Klaus Peters

Predictors of response to exercise training in severe chronic congestive heart failure.

We prospectively assessed whether baseline central hemodynamics and exercise capacity can predict improvement of VO2 at ventilatory threshold (VT) after exercise training in patients with severe chronic congestive heart failure. Eighteen patients (mean +/- SEM; age 52 +/- 2 years), half of them listed for transplant, underwent 3 weeks of exercise training (interval cycle and treadmill walking; 5 x/week) and 3 weeks of activity restriction in a random-order crossover trial. Baseline data were not significantly different for groups with exercise training first and activity restriction first: cardiac index at rest (2.1 +/- 0.1 L/m2/min), maximum cardiac index (3.1 +/- 0.2 L/m2/min) (Fick), and echocardiographic ejection fraction (21 +/- 1%). The same was true for cardiopulmonary exercise data (cycle ergometry; up 12.5 W/min): VO2 at VT (9.3 +/- 0.4 ml/kg/min), maximum VO2 (12.2 +/- 0.7 ml/kg/min), VT in percentage of predicted maximum VO2 (31 +/- 2%), heart rate at VT (95 +/- 4 beats/min), and decrease of dead space-to-tidal volume ratio from rest to VT (33 +/- 1 --> 29 +/- 1). Improvement of VO2 at VT after training (2.2 +/- 0.4 ml/kg/min; p <0.001) was not related to baseline central hemodynamics (r = <0.10 for each), but was greater in patients with a lower baseline VO2 at VT (r = -0.65; p <0.01), peak VO2 (r = -0.66; p <0.01), VT in percentage of predicted maximum VO2 (r = -0.74; p <0.001), heart rate at VT (r = -0.63; p <0.01), and smaller decrease of dead space-to-tidal volume ratio from rest to VT (r = 0.65; p <0.01). Ejection fraction after exercise training (24 +/- 2%) and activity restriction (23 +/- 2%) did not differ significantly compared with baseline, and patient status (heart failure and cardiac rhythm) remained stable. Three parameters accounted for 84% of the variance of improvement in VO2 at VT: VO2 at VT in percent predicted maximum VO2, decrease of dead space-to-tidal volume ratio, and heart rate at VT. The findings suggest that there was a greater increase in VO2 at VT after exercise training in patients with greater peripheral deconditioning at baseline. The improvement was unrelated to central hemodynamics. Clinically stable patients with severe chronic congestive heart failure, potential heart transplant candidates, and those awaiting transplantation may benefit from involvement in a short-term exercise training program.

Short-term reproducibility of cardiopulmonary measurements during exercise testing in patients with severe chronic heart failure ☆ ☆☆ ★

Eleven men with severe chronic heart failure (peak cardiac index 4.0 +/- 0.2 L/m2/min), six on a heart transplantation waiting list, were prospectively assessed. To determine reproducibility of cardiopulmonary and hemodynamic variables for clinical purposes during ramp bicycle ergometry, the patients underwent two ramp bicycle ergometer tests (3 minutes unloaded, work rate increments of 12.5 W/min) with a 1-week interval between tests. Oxygen uptake (VO2) carbon dioxide production (VCO2), and ventilation were measured breath by breath, and calculations were performed to determine gas exchange ratio, oxygen pulse, ventilatory equivalents of oxygen and carbon dioxide, and end-tidal partial pressure for oxygen and carbon dioxide. Additionally, heart rate, blood pressure, and lactate levels were assessed. Measurements were performed at submaximum work rate levels of 25 W, 50 W, and 75 W at ventilatory threshold and at peak work rate. At all measurement points, the coefficient of variation for cardiopulmonary variables was between 1.4% and 7.1% for submaximum work rate levels, between 1.2% and 4.4% at ventilatory threshold, and between 2.4% and 7.1% at peak work rate. For heart rate, blood pressure, and lactate levels, coefficient of variation was between 2.7% and 5.7% for submaximum work rate levels, between 1.4% and 6.1% at ventilatory threshold, and between 1.2% and 5.5% at peak work rate. The data suggest high reproducibility for duplicate measurements of cardiopulmonary and hemodynamic variables during ramp bicycle ergometry in patients with severe chronic heart failure. The results may be used to determine whether any variable in a single patient is significantly different from that obtained in a previous exercise test or if the change is within experimental error.

