Perindopril treatment for congestive heart failure.

Congestive heart failure (CHF) is the most common and lethal consequence of atherosclerotic cardiovascular disease, with a prevalence estimated between 1% and 10%, and very high associated mortality. Preventing the continued progression of established heart failure and improving the prognosis for patients with this disease is difficult, but angiotensin-converting enzyme (ACE) inhibitors have been shown to be effective in reducing mortality in patients with CHF. In a review of the worldwide literature of the efficacy and safety of perindopril erbumine for the treatment of patients with CHF, once-daily treatment with this ACE inhibitor was shown to be effective in patients with CHF of all severities. Its use is associated with a low risk of first-dose hypotension and no unwanted effects on blood pressure in normotensive patients. Perindopril also improves arterial compliance and reverses left ventricular hypertrophy in patients with hypertension. It is well tolerated and has no significant effects on heart rate, indexes of renal function, or plasma lipid profile. It also has no clinically significant interactions with other drugs, including digoxin, likely to be taken by patients with CHF.

Angiotensin II receptor subtypes in the skeletal muscle vasculature of patients with severe congestive heart failure.

BACKGROUND: Vascular remodeling occurs in the skeletal muscle of patients with severe congestive heart failure (CHF); this remodeling is mediated in part by increased activity of the renin-angiotensin system. Animal models suggest that in the vasculature, angiotensin II receptor type 2 (AT2-R) expression may be upregulated in pathological states associated with vascular remodeling. The therapeutic effects of an AT1-R antagonist may, therefore, be in part due to increased plasma angiotensin II levels, which stimulate AT2-R. However, whether AT2-R is expressed in the skeletal muscle vasculature of patients with severe CHF is unknown. METHODS AND RESULTS: The steady-state transcript levels of the AT1-R and AT2-R genes were analyzed by reverse transcription-polymerase chain reaction in RNA samples prepared from the skeletal muscle of 12 patients with severe CHF (f1.gif" BORDER="0">O(2)<10 mL. kg(-1). min(-1)) and 5 age-matched healthy subjects who underwent vastus lateralis biopsies. Human fetal skeletal muscle RNA served as a positive control for the expression of AT1-R and AT2-R gene transcripts. Transcripts from the AT1-R gene were detected readily in all samples. In contrast, transcripts from the AT2-R gene were only detected in fetal skeletal muscle samples and could not be detected in the skeletal muscle vasculature of healthy subjects or that of CHF patients, who were treated with either angiotensin-converting enzyme inhibitors or AT1-R antagonists. CONCLUSIONS: The AT2-R gene is not expressed in the skeletal muscle of patients with CHF. In the absence of detectable AT2-R gene transcripts, the AT2-R pathway is unlikely to contribute to the effects of AT1-R antagonists on the skeletal muscle vasculature in patients with severe CHF.

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.

Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent.

To determine whether myocyte death and angiotensin II (AT II) formation are implicated in the development of diabetic cardiomyopathy, rats were injected with streptozotocin, and apoptosis and necrosis were measured at 3, 10, and 28 days. Expression of the components of the renin-angiotensin system (RAS) and AT II levels were assessed at 3 days. The percentage of AT II-labeled myocytes and the number and distribution of AT II sites in myocytes were measured at 3 and 10 days. The effects of AT1 blockade on local RAS and cell death were examined at 3 days. Diabetes was characterized by myocyte apoptosis that peaked at 3 days and decreased at 10 and 28 days, in spite of high concentrations of blood glucose. Cell necrosis was absent throughout. Angiotensinogen, renin, and AT1 receptor increased in myocytes from diabetic rat hearts, while angiotensin-converting enzyme and AT2 remained constant. AT II quantity increased severalfold, as did the fraction of AT II positive cells and the number of AT II sites per myocyte. However, AT II labeling decreased at 10 days, which paralleled the reduction in myocyte death. AT1 antagonist inhibited upregulation of this receptor and angiotensinogen, which prevented AT II synthesis and myocyte death at their peaks with diabetes. An aggregate 30% myocyte loss and a 14% increase in the volume of viable cells were found in diabetic rats at 28 days. Thus diabetic cardiomyopathy may be viewed as an AT II-dependent process in which that peptide plays a critical role in myocyte death and hypertrophy.

