[Significance of hawthorn extract in general practice - a current positioning]. / Stellenwert von Weißdornextrakt in der hausärztlichen Praxis ­ eine aktuelle Standortbestimmung.

BACKGROUND: Traditionally, hawthorn extract has been used for preventive and curative support in mild forms of age-related cardiovascular problems. There are now solid data demonstrating pre-clinical effects and mechanisms of action on a molecular-biological and cellular level that appear to be of particular interest in influencing vascular ageing and in arterial vascular disorders. METHOD: The review presents the results of a meeting of experts that took place to work out a current assessment of the therapeutic suitability of hawthorn extract in the treatment of cardiovascular disease. RESULTS AND CONCLUSIONS: Although currently no general recommendation can be given on the use of hawthorn extract in cardiac insufficiency, its use is indicated for typical challenges arising in general practice, where particularly patients with functional cardiorespiratory complaints present, possibly those with cardiac insufficiency with preserved heart function for whom there has thus far been no effective therapy apart from exercise. This recommendation is supported by the findings of studies on the safety and very good tolerability of hawthorn extract, particularly for therapy adjuvant to standard practice.

Benefit-Risk Assessment of Crataegus Extract WS 1442: An Evidence-Based Review.

Preparations from Crataegus (hawthorn) have a long history in the treatment of heart failure. WS 1442 is a dry extract from hawthorn leaves with flowers (4-6.6:1), extraction solvent of ethanol 45% (w/w), adjusted to 17.3-20.1% of oligomeric procyanidins. Nonclinical studies show that WS 1442 has positive inotropic and antiarrhythmic properties and protects the myocardium from ischemic damage, reperfusion injury, and hypertension-related hypertrophy, improves endothelial functions such as NO synthesis, and delays endothelial senescence. Randomized, controlled trials in patients with heart failure have demonstrated that the herbal medicinal product increases functional capacity, alleviates disabling symptoms, and improves health-related quality of life, all of which have become important targets of heart failure therapy according to current disease management guidelines. Clinical trials (including a 2-year mortality study with polypharmacy and > 1300 patients exposed) and post-marketing surveillance studies have shown that WS 1442 has a very favorable safety profile both as monotherapy and as add-on therapy, where no drug interactions have been observed. No specific adverse reactions to WS 1442 are known to date. WS 1442 may thus help to close the therapeutic gap between systolic and diastolic heart failure for which evidence of efficacy for other cardioactive drugs is sparse. Scientific evidence shows that WS 1442 is safe and has a beneficial effect in patients with heart failure corresponding to New York Heart Association classes II or III. The benefit-risk assessment for WS 1442 is therefore positive.

[Indications and Clinical Implications of the Use of the Cardiac Markers BNP and NT-proBNP]. / Einsatzgebiete und praktischer Nutzen der kardialen Marker BNP und NT-proBNP.

B-type natriuretic peptides are markers of myocardial wall stress. BNP or NT-proBNP are used for the differential diagnosis of acute dyspnoe where normal serum concentrations make a cardiac cause unlikely. New data show their importance for risk prediction in different stages of heart failure and in primary prevention. Natriuretic peptide guided therapy improves titration of heart failure medications. Compared to BNP, NT-proBNP is better suited during therapy with the new angiotensin-rezeptor-neprilysin-inhibitor Sacubitril/Valsartan. This review article summarizes current data on the importance of B-type natriuretic peptides for the interface of ambulatory and hospital care and presents recommendations for their practical use in patient care.

Ischemia triggers BNP expression in the human myocardium independent from mechanical stress.

BACKGROUND: It is unknown whether the increased B-type natriuretic peptide (BNP) values found in ischemic heart disease are triggered directly by ischemia or whether they are caused indirectly by ischemia through diastolic contractures or regional wall motion abnormalities. Therefore, we investigated the BNP expression in isolated human muscle strips under conditions of ischemia with and without mechanical stress. METHODS: Muscle strips (n=90) were isolated from human right atria (n=46). Contractures were induced by oxygen and glucose withdrawal. In 18 muscle strips contractures were prevented by means of butanedione monoxime (BDM). Sarcomere lengths were measured by electron microscopy (n=12). The gene expression and protein amount of BNP were determined and compared to control muscle strips contracting under physiological conditions. RESULTS: Hypoxia significantly decreased systolic force and induced diastolic contractures. This mechanical stress could be prevented in the group treated with BDM as evidenced by electron microscopy. Ischemia significantly increased BNP expression in both groups as evidenced by Northern blot analysis and immunohistochemistry. This increase was independent from mechanical stress. CONCLUSION: Our results indicate that ischemia is a potent mechanism for the expression of BNP. The increase in BNP expression under ischemic conditions is independent from concomitant mechanical alterations.

The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial.

