[Holistic therapy of chronic heart failure]. / Ganzheitliche Behandlung der chronischen Herzinsuffizienz.

The rising prevalence and increasing disease-related costs render chronic heart failure a rapidly growing socioeconomic challenge. The concerted action of guideline-adjusted therapy and holistic patient care is essential to achieve improvements in mortality, morbidity, functional status and quality of life of patients with symptomatic heart failure. Holistic care strategies comprise consideration of comorbidities and individual needs, lifestyle recommendations and multidisciplinary management programs for high-risk symptomatic patients in addition to basic medication and surgical therapies. For optimal patient care and coaching, seamless interaction is required between in-hospital treatment and outpatient facilities. Moreover, the palliative needs of heart failure patients need to be considered, a topic that is currently not receiving enough attention.

Prevention of hypertensive crises in rats induced by acute and chronic norepinephrine excess.

Calcium Channel Blockers (CCBs), competitive α-adrenoceptor blockers, and phenoxybenzamine (POB) are used for preoperative treatment of pheochromocytomas. We analyzed the protection from hypertensive crisis provided by these drugs during acute and chronic norepinephrine excess. To ensure adaptive changes during chronic norepinephrine (NE) excess, we continuously exposed male Wistar rats to NE for 3 weeks (osmotic pumps). Afterwards, blood pressure (BP) was continuously measured while NE boli (0-1000 µg/kg, i. v.) were administered before and after antihypertensive treatment in anesthetized and catheterized rats. A single dose of urapidil (10 mg/kg), nitrendipine (600 µg/kg) and POB (10 mg/kg) lowered BP from 212 ± 12 mmHg by 52 ± 7%, 31 ± 9%, and 50 ± 6%, respectively. With NE boli a maximum BP of 235 ± 29, 240 ± 30 and 138 ± 3 mmHg was measured in urapidil, nitrendipine, and POB treated animals (p<0.05). The number of hypertensive episodes (delta BP >30 mmHg) was 3 (3), 1.5 (0-3), and 0 (0-1) (p<0.05). Because of inferiority, urapidil was excluded from further testing. Chronically NE exposed rats were treated with POB (10 mg/kg/d), nifedipine (10 mg/kg/d), or vehicle for 7 days. Marked BP elevations were observed at baseline (167 ± 7, 210 ± 7 , and 217 ± 7 mmHg, p<0.01) and maximum blood pressure was 220 ± 32, 282 ± 26, and 268 ± 40 mmHg (p<0.001) with NE boli. Further stabilization was achieved combining POB pretreatment with a continuous nifedipine infusion, which effectively prevented BP elevations during NE excess. POB was the most effective drug used in monotherapy, but BP stabilization was superior using a combination of POB pretreatment with a continuous nifedipine infusion in this model.

Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction.

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) attenuate angiotensin II-induced cellular signaling. Because angiotensin II is involved in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of statin treatment in an experimental model of chronic heart failure after MI. METHODS AND RESULTS: Rats with extensive MI were treated with placebo or cerivastatin (0.3 mg/kg per day) as a dietary supplement or via gavage for 11 weeks starting on the 7th postoperative day. Infarct size and cholesterol levels were similar among all groups. LV cavity area, an index of LV dilatation, was reduced in MI rats on cerivastatin compared with placebo. LV end-diastolic pressure was increased in MI rats on placebo (24.1+/-4.1 mm Hg versus sham: 5.1+/-0.3 mm Hg; P<0.01), and it was significantly reduced by cerivastatin treatment (13.7+/-2.7 mm Hg; P<0.05 versus placebo). Cerivastatin partially normalized LV dP/dt(max) and dP/dt(min), indices of LV systolic and diastolic function, which were significantly reduced in MI rats on placebo. Improvement of LV function by cerivastatin was accompanied by a reduced expression of collagen type I and beta-myosin heavy chain. LV endothelial nitric oxide synthase was increased, whereas the nitrotyrosine protein level was decreased in MI rats by cerivastatin treatment. CONCLUSIONS: Cerivastatin improved LV remodeling and function in rats with heart failure. This effect was associated with an attenuated LV expression of fetal myosin heavy chain isoenzymes and collagen I. Statin treatment may retard the progression of chronic heart failure.

