with severe congestive heart failure (CHF) whose symptoms are not controlled by diuretics, nitrates, angiotensin converting enzyme (ACE) inhibitors, and digitalis. Maximal exercise capacity is limited in these patients by an inadequate rise in cardiac output and a fixed capacity to dilate the skeletal muscle vasculature, which is perhaps compounded by disorders of the skeletal muscle metabolism. To improve maximal exercise capacity, the increase in cardiac performance produced by specific phosphodiesterase inhibitors must, in turn, reverse the abnormalities present in the periphery, and more specifically augment the capacity to dilate the skeletal muscle vasculature. Increased vasodilatory response to maximal exercise probably depends on the regression of structural changes in the skeletal muscle vasculature. Such regression may be mediated by a reduction in neurohormonal vasoconstrictor stimuli and/or chronic augmentation in resting limb blood flow. Submaximal exercise capacity, at work loads equivalent to less than 70% of peak aerobic capacity, appears to be directly limited by depressed cardiac output and high sympathetic vasoconstrictor activity. Specific phosphodiesterase inhibition, which consistently increases left ventricular performance during exercise, is more likely to improve exercise capacity at submaximal work loads than at maximal work loads.

Effects of acute angiotensin converting enzyme inhibition on renal blood flow in patients with stable congestive heart failure.

Renal blood flow was serially measured as the left renal vein blood flow using the continuous thermodilution technique during acute angiotensin converting enzyme inhibition in 20 patients with stable congestive heart failure. Eleven patients received captopril orally, and the remaining nine patients received enalaprilat intravenously. During the control period, left renal vein blood flow and cardiac output did not correlate closely (r = 0.57). Following administration of captopril or enalaprilat, stroke volume index increased from 20 +/- 7 to 25 +/- 8 ml/M2 (p less than 0.001), while pulmonary capillary wedge pressure decreased from 26 +/- 8 to 19 +/- 8 mm Hg (p less than 0.001). Left renal vein blood flow increased in all patients despite a consistent reduction in systemic arterial pressure. At peak effect, left renal vein blood flow increased from 295 +/- 86 to 443 +/- 122 ml/min (p less than 0.001), while mean systemic arterial pressure fell from 81 +/- 13 to 71 +/- 14 mm Hg (p less than 0.001). Thus, in patients with stable congestive heart failure, acute angiotensin converting enzyme inhibition, although decreasing substantially systemic arterial pressure, consistently enhances renal blood flow.

Central and peripheral components of cardiac failure.

Chronic heart failure results from two processes, i.e., myocardial and congestive failure. Myocardial failure is clinically silent, most often progresses slowly, and is documented by a depressed left ventricular ejection fraction. Multiple etiologic factors include systolic and diastolic overloads, myocardial necrosis and/or ischemia, and, perhaps, microvascular spasm. Myocardial failure ultimately leads to exaggerated neurohumoral compensatory mechanisms and derangements of the peripheral circulation, which are the hallmarks of congestive heart failure. At that stage of the syndrome, patients have symptoms, initially, with exercise and, later, at rest. Objective assessment of severity is afforded by determination of maximal oxygen uptake during maximal exercise testing. When congestive heart failure supervenes, the prognosis is poor. Current medical therapy is aimed at improving the derangements of the peripheral circulation, which relieves the symptoms but leaves the primary myocardial process unaffected. The goal of future therapy is to intervene at an earlier stage of the syndrome to halt or even partially reverse the myocardial failure.