Abstract
Acute heart failure (AHF) is the most common primary diagnosis for hospitalized heart diseases in Africa. As increased fatty acid β-oxidation (FAO) during heart failure triggers detrimental effects on the myocardium, we hypothesized that trimetazidine (TMZ) (partial FAO inhibitor) offers cardioprotection under normal and obese-related diabetic conditions. Hearts were isolated from 12-14-week-old obese male and female diabetic (db/db) mice versus lean non-diabetic littermates (db/+) controls. The Langendorff retrograde isolated heart perfusion system was employed to establish an ex vivo AHF model: a) Stabilization phase—Krebs Henseleit buffer (10 mM glucose) at 100 mmHg (25 min); b) Critical Acute Heart Failure (CAHF) phase–(1.2 mM palmitic acid, 2.5 mM glucose) at 20 mmHg (25 min); and c) Recovery Acute Heart Failure phase (RAHF)–(1.2 mM palmitic acid, 10 mM glucose) at 100 mmHg (25 min). Treated groups received 5 μM TMZ in the perfusate during either the CAHF or RAHF stage for the full duration of each respective phase. Both lean and obese males benefited from TMZ treatment administered during the RAHF phase. Sex differences were observed only in lean groups where the phases of the estrous cycle influenced therapy; only the lean follicular female group responded to TMZ treatment during the CAHF phase. Lean luteal females rather displayed an inherent cardioprotection (without treatments) that was lost with obesity. However, TMZ treatment initiated during RAHF was beneficial for obese luteal females. TMZ treatment triggered significant recovery for male and obese female hearts when administered during RAHF. There were no differences between lean and obese male hearts, while lean females displayed a functional recovery advantage over lean males. Thus TMZ emerges as a worthy therapeutic target to consider for AHF treatment in normal and obese-diabetic individuals (for both sexes), but only when administered during the recovery phase and not during the very acute stages.
Highlights
Cardiovascular diseases (CVD) remain the leading cause of global mortality accounting for ~30% of all deaths worldwide [1, 2]
For the TMZ treatment regimens initiated during the critical acute heart failure (CAHF) phase, we found that females exhibited a much higher rate pressure product (RPP) (p
Our results showed that lean and obese males recovered in a similar manner at both treatment time points, i.e. TMZ treatment during the CAHF and recovery acute heart failure (RAHF) phases, respectively (Fig 3A and 3B)
Summary
Cardiovascular diseases (CVD) remain the leading cause of global mortality accounting for ~30% of all deaths worldwide [1, 2]. Future projections indicate that both developed and developing nations face a growing CVD burden, e.g. heart failure prevalence is expected to increase by 25% by 2030 [1]. TMZ treatment for acute heart failure poor lifestyle choices and inadequate control of CVD risk factors—will further fuel this growing burden of disease [2]. Acute heart failure (AHF) is a complex clinical syndrome that varies extensively in terms of underlying pathophysiologic mechanisms and clinical presentations [3]. Acute heart failure syndromes (AHFS) are most commonly diagnosed in US Medicare patients, resulting in hospitalization and significant expenses [5, 6]. Acute decompensated heart failure (ADHF) is the most common primary diagnosis in patients with heart disease admitted to hospitals in Africa [7, 8]. Registries of higher income countries reveal that women with AHFS are generally older than men [13,14], sub-Saharan Africa women are on average younger and more prone to de novo AHF compared to men [11]
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