Improved Exercise Tolerance After Losartan and Enalapril in Heart Failure

Vescovo, Giorgio; Libera, Luciano Dalla; Serafini, Francesco; Leprotti, C; Facchin, L; Volterrani, Maurizio; Ceconi, Claudio; Ambrosio, Giovanni B.

doi:10.1161/01.cir.98.17.1742

Cited by 125 publications

(18 citation statements)

References 46 publications

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“…Indeed, we did not find improvement in grip strength over time. Given the broad influence of the RAS on many tissues, and the fact that ARBs such as losartan impact multiple organ systems, we can speculate that some of the observed activity improvement may come from ARB related cognitive and cardiovascular improvements and from mitochondrial functional improvement, in addition to skeletal muscle improvement 3;9;18 . Next, the broad array of activity measures that we utilized in this study are not necessarily measuring the same kind of activity that equipment with sensor beams such as the Opto-M4 (Columbus Instruments, Columbus, OH, USA) uses.…”

Section: Discussionmentioning

confidence: 99%

“…Losartan has already been demonstrated to accelerate muscle healing and slow the development of disuse atrophy in aging mice 8 . In addition, an earlier pilot study of chronic losartan treatment in humans with heart failure demonstrated improvement in exercise capacity associated with a shift towards more fatigue resistant skeletal muscle fibers 9 . Although multiple hormonal and pharmaceutical treatments have been developed for age-related sarcopenia in humans, none have to date proven effective 10 .…”

Section: Introductionmentioning

confidence: 99%

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Losartan improves measures of activity, inflammation, and oxidative stress in older mice

Lin

Yang

Qin

et al. 2014

Experimental Gerontology

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Sarcopenia is an age-related decline in skeletal muscle mass and function that is multifactorial in etiology. Age-related changes in the renin-angiotensin system (RAS), increased oxidative stress, and chronic inflammation likely all contribute to its development. Losartan, an angiotensin II type I receptor blocker (ARB) decreases RAS activity and likely influences oxidative stress and inflammation. Given this, we hypothesized that losartan would improve activity levels and parameters related to inflammation and oxidative stress in older mice. We sought to test this hypothesis by comparing functional and molecular parameters between 18-month-old C57BL/6 mice treated with 50-70 mg/kg/day of losartan over a 4 month-period and age- and gender-matched mice receiving placebo. Losartan treatment significantly improved several activity measurements during treatment period compared to placebo controlled group, including increased time on treadmill, traveling activity, standing activity, and decreased grid contacts (p-values < 0.05, 0.001, 0.01; and 0.04 respectively). Grip strength did not improve in treatment group relative to control group over time. Serum IL-6 level in the treated group was significantly lower than that in the control group at the end of treatment, (30.3±12.9 vs. 173.0±59.5 pg/ml, p< 0.04), and mRNA expression of antioxidant enzymes catalase (3.9±0.9 vs. 1.0±0.4) and glutathione peroxidase (4.7±1.1 vs. 1.0±0.4) was significantly higher, P-value: 0.02, and 0.03 respectively) in quadriceps muscle after 4 months of treatment in treated and control groups. These results support the hypothesis that chronic losartan treatment improves skeletal muscle related activity measures in older mice, and that it is associated with more favorable relevant biological profiles in the treatment group. Additional studies are needed to 1) further quantify this functional improvement, 2) further identify mechanisms that influence this improvement, and 3) provide additional rationale for translating these findings into older adults.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Losartan improves measures of activity, inflammation, and oxidative stress in older mice

Lin

Yang

Qin

et al. 2014

Experimental Gerontology

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“…A shift in MHC isoform distribution of this nature could contribute to reduced exercise tolerance given the differing oxidative potential of MHC I and II fibers and this has been demonstrated in patients (Vescovo et al, 1998). However, this pattern of isoform distribution is also emblematic of muscle disuse (Narici and De Boer, 2011) and heart failure patients expend about half as many calories in volitional activity as healthy controls (Toth et al, 1997), suggesting that this adaptation might be due to inactivity accompanying the disease, rather than the disease process itself.…”