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.

Cardiomyocyte aging is gender-dependent: the local IGF-1-IGF-1R system.

To determine whether insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) are implicated in the aging process of the heart, and if their impact differs in the two genders, the expression of IGF-1, and extracellular alpha-subunit and transmembrane beta-subunit of IGF-1R was measured in left ventricular myocytes isolated from male and female Fischer 344 rats at 3, 8, 12, 16, and 26 months after birth. Additionally, the extent of myocardial damage in both sexes was evaluated in rats at 3 and 26 months by confocal microscopy. Finally, ventricular hemodynamics was assessed in the closed-chest preparation. From 3 to 26 months, aging was characterized by an 83%, 84% decrease and disappearance in the quantity of IGF-1, IGF-1Ralpha and IGF-1Rbeta in male myocytes. Corresponding changes in female myocytes were 40%, 28% and 43%. These molecular modifications at the myocyte level were coupled with tissue injury, consisting of multiple foci of replacement fibrosis across the left ventricular wall. However, myocardial fibrosis in females was 76% and 77% significantly less than in the young and old male heart, respectively. These multiple age-associated events were accompanied by cardiac decompensation in the senescent male rat, while modest indices of ventricular dysfunction were detected in old female rats. In conclusion, the enhanced IGF-1-IGF-1R system in female myocytes may condition the favorable outcome of age in this gender.

Models and remodeling: mechanisms and clinical implications.

Ventricular remodeling is a process by which the size, shape and composition of cardiac chambers as well as the thickness and composition of the walls are altered in response to physical loads and/or receptor activation, whether created by loss or overload of cardiac myocytes, or the effects of external hormonal or chemical factors. Involved in this process are hypertrophy, dilation, myocyte loss whether due to necrosis or apoptosis, and myocyte hyperplasia. The present review discusses the dynamic and plastic structure of the heart in its capacity to respond to loading. The mechanisms by which myocyte growth as well as myocyte loss are mediated offer therapeutic opportunities to alter these events.

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.

beta-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy.

To establish whether catecholamines per se in the absence of significant increases in systolic load induce myocardial damage via apoptosis, rats were treated with vehicle or isoproterenol (400 microg . kg-1 . h-1). Apoptotic cardiocytes (Apo) were identified in paraffin-embedded sections using terminal deoxynucleotide transferase-mediated dUTP nick end labeling. Results were confirmed using an independent ligase assay. Systolic blood pressures were comparable in isoproterenol-treated and control rats. Twenty-four hours of treatment with isoproterenol resulted in significant numbers of Apo compared with control [7.9 +/- 2.5 vs. 0.3 +/- 0.3 (SE) cm-2, P < 0.05]. A cohort of animals was subjected to ventricular pacing to induce a tachycardia equivalent to that induced by isoproterenol, and these animals did not show an increase in Apo. The left ventricular hypertrophy induced by 2 wk of abdominal aortic banding also increased Apo ( approximately 7. 2-fold); however, 24 h of isoproterenol infusion did not induce additional Apo in these rats. Thus catecholamines, in the absence of altered systolic load, induce Apo which is not mediated solely by tachycardia. Left ventricular hypertrophy secondary to abdominal aortic banding is associated with Apo, but this does not increase sensitivity to isoproterenol-induced Apo.

Effects of constitutive overexpression of insulin-like growth factor-1 on the mechanical characteristics and molecular properties of ventricular myocytes.

