High-intensity interval training attenuates endothelial dysfunction in a Dahl salt-sensitive rat model of heart failure with preserved ejection fraction

Abstract

Heart failure patients with preserved left ventricular ejection fraction (HFpEF) have endothelial dysfunction, but the underlying molecular mechanisms remain unknown. In addition, whether exercise training improves endothelial function in HFpEF is still controversial. The present study therefore aimed to determine the functional and molecular alterations in the endothelium associated with HFpEF, while further assessing the effects of high-intensity interval training (HIT). Female Dahl salt-sensitive rats were randomized for 28 wk into the following groups: 1) control: fed 0.3% NaCl; 2) HFpEF: fed 8% NaCl; and 3) HFpEF + HIT: animals fed 8% NaCl and HIT treadmill exercise. Echocardiography and invasive hemodynamic measurements were used to assess diastolic dysfunction. Endothelial function of the aorta was measured in vitro. Expression of endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase [NAD(P)H oxidase], and advanced glycation end product (AGE)-modified proteins were quantified by Western blot, and zymography quantified matrix metalloproteinase (MMP) activity. In this model of HFpEF, endothelium-dependent and -independent vasodilation was impaired. However, this was prevented by HIT. In HFpEF protein expression of eNOS was reduced by 47%, but MMP-2 and MMP-9 activity was elevated by 186 and 68%. The expression of AGE-modified proteins was increased by 106%. All of these changes were prevented by HIT. Endothelial function was impaired in this model of HFpEF, which was associated with reduced expression of eNOS, increased MMP activity, and increased AGE-modified proteins. HIT was able to attenuate both these functional and molecular alterations. These findings therefore suggest HFpEF induces endothelial dysfunction, but this is reversible by HIT.

Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity‐Driven Heart Failure With a Preserved Ejection Fraction

“…Alternatively, the primary mechanism that may have underpinned the increase in exercise capacity in HFpEF following the HIIT or MCT regimens may be directly related to improvements in endothelial function. It is well established that HFpEF can induce endothelial dysfunction, with available evidence showing that this can be reversed by exercise training . While inclusion of endothelial measurements was beyond the scope of the present study, where the main interest was to investigate the diaphragm, the potential for exercise training to improve peripheral endothelial function remains likely.…”

Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction

“…For the past decade, the Dahl salt-sensitive rat has been validated as a reasonable model of HFpEF by different groups. 21–23, 44, 45 The animals develop diastolic dysfunction after 6–7 weeks of high-salt diet along with abnormal relaxation and elevated left ventricular end-diastolic pressure. 21–23 Concurrently, rats develop HF symptoms including decreased activity, cachexia, labored breathing, and body edema starting from 14 weeks old.…”

Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

“…This coronary microvascular endothelial inflammation is seen in animal models of HFpEF and in human cardiac biopsies [38, 39]. Reduced endothelium-dependent vasodilation is seen in animal models as well [40]. …”

“…In HFpEF rats, exercise training restored endothelial-dependent vasodilation measured ex vivo in organ baths [40]. Endothelial function correlated well with eNOS expression, which was reduced in HFpEF rats and recovered after exercise training.…”