Verbesserung der aeroben Kapazität bei chronischer Herzinsuffizienz : Welche Trainingsmethode ist geeignet ?

Bislang existieren keine standardisierten Richtlinien zur Methodik eines körperlichen Trainings für Patienten mit schwerer chronischer Herzinsuffizienz. Patienten, die in der Vergangenheit in Trainingsstudien involviert wurden, zeigen eine große Variabilität der kardialen und funktionellen Einschränkungen, bei mittleren Werten der Ejektionsfraktion zwischen 18 und 35% und der peak VO2 zwischen 12,2 und 25,4 ml/kg/min. Zur Bestimmung der Trainingsbelastung wurde eine VO2 zwischen 40 und 70% der peak VO2 und/oder eine Herzfrequenz zwischen 60 und 80% der maximalen Herzfrequenz gewählt. Ferner variierten die Häufigkeit (zwischen 3- und 7x pro Woche) und die Dauer des Trainings (zwischen 20 und 60 min/Trainingseinheit) stark. Das Ausdauertraining wurde ausschließlich in der kontinuierlichen Dauermethode angewandt. Wir entwickelten eine neue Intervall-Trainingsmethode, die intensive Belastungsreize auf die periphere Muskulatur erlaubt, die kardiale Belastung jedoch gering hält. Nach nur 3 Wochen dieses Intervalltrainings zeigte sich die Verbesserung der aeroben Kapazität in einer Größenordnung, wie sie erst nach längeren Trainingsphasen bei Anwendung der Dauertrainingsmethode berichtet wurde. Zur Bestimmung der Belastung für die Belastungsphasen des Intervalltrainings wurde ein spezifischer steiler Rampentest entwickelt. Eine Analyse der akuten körperlichen Reaktionen während des steilen Rampentests und während des Intervalltrainings ergab, daß beide Belastungsformen selbst für solche Patienten tolerabel waren, die eine Ejektionsfraktion von nur 13%, einen maximalen Herzindex von nicht mehr als 1,6 l/m2/min oder eine peak VO2 von lediglich 8,5 ml/kg/min aufwiesen. Standardized guidelines for exercise training for patients with chronic congestive heart failure (CHF) have not been established. In the past CHF patients involved in exercise training studies demonstrated a wide range of cardiac and functional impairment, with an ejection fraction between 18 and 35% and a peak VO2 between 12.2 and 25.4 ml/kg/min on average. For determination of training intensity, a VO2 between 40 and 70% of peak VO2 and/or training heart rate between 60 and 80% of peak heart rate was used. There was also a wide range for frequency (between 3 and 7 times per week) and duration of training (between 20 and 60 min per session). For aerobic exercise training only continuous training methods were applied. We have developed a new interval training method which allows intense exercise stimuli on peripheral muscles with minimal cardiac strain. After only three weeks of training, the improvement in aerobic capacity was similar to that reported after longer training periods using continuous methods. To determine work rate for work phases of interval training, a special steep ramp test was developed. By analysis of acute physical responses to this testing procedure and to the interval training, both were proven to be tolerable in CHF patients, even if their ejection fraction is as low as 13%, or peak cardiac index not greater than 1.6 l/m2/min, and peak VO2 less than 8.5 ml/kg/min.