Prevention of endothelial dysfunction in heart failure by vitamin E: attenuation of vascular superoxide anion formation and increase in soluble guanylyl cyclase expression.

OBJECTIVES: Enhanced vascular superoxide anion generation contributes to endothelial dysfunction in heart failure. However, the effect of long-term treatment with the antioxidant vitamin E is unknown. METHODS AND RESULTS: Relaxant responses were determined in aortic rings from Wistar rats with heart failure 12 weeks after myocardial infarction (MI) and compared with responses in tissues from sham-operated animals. From the seventh post-operative day, rats were given either a standard chow or a chow enriched in vitamin E (approximate intake 100 mg/day). In rings from rats with heart failure, acetylcholine-induced relaxation was attenuated (maximum relaxation, R(max) 54 +/- 3%) when compared with rings from sham-operated animals (79 +/- 3%, n=12, P < 0.01), while endothelium-independent relaxation elicited by sodium-nitroprusside was unchanged. Aortic superoxide generation was significantly enhanced in rats with heart failure. Vitamin E supplementation significantly improved acetylcholine-induced relaxation in rats with heart failure (R(max) 75 +/- 4%, P < 0.01) and led to a leftward shift in sodium-nitroprusside-induced relaxation curve. Aortic expression of the beta(1)-subunit of soluble guanylyl cyclase was significantly enhanced by vitamin E supplementation. In addition, the elevated vascular superoxide formation was normalised by vitamin E. CONCLUSIONS: These results demonstrate that dietary supplementation with the antioxidant vitamin E restores normal endothelial function, reduces vascular superoxide anion formation and increases the expression of the soluble guanylyl cyclase in rats with heart failure.

Mechanisms of the effects of nicorandil in the isolated rat heart during ischemia and reperfusion: a 31P-nuclear magnetic resonance study.

Nicorandil (SG75) is a potent K+-channel activator with an additional nitro moiety. In the present study we investigated the potential mechanisms (K+-channel activation and nitric oxide [NO] release) for the effects of nicorandil on isolated perfused rat hearts during total global ischemia using 31P-nuclear magnetic resonance. After a 10-min control perfusion, hearts were subjected to treatment with nicorandil-containing (100, 300, or 1000 microM) buffer for 10 min, 15 min of total global ischemia, and 30 min of reperfusion. At high dose (10(-3) M), nicorandil reduced ATP depletion during ischemia by 26% compared with untreated hearts. Blockade of K+ channels by glibenclamide prevented this protective effect. At all doses (10(-4) to 10(-3) M), nicorandil reduced the accumulation of protons during ischemia compared with untreated hearts (pH 6.22 +/- 0.03 vs. 6.02 +/- 0.05 in untreated hearts at the end of ischemia). This effect was preserved after blockade of K+ channels by glibenclamide. Hearts treated with nitroglycerine before ischemia also showed reduced proton accumulation. Therefore, NO release accompanied by increased coronary flow before ischemia, which is caused by the nitro moiety of nicorandil and nitroglycerine treatment, results in reduced proton accumulation. During reperfusion, a pro-arrhythmic effect was observed in hearts treated with the nonpharmacologically high dose of nicorandil (1000 microM). Thus, we conclude that the effects of nicorandil are caused by the simultaneous action of both mechanisms K+-channel activation and NO release. The activation of K+ channels prevents deterioration of ATP during ischemia, whereas NO release and increased coronary flow reduce the accumulation of protons--and thus the decrease in pH--during ischemia.

