Carsten Krüger

Risk stratification in middle-aged patients with congestive heart failure: prospective comparison of the Heart Failure Survival Score (HFSS) and a simplified two-variable model

The performance of a US‐American scoring system (Heart Failure Survival Score, HFSS) was prospectively evaluated in a sample of ambulatory patients with congestive heart failure (CHF). Additionally, it was investigated whether the HFSS might be simplified by assessment of the distance ambulated during a 6‐min walk test (6′WT) instead of determination of peak oxygen uptake (peak VO2).

Baroreflex sensitivity and heart rate variability in conscious rats with myocardial infarction

The baroreflex sensitivity (BRS) and the heart rate variability (HRV) were studied in conscious rats after myocardial infarction (MI; induced by coronary artery ligation) and after sham operation (SH). BRS was determined by linear regression of R-R interval vs. arterial pressure changes induced by nitroprusside or methoxamine (intravenous bolus). HRV was calculated from 3-min electrocardiogram recordings. Left ventricular end-diastolic pressure and plasma atrial natriuretic peptide were increased after MI; plasma norepinephrine and basal heart rate (HR) remained unchanged. At 3 and 28 days after MI, BRS was reduced as indicated by decreased reflex bradycardia (RB) (MI, 0.66 ± 0.13 and 0.78 ± 0.07 ms/mmHg; SH, 1.27 ± 0.16 and 1.48 ± 0.14 ms/mmHg, respectively; P < 0.05 MI vs. SH). At 56 days after MI, BRS was normalized. RB was unaffected by atropine 3 and 28 days after MI but reduced in all other groups. The increase of basal HR by atropine 3 and 28 days after MI was less than in all other groups. HRV (SD of mean N-N interval, coefficient of variance, low- and high-frequency power; studied at 28 and 56 days) was similar in all groups. It is concluded that BRS is transiently depressed in rats with left ventricular dysfunction after MI probably due to a reduced reflex vagal activity. Even though basal HR and HRV are unchanged after MI, a temporary attenuation of tonic vagal activity is unmasked after autonomic blockade.The baroreflex sensitivity (BRS) and the heart rate variability (HRV) were studied in conscious rats after myocardial infarction (MI; induced by coronary artery ligation) and after sham operation (SH). BRS was determined by linear regression of R-R interval vs. arterial pressure changes induced by nitroprusside or methoxamine (intravenous bolus). HRV was calculated from 3-min electrocardiogram recordings. Left ventricular end-diastolic pressure and plasma atrial natriuretic peptide were increased after MI; plasma norepinephrine and basal heart rate (HR) remained unchanged. At 3 and 28 days after MI, BRS was reduced as indicated by decreased reflex bradycardia (RB) (MI, 0.66 +/- 0.13 and 0.78 +/- 0.07 ms/mmHg; SH, 1.27 +/- 0.16 and 1.48 +/- 0.14 ms/mmHg, respectively; P < 0.05 MI vs. SH). At 56 days after MI, BRS was normalized. RB was unaffected by atropine 3 and 28 days after MI but reduced in all other groups. The increase of basal HR by atropine 3 and 28 days after MI was less than in all other groups. HRV (SD of mean N-N interval, coefficient of variance, low- and high-frequency power; studied at 28 and 56 days) was similar in all groups. It is concluded that BRS is transiently depressed in rats with left ventricular dysfunction after MI probably due to a reduced reflex vagal activity. Even though basal HR and HRV are unchanged after MI, a temporary attenuation of tonic vagal activity is unmasked after autonomic blockade.

Heart rate variability enhances the prognostic value of established parameters in patients with congestive heart failure.