Section: Heart Failurementioning

confidence: 98%

Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans

2014

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Skeletal muscle contractile function declines with aging, disease, and disuse. In vivo muscle contractile function depends on a variety of factors, but force, contractile velocity and power generating capacity ultimately derive from the summed contribution of single muscle fibers. The contractile performance of these fibers are, in turn, dependent upon the isoform and function of myofilament proteins they express, with myosin protein expression and its mechanical and kinetic characteristics playing a predominant role. Alterations in myofilament protein biology, therefore, may contribute to the development of functional limitations and disability in these conditions. Recent studies suggest that these conditions are associated with altered single fiber performance due to decreased expression of myofilament proteins and/or changes in myosin-actin cross-bridge interactions. Furthermore, cellular and myofilament-level adaptations are related to diminished whole muscle and whole body performance. Notably, the effect of these various conditions on myofilament and single fiber function tends to be larger in older women compared to older men, which may partially contribute to their higher rates of disability. To maintain functionality and provide the most appropriate and effective countermeasures to aging, disease, and disuse in both sexes, a more thorough understanding is needed of the contribution of myofilament adaptations to functional disability in older men and women and their contribution to tissue level function and mobility impairment.

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“…The concentrations of intra-mitochondrial citrate synthase, total cytosolic creatine kinase (CK), skeletal muscle-specific CK (MM-CK) and lactate dehydrogenase (LDH) decrease in HF patients [18]. Notably, angiotensin-converting enzyme inhibition, an established therapeutic intervention with impact on survival and exercise performance in HF, seems to prevent the fiber type switch from type I to II in the skeletal muscle [31-33]. …”

Section: Histologic Changes Of Skeletal Muscle In Hfmentioning

confidence: 99%

Metabolic and structural impairment of skeletal muscle in heart failure

Zizola

Schulze

2012

Heart Fail Rev

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Physiologic endurance exercise performance is primarily limited by cardiac function. In patients with heart failure, there is dissociation between cardiac performance and exercise capacity, suggesting a distinct role of abnormal peripheral organ function, including skeletal muscle function. The impact of heart failure upon skeletal muscle and exercise performance will be discussed with a focus on molecular, structural, and functional derangements in skeletal muscle of patients with heart failure. KeywordsSkeletal Muscle; Metabolism; Heart Failure Heart failure is defined as the inability of the heart to adequately perfuse peripheral tissues. The clinical syndrome of heart failure (HF) involves a complex interplay of skeletal muscle and peripheral vascular adaptations resulting from decreased myocardial performance. The classic symptoms of HF are exertional fatigue and dyspnea. It has traditionally been hypothesized that the major limitation to exercise performance results from a reduced cardiac output response to exercise, leading to skeletal muscle hypoperfusion and lactic acidosis [1]. However, secondary changes in other organ systems such as skeletal muscle, the vascular system, and the lungs play important roles in the genesis of fatigue and dyspnea [2].Though peak exercise capacity is clearly dependent on the cardiac output response to exercise, it is not the sole determinant of exercise performance in patients with HF since patients with similar reductions in left ventricular function have a wide range of exercise capacity. Furthermore, therapeutic interventions aimed at acutely increasing cardiac output such as inotropic drugs have limited impact on exercise capacity or peak VO 2 [3][4][5]. This discrepancy between enhanced cardiac output and fixed peak VO 2 can be explained on the basis of the peripheral vascular and skeletal muscle derangements in HF. Due to regional vascular or skeletal abnormalities the augmented cardiac output cannot be utilized by the exercising muscle beds and, therefore, peak VO 2 is not altered. Evidence for a peripheral abnormality in HF was first described in the 1970s by Zelis [6,7] .

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Improved Exercise Tolerance After Losartan and Enalapril in Heart Failure

Cited by 125 publications

References 46 publications

Losartan improves measures of activity, inflammation, and oxidative stress in older mice

Losartan improves measures of activity, inflammation, and oxidative stress in older mice

Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans

Metabolic and structural impairment of skeletal muscle in heart failure

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