The treatment of diastolic heart failure.

Recommendations for the treatment of diastolic heart failure must be based on theoretical issues. Evidence-based outcomes from clinical trials are not available at this time, but there is an increasing mandate for more focused studies for this clinical disorder. Meaningful outcomes require delineation of patient populations, including identification of underlying disease and comorbid cardiovascular disorders. Until such information is available, we must rely on an understanding of the natural history of associated disorders, extrapolation of treatment strategies that are successful for systolic heart failure management, and use of pharmacologic agents that empirically target the observed hemodynamic abnormalities of diastolic heart failure.

Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure.

BACKGROUND: Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone. METHODS: Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group. RESULTS: Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group. CONCLUSIONS: Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation.

Angiotensin II enhances integrin and alpha-actinin expression in adult rat cardiac fibroblasts.

Angiotensin II (Ang II) plays an important role in cardiac remodeling through stimulation of proliferation and extracellular matrix (ECM) production in cardiac fibroblasts. Integrins are a family of transmembrane receptors that mediate the attachment of cells to ECM. We hypothesized that Ang II regulation of integrins further contributes to its role in cardiac remodeling. We cultured adult rat cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects on mRNA and protein levels of integrins, as well as alpha-actinin and other cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang II was also added in the presence of irbesartan (10 micromol/L), a specific Ang II type 1 (AT(1)) receptor antagonist, or PD 123319 (10 micromol/L), a specific Ang II type 2 receptor antagonist. To investigate the function of these integrins, we determined the effects of blocking antibodies on Ang II-induced adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an AT(1) receptor blocker, losartan, or with hydralazine to investigate integrin and alpha-actinin expression in treated and untreated SHR. Ang II enhanced alpha(v), beta(1), beta(3), and beta(5) integrins; osteopontin; and alpha-actinin mRNA and protein levels in cardiac fibroblasts. All of these effects were inhibited by irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II enhanced cell attachment to ECM proteins and induced focal adhesion kinase phosphorylation. Blocking antibodies to beta(3) and alpha(v)beta(5) attenuated Ang II-induced adhesion. In SHR, ventricular alpha(v) and beta(5) integrin expression and alpha-actinin were increased compared with those in Wistar-Kyoto rats. Although both losartan and hydralazine lowered mean arterial pressure and decreased peripheral vascular resistance, only losartan attenuated the increased integrin, alpha-actinin, fibronectin laminin, and osteopontin expression and the increased left ventricular mass (as determined with echocardiography). Hydralzine had none of these effects. Although both agents attenuated beta-myosin heavy chain expression, a marker of hypertrophy, losartan had a greater effect. These results suggest that integrins and alpha-actinin are upregulated by Ang II and in left ventricular hypertrophy and that the block of expression of these proteins through inhibition of the AT(1) receptor is associated with attenuation of the hypertrophic response. Ang II induces integrin and alpha-actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT(1) receptor.

A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: the U.S. ecadotril pilot safety study.

OBJECTIVE: To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. METHODS: Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction

The renin-angiotensin system antagonism in the treatment of hypertension.

The effective treatment of hypertension is associated with improved mortality and morbidity from diseases such as stroke, congestive heart failure, and renal failure. Use of medications that target the renin-angiotensin system for the treatment of hypertension can often achieve the desired decrease in blood pressure while causing a minimum of unwanted side effects. In this paper, the principles of the renin-angiotensin system antagonism are described. The approach to using these medications is discussed with special attention to specific indications as well as common side effects.

The sympathetic nervous system and the renin-angiotensin-aldosterone system in cardiovascular disease.

Both the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) have central roles in vascular adaptive processes. Stimulation of the 2 systems has been demonstrated in a range of cardiovascular disorders, including congestive heart failure and hypertension. However, elucidation regarding the interactions of the many factors involved in these 2 systems is lacking. Angiotensin-converting enzyme inhibitors have been used to reveal the contribution of some elements in the RAAS. Until relatively recently, little was known about the specific disturbances of the sympathetic nervous system in cardiovascular disease. Plasma norepinephrine levels, an indicator of sympathetic activity, have limited value because they are affected by various physiologic processes in addition to sympathetic activation. Newer approaches to the assessment of neurohormonal activity include the determination of the power content of heart-rate variability. More specific probes may lead to a better comprehension of neurohormonal physiology in health and disease and underlie future therapeutic advances targeted to prevention and treatment of specific syndromes.

Stevens-Johnson syndrome associated with carvedilol therapy.