Lipid-Intervention und koronare Herzkrankheit bei Männern unter 56 Jahren: Die Coronare Interventions-Studie: CIS

The CIS was undertaken with the aim to evaluate the effects of lipid modifications on angiographic progression and regression of CAD in patients with CAD and hypercholesterolemia. The design included a multicenter randomized, double-blind, parallel, placebo-controlled comparison, with target and safety limits for adjusting the trial medication depending on the LDL cholesterol level (LDL-C) achieved, i.e., up to 40 mg of simvastatin (S) or placebo (P) daily, add-on medication (up to 3 × 4 g Colestyramin), and diet counselling. Male patients, average age 48 (≤ 56) years, were included with angiographic CAD and a screening total cholesterol of 207–350 mg/dl, who were not due to undergo coronary bypass surgery or PTCA, wh did not suffer from serious other disease (e.g., diabetes mellituss), and who had not undergone coronary bypass surgery previously. Results: All baseline variables were comparable in the treatment groups, with 129 patients taking S and 125 taking P. Of these 254 patients 217 had their final study visit and 207 underwent a second angiography after an average treatment time of 2.3 years under an average daily dose of 37 mg S. 205 pairs of films were available for analysis. Vital information was obtained of all patients until closure of the data bank, half a year after the last study angiography. Five deaths occurred within the study period, 12 through March 15, 1995 (S: 1/6, P: 4/6). 37 patients (S: 18, P: 19) discontinued trial drug and protocol. Concomitant CAD medication was comparable in both groups, except lipid-lowering add-on medication which was significantly higher in the P group (38% versus 13%). Significant changes in lipid levels, on treatment, were observed in the S group amounting to a mean difference in LDL-C of −35%, in Apo-Protein B (ApoB) of −30%, in VLDL-C of −37%, and in triglycerides (TG) of −27%, and in HDL-C of +6%, in comparison to the control group; these differences were even greater in 137 fully compliant patients: −41, −36, −39, −31, and +7%, respectively. Progression in the S group was significantly less, as defined by the two primary target criteria: 1) the minimum obstruction diameter (MOD), determined by quantitative coronary angiography (QCA), decreased about five times less in comparison to the control group (S: by −0.017; P: −0.0954 mm), and 2) the standardized visual global change score (GCS) deteriorated almost three times less in the S group (by +0.20) than in the P group (+0.58). Of the secondary target criteria, the mean lumen diameter (QCA) also developed a significant difference (S: −0.20; P: +0.23 mm; P = 0.0006) with a trend toward regression in the S group. The QCA-%-stenosis deteriorated three- to fourtimes less in the S group as compared to the control group (S: by 0.69%; P: by 2.73 %; p = 0.0022), and the number of patients with angiographic progression was nearly halved (S: 30%; P: 56%; P < 0.0000). These differences were determined by intention to treat analysis (ITT), and they were obtained in spite of lipid lowering add-on medication in 38% of the P patients; they turned out to be more pronounced in 137 fully compliant patients, in an analysis “as treated”. The mean decrease in LDL-C serum level caused by S was significantly correlated to the decrease in progression, and multivariate regression analysis of both treatment groups identified LDL-C (or ApoB) and TG as independent predictors of progression. Progression appeared to be most pronouncedf in low and medium sized lesions, and the beneficial effect of lipid intervention dominated in lesions with 12–56% QCA stenosis severity. A small fraction of patients who suffered from exercise-induced angina, with ST-segment-depression at the beginning of the study, experienced a significant improvement under S as compared to P treatment. Although the study was not designed to show differences in clinical events, the combined number of all major cardiovascular events tended to be less frequent in the S than in the C group (n.s.), and so did the number of patients