Recently, insulin-like growth factor-1 (IGF-1) has been claimed to positively influence the cardiac performance of the decompensated heart. On this basis, the effects of constitutive overexpression of IGF-1 on the mechanical behavior of myocytes were examined in transgenic mice in which the cDNA for the human IGF-1B was placed under the control of a rat alpha-myosin heavy chain promoter. In mice heterozygous for the transgene and in nontransgenic littermates at 2.5 months of age, the alterations in Ca2+ sensitivity of tension development, unloaded shortening velocity, and sarcomere compliance were measured in skinned myocytes. The quantities and state of phosphorylation of myofilament proteins in these enzymatically dissociated ventricular myocytes were also examined. The overexpression of IGF-1 was characterized by a nearly 15% reduction in myofilament isometric tension at submaximum Ca2+ levels in the physiological range, whereas developed tension at maximum activation was unchanged. In contrast, unloaded velocity of shortening was increased 39% in myocytes from transgenic mice. Moreover, resting tension in these cells was reduced by 24% to 33%. Myocytes from nontransgenic mice pretreated with IGF-1 failed to reveal changes in myofilament Ca2+ sensitivity and unloaded velocity of shortening. The quantities of C protein, troponin I, and myosin light chain-2 were comparable in transgenic and nontransgenic mice, but their endogenous state of phosphorylation increased 117%, 100%, and 100%, respectively. Troponin T content was not altered, and myosin isozymes were essentially 100% V1 in both groups of mice. In conclusion, constitutive overexpression of IGF-1 may influence positively the performance of myocytes by enhancing shortening velocity and cellular compliance.

Prolonged ejection duration helps to maintain pump performance of the renal-hypertensive-diabetic rat heart: correlations between isolated papillary muscle function and ventricular performance in situ.

OBJECTIVE: The purpose of this study was to examine the degree to which mechanical alterations in left ventricular papillary muscles of renal hypertensive-diabetic rat hearts correlate with functional measurements made on the same hearts in situ. METHODS: Female Wistar rats weighing 170-200 g were made hypertensive by placing a 0.24 mm clip on the left renal artery, and made diabetic 1 week later by a single intravenous injection of streptozotocin (60 mg/kg). Approximately 3-5 months later hemodynamic measurements including left ventricular pressure and dP/dtmax, arterial pressure and aortic flow were made on control and hypertensive-diabetic hearts in situ and correlated with mechanical measurements in left ventricular papillary muscles isolated from the same hearts. Body and tissue weights and biochemical and histological measurements were made at the time of sacrifice. RESULTS: Hypertensive-diabetic rats which survived to the time of study had decreased body weights, increased left ventricular weights and increased right ventricular weight to body weight and lung weight to body weight ratios. Those rats which died before the scheduled in-situ measurements had significantly more severe hypertension, greater left ventricular hypertrophy, increased right ventricular and lung weights, and more interstitial fibrosis than either surviving hypertensive-diabetics or controls. Rates of isometric tension development (normalized) and relaxation as well as shortening and relaxation velocities were significantly depressed in papillary muscles from hypertensive-diabetic rat hearts despite unchanged developed tension and peak shortening. Time to peak tension and time to peak shortening were markedly prolonged. Mean aortic flow was maintained in the hypertensive-diabetic group despite significant depression of left ventricular dP/dtmax (normalized), peak aortic flow, peak aortic flow acceleration and heart rate. There was also significant depression of left ventricular-dP/dtmax. Ejection duration was markedly prolonged and correlated with both time to peak shortening in vitro and with stroke volume in vivo. CONCLUSIONS: Surviving hypertensive-diabetic rats were not in overt congestive heart failure; nevertheless, their hearts showed abnormal contractile performance which was qualitatively and quantitatively similar to that of left ventricular papillary muscles obtained from them. Depression of peak aortic flow, peak aortic flow acceleration and heart rate in the hypertensive-diabetic group was offset by increased ejection duration, resulting in normal mean aortic flow. The close correlation of ejection duration with time to peak shortening of the isolated papillary muscles suggests that it is a manifestation of an intrinsic change in the myocardium. To the extent that this prolongation is already maximized, further decreases in contractile speed would be expected eventually to cause depressed pump function and congestive heart failure. The possibility that this sequence of events occurred in the dying animals needs to be examined by evaluating in-vitro and in-vivo myocardial function at various stages of this disease model.

Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research.

The SEP identified priorities to support in future basic and clinical research and pointed out directions likely to result in advances against heart failure. The list is not intended to be all-encompassing and does not address, for example, exciting lines of work already under way. Rather, the recommendations are designed to point out gaps in current knowledge not being adequately addressed and highly promising new directions. Although the incidence of heart failure continues to grow, emerging lines of research provide hope that research advances will eventually lead to more effective treatment and ultimately to prevention. This research will be well served by bringing the latest multidisciplinary approaches and the best investigators to focus on the problems of heart failure. It is hoped the efforts of distinguished expert entities such as the task force and SEP will be a useful guide in addressing the needs of the biomedical community and assisting in its success.

