BACKGROUND—Polymorphisms in the promoter (T−786C) and exon 7 (G894T) of the endothelial nitric oxide synthase (eNOS) gene were shown to be associated with reduced vascular NO production or increased ...proteolytic cleavage of eNOS. Therefore, we aimed to determine the effects of these polymorphisms on endothelial function and endothelial response to physical exercise in patients with coronary artery disease (CAD).
METHODS AND RESULTS—Sixty-seven patients were randomized to either a training or a control group. At the beginning and after 4 weeks, acetylcholine-induced changes in average peak velocity (APV) of a coronary or mammary artery were invasively assessed by Doppler velocimetry. Polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism. At the beginning, in subjects with the wild-type (WT) variant, APV increased by 88±7% in response to acetylcholine. This response was significantly blunted in patients who were positive for the promoter (44±7%) or the exon 7 (62±9%) polymorphism. Four weeks of exercise training resulted in augmentation of an endothelium-dependent increase in APV by +36±12% in promoter polymorphism–positive patients but by +81±18% and +91±15% in WT variant- and exon 7 polymorphism–positive subjects, respectively.
CONCLUSIONS—These results suggest that the presence of either one of the polymorphisms attenuates endothelium-dependent vasodilatation in CAD patients. Only the promoter polymorphism might have an adverse effect on training-induced improvement in endothelial function.
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BACKGROUND: Diastolic left ventricular dysfunction may occur in both physiologic aging and chronic heart failure (CHF). It has, however, never been assessed, whether the degree of ...diastolic impairment in CHF is influenced by age and if the previously observed beneficial effects of exercise (ET) on left ventricular filling are diminished in old age.
METHODS: In this study we randomised 53 pts. with stable CHF(LVEF 27.3±2.1%) and 51 healthy subjects (HS) (LVEF 61.5±2.7%) to a training (T) or a control group (C). To detect possible aging effects we included subjects <55 (young) and >65 years (old). Subjects in the T-group exercised 4 times daily at 60 to 70% of VO
2
max for 4 weeks under supervision. At baseline and after the intervention E/A ratio and lateral E/E′ ratio were determined by echocardiography and with tissue Doppler imaging.
RESULTS: As compared to young HS, old HS showed at baseline a reduced E/A ratio and an increased E/È ratio (young: E/A 1.2±0.2; E/È 7.3±0.1 old: E/A 0.7±0.1; E/È 13.5±0.3; p<0.05). In CHF pts., diastolic function was impaired (young E/A 0.8±0.2; E/È 12.9±0.5 old: E/A 0.8±0.1; E/È 13.7±0.4). No difference of these baseline parameters between the age groups was observed (p=0.72). As a result of ET, E/A ratio improved from 0.7±0.1 to 1.2±0.2 and E/È ratio improved from 13.7±0.3 to 9.3±0.4 in old HS (p<0.05), while it remained unchanged in young training HS and C. In young and old pts. with CHF four weeks of ET resulted in a significant change in E/A ratio (young: from 0.8±0.1 to 1.2±0.1; p<0.05; old: from 0.7±0.1 to 1.1±0.2 p<0.05) and E/È ratio (young: from 13.1±0.3 to 10.1±0.2; p<0,05; old: from 14.1±0.3 to 11.2±0.3; p<0.05). In C no effect was detectable.
CONCLUSIONS: The present trial provides new insight into chronobiology of cardiovascular training effects: Among HS aging is associated with the development of significant left ventricular diastolic dysfunction. In CHF both young and old pts. exhibit a similar degree of LV-dysfunction. Four weeks of ET are effective in improving diastolic function in old HS and in young and old CHF pts. The lusitropic training effects were not significantly diminished among older pts. underlining the potentials of rehabilitation interventions in this patient group.
Exercise training (ET) has been shown to improve functional work capacity in patients with stable chronic heart failure (CHF) having moderate symptoms (NYHA class II). This analysis was conducted, to ...evaluate the effects of ET on left ventricular function and haemodynamics in patients with advanced CHF (NYHA class III) fulfilling the inclusion criteria of the COPERNICUS trial.
Seventy-three patients with moderate and advanced CHF were prospectively randomised to a training (n=36), or to a control group (n=37). At baseline and after six months, patients underwent echocardiography and symptom-limited ergospirometry with measurement of central haemodynamics by thermodilution.