In dieser prospektiven Studie wurde untersucht, ob die aus dem Langzeit-EKG bestimmte Herzfrequenz-Variabilität (HRV) einen prognostischen Wert zusätzlich zu bereits etablierten Prädiktoren bei Patienten mit chronischer Herzinsuffizienz besitzt.    In die Studie wurden 222 Patienten mit dilatativer oder ischämischer Kardiomyopathie (linksventrikuläre Ejektionsfraktion LVEF 21±1%; Mittelwert±SEM) im Sinusrhythmus eingeschlossen. Während eines mittleren Beobachtungszeitraums von 15±1 Monaten verstarben 38 (17%) Patienten aus kardialer Ursache; 45 (20%) Patienten wurden infolge kardialer Dekompensation hospitalisiert. Der HRV-Parameter SDNN (Standardabweichung aller Intervalle zwischen Normalschlägen) war bei verstorbenen bzw. dekompensierten Patienten signifikant niedriger als bei ereignisfreien Patienten (118±6 vs. 142±5 ms). Die LVEF (18±1 vs. 23±1%) und die maximale Sauerstoff-Aufnahme während Spiroergometrie (peak VO2) (12,8±0,5 vs. 15,6±0,5 ml/min/kg) waren bei Patienten mit kardialem Endpunkt ebenfalls signifikant erniedrigt. Bei univariater Analyse stellte jeder dieser Parameter einen eigenständigen Risikoprädiktor dar. In der multivariaten Analyse zeigte sich, dass die HRV eine unabhängige prognostische Aussagekraft besitzt. Dabei wurde deutlich, dass bei Patienten mit stark verminderter LVEF und peak VO2 niedrige Werte des HRV-Parameters SDNN eine weitere Erhöhung des Risikos für schwere kardiale Ereignisse widerspiegeln.    Bei Patienten mit deutlich eingeschränkter linksventrikulärer Funktion besitzt die einmalig aus dem Langzeit-EKG bestimmte HRV eine hohe prognostische Wertigkeit über einen mittleren Zeitraum von 1‡ Jahren. Durch kombinierte Bestimmung der HRV und der beiden meistetablierten Parameter LVEF und peak VO2 kann eine Optimierung der Stratifikation hinsichtlich des Risikos von Dekompensation oder Versterben aus kardialer Ursache angestrebt werden. This prospective study evaluated whether heart rate variability (HRV) assessed from Holter ECG has prognostic value in addition to established parameters in patients with congestive heart failure (CHF).    The study included 222 patients with CHF due to dilated or ischemic cardiomyopathy (left ventricular ejection fraction LVEF 21±1%; mean±SEM). During a mean follow-up of 15±1 months, 38 (17%) patients died and 45 (20%) were hospitalized due to worsening of CHF. The HRV parameter SDNN (standard deviation of all intervals between normal beats) was significantly lower in non-surviving or hospitalized than in event-free patients (118±6 vs 142±5 ms), as were LVEF (18±1 vs 23±1%), and peak oxygen uptake during exercise (peak VO2) (12.8±0.5 vs 15.6±0.5 ml/min/kg). While each of these parameters was a risk predictor in univariate analysis, multivariate analysis revealed that HRV provides both independent and additional prognostic information with respect to the risk ‘cardiac mortality or deterioration of CHF’.    It is concluded that the determination of HRV enhances the prognostic power given by the most widely used parameters LVEF and peak VO2 in the prediction of mortality or deterioration of CHF and thus enables to improve risk stratification.

The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction

OBJECTIVE The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). METHODS Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. RESULTS In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. CONCLUSIONS Both BRS and HRV are reduced in rats early after MI, indicating a depressed reflex and tonic vagal activity. Treatment with zatebradine enhances both BRS and HRV. These data suggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate.

Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: Modulation by single components of ischaemia

The influence of single components of myocardial ischaemia, such as anoxia, substrate withdrawal, hyperkalemia and extracellular acidosis, on nicotine-induced norepinephrine (NE) release was investigated in the isolated perfused guinea-pig heart, in incubated human atrial tissue and in cultured bovine adrenal chromaffin cells (BCC). In normoxia, nicotine (1-1000 mumol/l) evoked a concentration-dependent release of NE (determined by high pressure liquid chromatography and electrochemical detection) from guinea-pig heart and human atrium. In contrast to selective anoxia (Po2 < 5 mmHg) or glucose withdrawal, respectively, anoxia in combination with glucose withdrawal (5-40 min) markedly potentiated nicotine-induced NE release both in guinea-pig heart and human atrium. The sensitization of cardiac sympathetic nerve endings to nicotine was characterized by a lower threshold concentration and an approximate two-fold increase of maximum NE release, peaking after 10 min of anoxia and glucose withdrawal. Cyanide intoxication (1 mmol/l) combined with glucose withdrawal resulted in a similar increase of nicotine-induced sympathetic transmitter release both in guinea-pig heart and human atrium. In contrast, the nicotine-induced (10 mumol/l) NE overflow was only slightly potentiated by 10 min of global ischaemia in guinea-pig heart. Both hyperkalemia ([K+] 16 mmol/l) and acidosis (pH 6.8-6.0) distinctly attenuated the stimulatory effect of nicotine in guinea-pig heart and human atrium under normoxic conditions. Consistent with an exocytotic release mechanism, NE release was dependent on the presence of extracellular calcium under all conditions tested. Furthermore, NE overflow from guinea-pig heart was accompanied by a release of the exocytosis marker neuropeptide Y (NPY; determined by radioimmunoassay). In BCC, nicotine (1-10 mumol/l) evoked a release of NE and NPY and a transient rise of [Ca2+]i (determined with fura-2) during normoxia which were both dependent on the presence of extracellular calcium. Both hyperkalemia and acidosis markedly reduced the exocytotic release of sympathetic transmitters and the corresponding [Ca2+]i-transients. These data demonstrate that nicotine-induced cardiac exocytotic NE release is markedly potentiated during short-term anoxia in combination with glucose withdrawal. In contrast, a brief period of ischaemia causes only a slight sensitization of cardiac sympathetic nerve endings to nicotine. This discrepancy may be due to an attentuation of nicotine-evoked NE release by hyperkalemia and by acidosis. The protective effect of these factors against anoxia-induced sensitization to nicotine appears to be related to the inhibition of nicotine-evoked [Ca2+]i-transients.