Chronic high-dose creatine feeding does not attenuate left ventricular remodeling in rat hearts post-myocardial infarction.

OBJECTIVE: In heart failure, cardiac energy metabolism is compromised. The failing myocardium is characterized by reduced contents of both phosphorylated (phosphocreatine) and non-phosphorylated (free) creatine content as well as decreased energy reserve via creatine kinase (creatine kinase reaction velocity). These changes may contribute to cardiac dysfunction. The purpose of the present study was to determine whether chronic feeding with high-dose dietary creatine prevents the derangement of energy metabolism and the development of left ventricular remodeling in a rat model of heart failure, i.e. post-myocardial infarction (MI). METHODS AND RESULTS: Rats were subjected to sham operation or left coronary artery ligation. Surviving rats were fed with 0% (untreated) or 3% creatine (related to weight of diet) for 8 weeks. Creatine feeding increased serum creatine levels significantly approximately 2-fold. Thereafter, hearts were isolated, perfused and left ventricular pressure-volume curves obtained. Steady state and dynamic (CK reaction velocity) high-energy phosphate metabolism was determined with 31P NMR spectroscopy. In both MI groups (treated n = 8, untreated n = 7), pressure-volume curves were shifted right- and downward compared to both sham groups (treated n = 5, untreated n = 7), i.e. creatine had no effect on left ventricular remodeling. Likewise, similar reductions of phosphocreatine, free creatine and creatine kinase reaction velocity (untreated sham 12.0 +/- 0.7 mmol/lxs; untreated MI 7.8 +/- 0.7*; treated sham 13.6 +/- 1.0; treated MI 7.2 +/- 1.1*; *p < 0.025 sham vs. MI) were found in both MI groups. CONCLUSIONS: Chronic creatine feeding of post-MI rats is ineffective in preventing the functional and energetic derangements occurring post-MI. Inspite of increased serum creatine levels, neither the normal nor the failing heart accumulates additional creatine.

Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy.

BACKGROUND: In patients with heart failure due to dilated cardiomyopathy, cardiac energy metabolism is impaired, as indicated by a reduction of the myocardial phosphocreatine-to-ATP ratio, measured noninvasively by 31P-MR spectroscopy. The purpose of this study was to test whether the phosphocreatine-to-ATP ratio also offers prognostic information in terms of mortality prediction as well as how this index compares with well-known mortality predictors such as left ventricular ejection fraction (LVEF) or New York Heart Association (NYHA) class. METHODS AND RESULTS: Thirty-nine patients with dilated cardiomyopathy were followed up for 928+/-85 days (2.5 years). At study entry, LVEF and NYHA class were determined, and the cardiac phosphocreatine-to-ATP ratio was measured by localized 31P-MR spectroscopy of the anterior myocardium. During the study period, total mortality was 26%. Patients were divided into two groups, one with a normal phosphocreatine-to-ATP ratio (>1.60; mean+/-SE, 1.98+/-0.07; n=19; healthy volunteers: 1.94+/-0.11, n=30) and one with a reduced phosphocreatine-to-ATP ratio (<1.60; 1.30+/-0.05; n=20). At re-evaluation (mean, 2.5 years), 8 of 20 patients with reduced phosphocreatine-to-ATP ratios had died, all of cardiovascular causes (total and cardiovascular mortality, 40%). Of the 19 patients with normal phosphocreatine-to-ATP ratios, 2 had died (total mortality, 11%), one of cardiovascular causes (cardiovascular mortality, 5%). Kaplan-Meier analysis showed significantly reduced total (P=.036) and cardiovascular (P=.016) mortality for patients with normal versus patients with low phosphocreatine-to-ATP ratios. A Cox model for multivariate analysis showed that the phosphocreatine-to-ATP ratio and NYHA class offered significant independent prognostic information on cardiovascular mortality. CONCLUSIONS: The myocardial phosphocreatine-to-ATP ratio, measured noninvasively with 31P-MR spectroscopy, is a predictor of both total and cardiovascular mortality in patients with dilated cardiomyopathy.