Nine out of 37 patients in the control group (C) and 10 out of 36 patients in the training group (T) had symptoms of advanced CHF. Exercise training over a period of six months resulted in an improvement of functional status on average by one NYHA class in patients with advanced CHF. Moreover, oxygen uptake at the ventilatory threshold increased by 49% (from 7.7+/-1.0 to 11.4+/-0.4 mL/min/kg, P<0.01 versus baseline) and at peak exercise by 32% (from 16.3+/-1.6 to 21.5+/-1.2 mL/min/kg, P<0.01 versus baseline) in training patients. The small, but significant reduction in left ventricular end-diastolic diameter by 7% (from 70+/-2 to 66+/-2 mm; P<0.05 versus baseline) was accompanied by an augmentation in stroke volume at rest by 32% (from 45+/-3 to 60+/-6 mL, P<0.05 versus baseline) and at peak exercise by 27% (63+/-9 to 81+/-9 mL, P<0.05 versus baseline) as a result of ET in patients with advanced CHF.
In patients with advanced CHF (NYHA class III), long-term exercise training is associated with an enhanced physical work capacity, an improvement in stroke volume and a reduction in cardiomegaly.
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Background: Progressive muscle wasting frequently occurs in the course of chronic heart failure (CHF) and has recently been identified as independent predictor of mortality in clincal ...studies. However, the molecular mechanisms that mediate muscle catabolism are still largely unknown and no specific pharmacological agents are available to antagonize the loss of muscle mass. We therefore tested the potential of an established anabolic intervention, i.e. exercise training, to prevent cytokine-induced ubiquitin-proteasome-mediated protein degradation in the skeletal muscle of stable patients with advanced CHF.
Methods: 43 CHF-patients and 41 healthy subjects (HS) were prospectively randomized to 4 weeks of supervised bicycle ergometer training at 70% of the heart rate reserve 4 times 20 min/day or to a control group (C). Before and after the intervention a spiroergometry, echocardiography, and skeletal muscle biopsy from the vastus lateralis muscle were performed. Expression of TNF-alpha and the E3 ligase Murf-1, which tags proteins for degradation via the ubiquitin-proteasome system, were quantified by real-time PCR standardized for 18S-rRNA.
Results:
In CHF patients (age 60.3 ± 2.9 years, BMI 28.9 ± 1.7, LV-EF 27.4 ± 1.7%): training increased VO2max from 14.9 ± 3.3 to 18.1 ± 4.7 mL/min/kg (p<0.01 vs. C), and LV-EF from 26.8 ± 4.6 to 33.1 ± 5.5% (p=0.001 vs. C). At baseline Murf-1 expression was significantly higher as compared to HS. Training decreased Murf-1 expression from 0.49 ± 0.21 to 0.22 ± 0.07 rel. units (p<0.05) and TNF-alpha expression from 79 ± 7.1 to 44.7 ± 5.9 rel. units (p<0.001).
In HS (age 64.7 ± 2.7 years, BMI 26.2 ± 0.5, LV-EF 63 ± 0.8%) training increased VO2 max from 20.3 ± 2.1 to 27.9.2 ± 1.3 mL/kg min (p=0.01 vs. C). Murf-1 and TNF-alpha expression remained unchanged versus untrained HS.
Conclusions:
CHF is associated with local inflammatory and catabolic activation in the skeletal muscle as indicated by higher baseline TNF-alpha and Murf-1 levels.
Training cuts the elevated TNF-alpha and E3-ligase expressions by half within only four weeks of intervention.
These findings emphasize the role of training for the prevention of muscle atrophy and may provide a novel explanation for the prognostic benefits of exercise in CHF.
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Background:
MRI is an excellent diagnostic tool for serial assessment of changes in myocardial perfusion, left ventricular function, and infarct size. In chronic total occlusions (CTO) ...the effects of recanalization on perfusion and function are contradictory and might depend primarily on viability. Circulating progenitor cells (CPC) injected intracoronarily after successful CTO recanalization might improve perfusion and function.