The cardiac troponin C isoform and the length dependence of Ca2+ sensitivity of tension in myocardium.

The Ca2+ sensitivity of tension in cardiac muscle is length dependent, such that the sensitivity is diminished with decreasing sarcomere length below 2.4 microm. This length dependence of Ca2+ sensitivity of tension also forms the basis for the Frank-Starling mechanism in the heart. The fast-twitch skeletal muscle has a much lower length dependence of Ca2+ sensitivity. In a recent study of skinned cardiotrabeculae, we indicated that the exchange of endogenous cardiac troponin C (TnC) for skeletal troponin C also resulted in a major reduction in the length dependence to the level of skeletal muscle. These findings suggested that cardiac troponin C has a key role in the length-sensing mechanism. The present investigation supports this conclusion and delineates the specific domain in cardiac TnC responsible for the length effect. Chimeras splicing either 41, 61, or 96 N-terminal cardiac amino acids with the remaining skeletal residues have indicated that while Ca2+ binding in all three constructs is similar to that in wild type cardiac TnC, the functional responsiveness of the 96-cardiac residue construct is improved over the other two. This 96-cardiac residue construct yielded a tension response indistinguishable from that of wild-type cardiac TnC. A tryptophan variant of the chimera indicated fluorescence characteristics indistinguishable from cardiac troponin C. The findings provide further support for the idea that cardiac troponin C in situ is modified in response to sarcomere length change and thereby participates in the Frank-Starling mechanism. Moreover, the study indicates that the tropinin C length-sensing attribute originates within the N-terminal domain constituted by these 96 residues.

Myocardial infarction alters myofilament calcium sensitivity and mechanical behavior of myocytes.

To determine whether myocardial infarction leads to alterations in myofilament isometric tension as a function of Ca2+ concentration, unloaded shortening velocity, and sarcomere compliance, these properties were examined in skinned myocytes 7 days after coronary artery occlusion. Changes in myofilament proteins were also evaluated Myocardial infarction was characterized by a 10-15% reduction in myofilament isometric tension at submaximum Ca2+ levels in the physiological range. However, developed tension at maximum activation was unaltered. Conversely, unloaded shortening velocity was decreased by 31% in the remaining viable cells, whereas resting tension was increased by 30-40%. The regulatory protein troponin I content was reduced, but phosphorylation of troponin I and troponin T was increased. Myosin isoenzymes and troponin T contents were not altered. In conclusion, molecular responses occurred acutely after myocardial infarction, and these adaptations may depress the mechanical behavior of the unaffected cells, contributing to acute impairment in global cardiac pump function beyond that resulting from myocyte loss.

Molecular basis of depression of Ca2+ sensitivity of tension by acid pH in cardiac muscles of the mouse and the rat.

BACKGROUND: Acid pH decreases the Ca2+ sensitivity of myocardial tension generation, and recent studies have suggested that regulatory proteins are involved. The current study defines the molecular basis of this effect on troponin C (TnC) and troponin I (TnI) and also addresses previous differences between the rat and mouse. METHODS AND RESULTS: Endogenous cardiac TnC and cardiac TnI in isolated trabeculae from mice and rats were exchanged with their fast-twitch skeletal muscle counterparts. A cardiac-skeletal TnC chimera was used to define the target region for proton action on cardiac TnC. Finally, cardiac TnC and skeletal TnC were genetically modified by insertion of a tryptophan for phenylalanine-26 to probe the pH effects with fluorescence spectroscopy. The pH 6.2 effects on Ca2+ sensitivity of force development in mouse and rat cardiotrabeculae are largely accounted for by the proton influences on TnC (23%) and TnI (53%). In cardiac TnC, residues 1 to 41 provide the target region. Comparison of the Ca(2+)-induced fluorescence in isolated cardiac TnC and skeletal TnC also indicated a greater pH effect in the cardiac isoform. CONCLUSIONS: The studies provide firm evidence that both TnC and TnI moieties are involved in the mechanism of acidosis causing reduction in the Ca sensitivity of force development in the myocardium. The findings rule out the possibility of interspecies variations in the underlying mechanisms. The genetically designed TnCs and a chimera demonstrate that the observed TnC-mediated difference in the pH effects on Ca2+ sensitivity of tension between cardiac and skeletal muscles is preserved in these isolated proteins. The N-terminal amino acid residues 1 to 41 in cardiac TnC are established as the pH sensor of this protein in the mouse as in the rat.