with any major adverse event and the absolute number of such events as well as the number of patients with minor adverse experiences and with minor laboratory deviations. Conclusion: In young men, on otherwise full CAD treatment, additional medication with 37 mg simvastatin daily for an average of 2.3 years slowed down angiographic progression of CAD significantly, with a predominant beneficial effect on medium sized coronary lesions. This emerged from the visual as well as the quantitative coronary analysis which gave equivalent and complementing results. By multivariate regression analysis, the inhibitory effect on progression is correlated to the considerable and highly significant difference in LDL-C (or ApoB) and TG effected by simvastatin in comparison to placebo according to the regression equation: ΔMOD [mm] = −0.109 + 0.0003 [TG mg/dl] + 0.0008 [LDL-C mg/dl]. Ziel: Die CIS beschreibt die Auswirkungen einer starken Lipid-Intervention auf Progression und Regression bei Patienten mit koronarer Herzerkrankung (KHK) und hohem Cholesterin. Die Studienanlage war multizentrisch, randomisiert, doppelblind, parallel, placebokontrolliert, mit definierten Ziel- und Sicherheitsgrenzen für die Anpassung der Prüfmedikation (Simvastatin = S) und Zusatzmedikation (Colestyramin) undDiätberatung. Eingeschlossen wurden Männer im Alter von durchschnittlich 49 (≤ 56) Jahren mit angiographisch gesicherter KHK und einem Gesamtcholesterin von 207–350 mg/dl. Ausgeschlossen wurden Patienten mit bedeutenden anderen Krankheiten oder die bereits eine Bypassoperation hinter sich oder eine koronare Intervention zu erwarten hatten. Ergebnisse: Von 254 rekrutierten Patienten erhielten 129 S, die übrigen Placebo (P). Insgesamt 217 Patienten kamen zur Abschlußvisite, und 207 von ihnen unterzogen sich einer 2. Angiographie nach einer durchschnittlichen Behandlungszeit von 2, 3 Jahren. Von allen Patienten wurden die Informationen über den vitalen Status bis zum Schluß der Datenbank, 1/2 Jahr nach der letzten Studienangiographie, eingeholt. Während der Studie traten 5 Todesfälle ein, bis zum Schluß der Datenbank insgesamt 12 (S: 1 bzw. 6, P: 4 bzw. 6). Bei der Analyse nach der primären Behandlungsabsicht (intention to treat : ITT) ergaben sich signifikante mittlere Unterschiede der Serumlipide zwischen den Behandlungsgruppen: −35% für das LDL-C, −30% für ApoB, −44% für VLDL-C, −27% für TG und +6% für HDL-C. Deutliche und signifikante Unterschiede ließen sich auch in den beiden primären und in wichtigen sekundären Zielkriterien erkennen. Die Unterschiede zwischen den Gruppen waren sowohl bezüglich der Lipidveränderungen wie auch der Zielkriterien deutlicher in einer Untergruppe von 137 Patienten, welche das Studien-Medikament praktisch ununterbrochen einnahmen. Die günstige Wirkung der Intervention dominierte in mittleren Koronarläsionen mit 12–56 % Stenosierung (QCA). Der durch Simvastatin abgesenkte mittlere LDL-C-Spiegel war signifikant korreliert zur Hemmung der Progression, und mittels multivariater Regressionsanalyse beider Behandlungsgruppen ließen sich die mittleren Serum-Spiegel des LDL-C (oder des APOB) einerseits und der TG andererseits als unabhängige Determinanten identifizieren. Schlußfolgerungen: Bei jungen Männern von durchschnittlich 49 (≤ 56) Jahren läßt sich durch starke Lipid-Interventionen unter Einschluß von etwa 37 mg S täglich die angiographische Progression der KHK (visuell und quantitativ gemessen) innerhalb von 2,3 Jahren deutlich hemmen, die Zahl der Patienten mit Progression halbieren und die Ischämielast senken; dabei dominiert das Ausmaß der Progressionshemmung in geringen und mittleren Koronarstenosen mit einem Ausgangswert von etwa 12–56 %. Unter vielen anderen Lipidveränderungen in der CIS bestimmten vor allem die erreichten Serumspiegel das LDL-C (bzw. ApoB) und der TG das Ausmaß der Progression, was die multivariate Regressionsgleichung quantitativ beschreibt. Diese günstigen Ergebnisse ließen sich erzielen trotz umfassender und gleicher Begleitmedikation für die KHK in beiden Behandlungsgruppen und trotz medikamentöser Lipid-Intervention bei 39% der Patienten in der P-Gruppe.