Stevens-Johnson syndrome, related to carvedilol use, has not been previously reported as a serious adverse experience requiring hospitalization. We report this reaction in a 71-year-old man with stable ischemic cardiomyopathy.

The integrated effects of angiotensin II.

In recent years, a prodigious amount of information has been gathered regarding the relationship between vascular biology and the mechanisms underlying cardiovascular disease. Activation of elements of the reninangiotensin system (RAS) appear to play an important role in the development and progression of conditions such as hypertension, coronary artery disease, and heart failure. Indeed, converging lines of evidence indicate that angiotensin-converting enzyme (ACE) regulates a delicate balance among a multitude of factors responsible for vascular tone, cellular growth promotion and inhibition, and pro- and anti-inflammatory effects. Because angiotensin II inhibits fibronectin, stimulates expression of plasminogen activator inhibitors, and degrades bradykinin, thereby impairing production of nitric oxide, ACE and the RAS are also involved in thrombosis and fibrinolysis. The favorable effects of ACE inhibition on endothelial function and, potentially, on cardiovascular morbidity and mortality are believed to result not only from angiotensin II suppression but also its consequent bradykinin preservation and nitric oxide production.

Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.

BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Vascular hypertrophy is an early finding in essential hypertension and is related to arterial pressure waveform contour.

The effects of hypertension on the arterial vasculature were examined in a study group of 20 patients with newly diagnosed essential hypertension, 18 patients with chronic essential hypertension, and 32 control subjects with normal blood pressure. Left ventricular mass was determined echocardiographically. Carotid artery intimal-medial thickness was measured by means of B-mode ultrasound imaging, and carotid arterial waveforms were obtained by applanation tonometry. Compared with that in control subjects, carotid intimal-medial thickness was increased in patients with chronic hypertension (0.74 +/- 0.17 mm vs 0.61 +/- 0.15 mm in control subjects; p < 0.01) and in patients with newly diagnosed hypertension (0.66 +/- 0.12 mm vs 0.61 +/- 0.15 mm in control subjects; p < 0.05). Left ventricular mass was also higher in patients with chronic hypertension than in control subjects but was very similar between control subjects and those with newly diagnosed hypertension. Both the group with early hypertension and the group with chronic hypertension had an increased incidence of early waveform reflection evident on carotid arterial waveform examination. By multiple regression analysis, independent predictors of increased carotid intimal-medial thickness were age, systolic arterial pressure, and Murgo class of arterial waveform. Conduit arterial wall thickening precedes left ventricular remodeling in essential hypertension and is significantly related to the degree of pressure elevation and the arterial waveform contour.

Assessment of left ventricular function by meridional and circumferential end-systolic stress/minor-axis shortening relations in dilated cardiomyopathy.

Echocardiographic meridional wall stress-endocardial shortening relations provide estimates of left ventricular (LV) contractility that do not uniformly detect myocardial dysfunction despite severe symptoms in dilated cardiomyopathy. To improve detection of myocardial dysfunction in patients with congestive heart failure (CHF) due to dilated cardiomyopathy, echocardiographic meridional and circumferential end-systolic stress were related to endocardial and midwall shortening in 42 patients (95% dead within a mean of 22 months) with dilated cardiomyopathy and 140 normal subjects. A method to estimate LV long-axis dimension from M-mode minor-axis epicardial measurements was developed in a separate series of 115 subjects. Endocardial shortening to meridional wall stress relation identified 31 of 42 CHF patients falling below the 95% normal confidence interval of the reference population; use of midwall shortening decreased this number to 26 (p = NS). The use of circumferential wall stress identified 39 of 42 patients with subnormal endocardial LV shortening and 41 of 42 patients with depressed midwall performance (p < 0.01 vs use of meridional stress). The circumferential/meridional wall stress ratio was 2.6 +/- 0.5 in normal subjects and 1.3 +/- 0.2 in CHF patients (p < 0.0001). Thus, use of circumferential end-systolic stress as the measure of afterload improves the detection of myocardial dysfunction by stress/shortening relations in patients with CHF. The ratio between the 2 stresses decreases with more spherical LV shape. Midwall and endocardial shortening measurements are equivalent in the setting of thin LV walls as occurs in dilated cardiomyopathy.

Influence of pressure overload and ACE inhibitor therapy on constitutive protein mRNA expression in the spontaneously hypertensive rat.