Methods and results:
Twenty-eight patients with reperfused CTO were randomized to either CPC’s or inactive serum (control), which were infused into the target vessel. First-pass myocardial perfusion MRI at rest and stress using adenosine at standard dose revealed a significant improvement of the myocardial perfusion reserve index (MPRI) in the affected segments. The baseline MPRI in affected segments was 1.50±0.17 in CPC versus 1.46±0.16 in control (p=0.62). In CPC the MPRI improved to 1.76±0.16 (p<0.001) at 3 and 1.82±0.20 (p<0.001) at 15 months; in control the change was 1.58±0.10 (p=0.01) at 3 and 1.61±0.08 (p=0.004) at 15 months follow-up. However, the MPRI recovery was significantly better in CPC as compared to control at 3 (p=0.004) and 15 months (p=0.005). In remote myocardium the MPRI was 1.70±0.30 and 1.69±0.25 (p<0.01 versus affected segments), respectively. At follow-up there was no significant improvement for both groups. The change in MPRI at 3 and 15 months was correlated with a change in overall infarct size for CPC (3 months: r=−0.68, p<0.02; 15 months: r=−0.81, p=0.001), whereas in control there was no correlation (r=−0.38, p=0.26; 15 months: r=−0.21, p=0.56). Infarct transmurality influenced MPRI improvement at follow-up. CPC patients had a trend towards more improved segments in particular those with higher transmurality (p=0.06).
Conclusions:
Analysis of serial contrast-enhanced MRI suggests that intracoronary application of CPC post recanalization of CTO is associated with improved myocardial perfusion and subsequent improved recovery of left ventricular function as compared to a control group at mid- and long-term follow-up. Further investigations of the pathophysiological CPC effects on macro- and microvascular function are required.
Objectives. This study was designed to analyze the effect of iNOS on mitochondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF).
Background. The molecular ...mechanisms underlying exercise intolerance in CHF are still unclear. Expression of inducible nitric oxide synthase (iNOS) and reduced phosphocreatine resynthesis have been described in skeletal muscle of patients with CHF. However, it is unknown whether these phenomena are causally related to each other and to exercise tolerance.
Methods. Thirty-eight patients with CHF and 8 healthy controls (C) underwent bicycle ergospirometry and biopsy of the vastus lateralis muscle. Expression of iNOS was quantified by immunohistochemistry and reverse-transcriptase polymerase chain reaction, mi-CK by Western-blot. Intracellular presence of NO was confirmed by immunohistochemical quantification of nitrotyrosine (NT). To corroborate clinical findings, L6 rat skeletal myoblasts were incubated with sodium nitroprusside (SNP).
Results. Expression of iNOS was significantly increased in CHF (4.0 ± 2.8 vs. 0.8 ± 0.7% iNOS positive tissue area, p < 0.001 vs. C) and inversely correlated to maximal oxygen uptake (r = −0.65, p < 0.001). Intracellular NO-accumulation was confirmed by increased NT levels (13.5 ± 8.5 vs. 2.0 ± 1.7% NT-positive tissue area, p < 0.001 vs. C). Mi-CK was decreased in CHF (0.84 ± 0.36 vs. 1.57 ± 0.60, p < 0.001 vs. C). The inverse correlation seen between iNOS and mi-CK expression in patients (r = −0.68, p < 0.001) was reproduced in incubation experiments with SNP.
Conclusions. Increased expression of iNOS in skeletal muscle of patients with CHF was inversely correlated with mi-CK expression and exercise capacity. Cell experiments confirmed a causal relationship via NO. These findings extend our knowledge of the pathophysiology of exercise intolerance in CHF.
This study investigated the differences in clinical outcomes between patients with bifurcation lesions (BL) treated with a biolimus-eluting stent (BES) with a biodegradable polymer, and a ...sirolimus-eluting stent (SES) with a durable polymer.
The clinical outcomes were assessed in the 497 patients (BES 258, SES 239) enrolled in the multicentre, randomised LEADERS trial who underwent treatment of ≥1 BL (total=534 BL). At 12-months follow-up there was no significant difference in the primary endpoint of MACE, a composite of cardiac death, myocardial infarction and clinically indicated target vessel revascularisation (BES 12.8% vs. SES 16.3%, p=0.31). Patients treated with BES had comparable rates of cardiac death (BES 2.7% vs. SES 2.9%, p=1.00), numerically higher rates of myocardial infarction (BES 8.9% vs. SES 5.4%, p=0.17), and significantly lower rates of clinically indicated target vessel revascularisation (4.3% vs. 11.3%, p=0.004) when compared to those treated with SES. The rate of stent thrombosis at 12-months was 4.3% and 3.8% for BES and SES, respectively (p=0.82).
In the treatment of BL the use of BES lead to superior efficacy and comparable safety compared to SES.
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