BACKGROUND: Crataegus preparations have been used for centuries especially in Europe. To date, no proper data on their efficacy and safety as an add-on-treatment are available. Therefore a large morbidity/mortality trial was performed. AIM: To investigate the efficacy and safety of an add-on treatment with Crataegus extract WS 1442 in patients with congestive heart failure. METHODS: In this randomised, double-blind, placebo-controlled multicenter study, adults with NYHA class II or III CHF and reduced left ventricular ejection fraction (LVEF< or =35%) were included and received 900 mg/day WS 1442 or placebo for 24 months. Primary endpoint was time until first cardiac event. RESULTS: 2681 patients (WS 1442: 1338; placebo: 1343) were randomised. Average time to first cardiac event was 620 days for WS 1442 and 606 days for placebo (event rates: 27.9% and 28.9%, hazard ratio (HR): 0.95, 95% CI [0.82;1.10]; p=0.476). The trend for cardiac mortality reduction with WS 1442 (9.7% at month 24; HR: 0.89 [0.73;1.09]) was not statistically significant (p=0.269). In the subgroup with LVEF> or =25%, WS 1442 reduced sudden cardiac death by 39.7% (HR 0.59 [0.37;0.94] at month 24; p=0.025). Adverse events were comparable in both groups. CONCLUSIONS: In this study, WS 1442 had no significant effect on the primary endpoint. WS 1442 was safe to use in patients receiving optimal medication for heart failure. In addition, the data may indicate that WS 1442 can potentially reduce the incidence of sudden cardiac death, at least in patients with less compromised left ventricular function.

A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study.

Etomoxir is an inhibitor of mitochondrial CPT1 (carnitine palmitoyltransferase 1) and thereby switches energy metabolism from fatty acids to glucose oxidation. Such a metabolic change may be beneficial in CHF (congestive heart failure). The ERGO (etomoxir for the recovery of glucose oxidation) study was designed in which etomoxir was tested at a dose of 80 and 40 mg compared with placebo for a period of 6 months in patients with CHF. As the principle measure of efficacy, a maximal exercise tolerance test and a submaximal 6-min corridor walk test were used. Secondary end points were echocardiographical dimensions and quality-of-life assessment scores. A total of 350 patients were planned to be screened, with the expectation that end point data would be available from approx. 260 patients. However, the study had to be stopped prematurely, because unacceptably high liver transaminase levels were detected in four patients taking etomoxir. At the termination of the study, 121 patients were randomized to placebo, 118 to 40 mg of etomoxir and 108 to 80 mg of etomoxir. At that time, 21 patients in the placebo group, 16 in the 40 mg of etomoxir group and 14 patients in the 80 mg of etomoxir group had completed the study. The mean increases in exercise time were 3.3, 10.2 and 19.4 s for the placebo, 40 mg of etomoxir and 80 mg of etomoxir groups respectively (P value was not significant). No changes were obvious in the 6-min corridor walk test or in echocardiographical parameters from baseline. The number of patients that completed the study was too small to demonstrate significant effects on exercise time, although there was a tendency towards an increase in exercise time. Therefore, before rejecting the hypothesis that inhibition of fatty acid oxidation might be beneficial in CHF, similar studies have to be performed using different inhibitors of fatty acid oxidation targeting CPT1 and other enzymes in this metabolic pathway.

Contractile effects of angiotensin and endothelin in failing and non-failing human hearts.

BACKGROUND: Angiotensin II (Ang II) and endothelin-1 (ET-1) share their effects on growth of myocardial cells but have been shown to elicit different effects on myocardial function. However, these effects vary markedly among species, cardiac regions (atrium or ventricle) and failing or non-failing myocardium. We therefore investigated the effects of both peptides on contractile function of isolated human myocytes from failing and non-failing hearts. METHODS AND RESULTS: Cardiomyocytes were enzymatically isolated and electrically stimulated (15 V, 0.2 Hz). Ang II elicited a positive inotropic effect (PIE) mediated by activation of protein kinase C (PKC) in atrial but no effect in ventricular myocytes. ET-1 (10(-8) M) increased cell-shortening by 146+/-9.3% (p<0.05) in atrial myocytes, by 99.1+/-16.5% (p<0.05) in non-failing ventricular but only by 40.5+/-6.4% (p<0.05) in failing ventricular myocytes. The PIE of ET-1 in failing myocytes was more pronounced at low extracellular pH (+112.6+/-27% at pH 7.0 vs. +40.5+/-6.4% at pH 7.4, p<0.05). Amiloride, a sodium-hydrogen-exchange inhibitor, inhibited two thirds of the PIE of ET-1 in failing myocytes. The PKC-inhibitor decreased the PIE by 50% from 113% to 64% in ventricular myocytes under acidotic conditions. CONCLUSION: Ang II and ET-1 elicited PIE in atrial myocytes, whereas in ventricular myocytes Ang II did not induce PIE in contrast to ET-1. The PIE of ET-1 was markedly attenuated in failing myocytes. Under acidotic conditions, the PIE of ET-1 was more pronounced in failing myocytes, indicating that ET-1 may activate signaling processes in failing myocytes, which are not activated in normal myocytes.