[The direct measurement of the spin-grid-relaxation times of phosphorus metabolites in the human myocardium]. / Direkte Messung der Spin-Gitter-Relaxationszeiten von Phosphormetaboliten im menschlichen Myokard.

The T1 relaxation times of the phosphorus metabolites in human heart muscle measurable by 31P-MR spectra were determined in 12 individuals using a 1.5 Tesla system. Several spectra were recorded consecutively with a pulse repetition time of 1.6 s to 24 s. The T1 times of creatine phosphate (CP), of gamma-, alpha-, beta-adenosintriphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG) together with anorganic phosphate) and phosphodiester (PDE) showed mean measurements of 6.1 +/- 0.5, 5.4 +/- 0.5, 5.0 +/- 0.5, 5.8 +/- 1.0, 7.6 +/- 1.0, and 5.0 +/- 1.0 s (M +/- SE). The accuracy of the ISIS technique was tested with a special phantom. T1 times were also measured in standard solutions (20 mM CP, 10 mM ATP); CP was 8.7 +/- 0.2 s and gamma-ATP was 9.9 +/- 0.7 s. Corrections for partially saturated 31P-MR spectra--at least for CP/ATP ratios--are relatively small.

Effects of endothelin-1 in isolated perfused rat heart.

We examined the effects of the vasoconstrictor peptide endothelin-1 in the isolated heart and defined interactions of endothelin-1 with other hormone systems. Isolated isovolumic rat hearts were perfused with Krebs-Henseleit buffer at constant pressure. First, the effect of a single bolus of endothelin-1 (4-400 pmol) was followed for 90 min. The effect of high dosages (40 and 400 pmol) of endothelin-1 on coronary flow was biphasic, with an early vasodilator and a late vasoconstrictor component that was irreversible. Second, cumulative dose-response curves were obtained for endothelin-1 boluses of 0.04-400 pmol. Coronary flow declined with increasing dosages and was almost abolished at 400 pmol. Neither alpha- nor beta-blocking agents (phentolamine and propranolol) nor the Ca2(+)-channel blocker nifedipine altered the effects of endothelin-1, but prostaglandin synthesis inhibition by indomethacin significantly augmented vasoconstriction by endothelin-1. Angiotensin-converting enzyme (ACE) inhibition by captopril antagonized endothelin-1-dependent vasoconstriction to a small extent at 400 pmol. Coronary constriction due to endothelin-1 could not be reversed by nitroglycerin. We conclude that in isolated rat heart endothelin-1 causes marked and long-lasting coronary constriction. The effect is not influenced by sympathetic and Ca2(+)-channel blockade, is enhanced by prostaglandin synthesis inhibition, and is reduced by ACE inhibition.

Muzolimine therapy in patients with congestive heart failure in comparison with furosemide pretreatment. Effect on digoxin plasma concentration.

Eight patients suffering from congestive heart failure (NYHA III-IV) and pretreated with digoxin received muzolimine over 14 days in an open clinical study. The muzolimine dose was adjusted to 3/4 of the daily furosemide dose necessary to keep the body weight constant at least three days prior to the onset of muzolimine treatment. Plasma concentrations of epinephrine, norepinephrine, aldosterone, renin and digoxin were determined on the last day of the furosemide treatment period and on the last day of the muzolimine period. No significant changes were observed in plasma concentrations of epinephrine, aldosterone, renin, creatinine, and potassium. After muzolimine treatment, however, body weight and sonographically determined liver size decreased further and plasma norepinephrine concentrations were significantly lower. The digoxin concentrations did not change after muzolimine treatment. The results demonstrate the beneficial effect of muzolimine in heart failure patients. Since plasma concentration of digoxin does not change despite marked diuretic effects of muzolimine no relevant interaction between both substances has to be expected.