Time to dP/dtmax reflects both inotropic and chronotropic properties of cardiac contraction: a conscious dog study.

This study supports a mathematical model and previous findings indicating that td, the time from onset of contraction to dP/dtmax, reflects the time-dependent aspects of contraction and hence decreases with increasing contractility. Combined data from 20 conscious instrumented dogs create a highly significant inverse and linear td-HR (heart rate) relation. Both norepinephrine and isoproterenol decreased td values, but norepinephrine, in contrast to isoproterenol, decreased the heart rate by a reflex response. Despite the remarkable decline in heart rate (25.8%) td was decreased (16.5%). During wide spontaneous R-R variations longer preceding intervals gave shorter td values. The latter two facts indicate the dependence of td on the contractile state rather than it being merely interval dependent.

Myocardial alterations in diabetes and hypertension.

Diabetes mellitus is a complex group of diseases that has hyperglycemia as a common metabolic abnormality. Although it is well-known that diabetic patients are susceptible to the effects of large vessel atherosclerosis with specific cardiac and cerebral complications, the association of diabetes mellitus with cardiac dysfunction caused by cardiomyopathy in the absence of significant coronary artery disease has been recognized for many years. However, the pathogenesis of diabetic cardiomyopathy remains unknown and has been somewhat controversial. Specifically, whether diabetes mellitus with its metabolic effects is sufficient to account for cardiomyopathy remains to be proven. This paper reviews the evidence for and against a metabolic etiology. In addition, we review the clinical and experimental evidence that supports the view that diabetes mellitus acts together with hypertension to produce structural damage in the heart that manifests as ventricular dysfunction and ultimately congestive heart failure. The concomitant effects of the metabolic derangements of diabetes and the vascular abnormalities associated with hypertension may lead to microvascular-induced tissue injury. Findings supporting this hypothesis are presented, along with observations suggesting that treatment with vasodilating calcium channel blockers or angiotensin converting enzyme inhibitors may be beneficial in regard to tissue pathology and mortality in experimental models. Recent clinical studies also support a role for the microcirculation in diabetics. Finally, it is suggested that if the microcirculation is pathogenetically involved in diabetic cardiomyopathy, then agents that improve microcirculatory flow along with tight control of hypertension may be as beneficial in the treatment or prevention of diabetic cardiomyopathy as strict metabolic control of hyperglycemia.

Time to dP/dt(max), a useful index for evaluation of contractility in the catheterization laboratory.

HYPOTHESIS: The time from onset of contraction to dP/dt(max), td, is suggested as an index of contractility in the catheterization laboratory. METHODS: We studied 22 normal patients and 18 patients with myocardial failure in the catheterization laboratory. The two groups were completely separated on the td-heart rate (HR) plane. In the normal patients, HR = 73 +/- 19 beats/min, td = 73 +/- 11 ms, and an inverse linear relation td = 109-0.49 x HR (p < 0.001) exist. In the patients with myocardial failure, despite significantly higher HR than in normal patients (HR = 93 +/- 14 beats/min) (p < 0.001), td paradoxically increased (td = 89 +/- 11 ms, p < 0.0001). CONCLUSIONS: These findings support a mathematical analysis of the left ventricular pressure (LVP) during isovolumic contraction in the time domain which shows that td and (dP/dt)/P reflect the time-dependent aspects of contraction and, hence, decrease with increasing contractility. This study shows that td, at any given HR, is a reliable index of contractility. Thus, a ready-to-use td-HR plot containing a well-based separation line can provide a reliable and simple method for determining contractility in the catheterization laboratory by examining whether a patient's td value at any HR is below (normal) or above (impaired contractility) the separation line.