Despite use as constitutive protein standards to quantify mRNA, data are limited regarding alteration of cyclophilin or glyceraldehyde-3-phosphate dehydrogenase (G3PDH) in hypertension or angiotensin converting enzyme (ACE) inhibitor treatment. We assessed these standards in 6 month old Wistar-Kyoto rats (WKY, n = 16), compared to age-matched spontaneously hypertensive rats (SHR, n = 14). Additional SHR (n = 8) had received enalapril for 3 to 4 months at evaluation. Left ventricular (LV) and kidney RNA was extracted for dot blot cyclophilin and G3PDH cDNA hybridization. Cyclophilin and G3PDH mRNA densitometries were expressed as a ratio. Cyclophilin/G3PDH for the WKY, untreated SHR, and enalapril SHR were 1.56 +/- 0.33, 1.45 +/- 0.42, and 1.49 +/- 0.51, respectively, for the LV, and 1.52 +/- 0.09, 1.43 +/- 0.22, and 1.38 +/- 0.22, respectively, for the kidney. Differences were not significant. Relative expression of cyclophilin/G3PDH was unaffected by genetic SHR hypertension, or long term enalapril. Thus, either constitutive mRNA may be confidently used to index structural or functional protein responses, at the transcriptional level, in the SHR.

Role of spectral measures of heart rate variability as markers of disease progression in patients with chronic congestive heart failure not treated with angiotensin-converting enzyme inhibitors.

Measures of heart rate variability in the frequency domain quantify autonomic activity. However, the relation of these measures to the severity of ventricular dysfunction in patients with congestive heart failure remains uncertain. We applied spectral analysis of heart rate variability to 24-hour Holter monitor recordings obtained from 20 patients with congestive heart failure who were not treated with angiotensin-converting enzyme inhibitors to determine whether significant changes in parameters of heart rate variability reflect the progression of symptoms in patients with ventricular failure. Both total and low-frequency heart rate spectral power were seen to decrease with worsening New Heart Associate (NYHA) functional class. A significant (p = 0.04) higher total power was noted in NYHA class II than in class III patients (3.0 x 10(-3) +/- 3.6 10(-4) and 2.5 x 10(-3) +/- 5.9 x 19(-4) [beats/min]2, respectively). Similarly, low-frequency heart rate spectral power was significantly (p = 0.008) higher in class II than in class III patients (1.7 x 10(-3) +/- 4.6 x 10(-4) and 1.1 x 10(-3) +/- 3.5 x 10(-4) [beats/min]2, respectively). Only the low-frequency component of the spectrum was directly correlated with left ventricular ejection fraction (LVEF) (r = 0.40) with a trend toward statistical significance (p = 0.07). Measures of heart rate variability and the changes in autonomic tone that they reflect may therefore serve as markers of the extent of disease progression in patients with congestive heart failure.

ACE inhibitors: myocardial infarction and congestive heart failure.

Myocardial infarction and congestive heart failure are associated with high morbidity and mortality rates. The results of recent clinical trials support a beneficial role for angiotensin-converting enzyme (ACE) inhibitors in attenuating mortality from myocardial infarction and left ventricular dysfunction. Large-scale survival studies provide practical evidence that the addition of an ACE inhibitor to conventional therapy with diuretics and digoxin can significantly reduce the number of hospital admissions and the risk of death related to progressive heart failure.

Echocardiographic characterization of left ventricular adaptation in a genetically determined heart failure rat model.

This study uses echocardiography to characterize the pattern of left ventricular hypertrophy in a new hypertensive heart failure-prone rat strain designated SHHF/Mcc-cp (SHHF). M-mode echocardiograms of the left ventricle in nine 10- to 12-month old SHHF rats and nine age-matched spontaneously hypertensive rats (SHR) were compared. Wistar-Kyoto and Sprague-Dawley strains served as the normotensive control group. SHHF rats had significantly greater left ventricular mass than did rats in the normotensive control group. Although left ventricular mass was not different between SHHF and SHR, significant differences were seen in the pattern of left ventricular remodeling as determined by relative wall thickness. These differences in left ventricular remodeling may explain the earlier development of heart failure in SHHF. The different patterns of left ventricular hypertrophy in SHHF and SHR suggests that heart failure in SHHF is not mediated by hypertension alone.

Hypertensive heart disease and heart failure.

Hypertension is associated with the remodeling of left ventricular geometry and abnormalities of function that may precede geometric changes. Rather than a specific disease, "hypertensive heart failure" is a spectrum of disorders that result from left ventricular geometric changes and comorbid conditions. Heart failure may present as abnormalities of diastolic or systolic function, although symptoms (dyspnea, fatigue) and physical findings (edema, rales) may be similar.