Abstract
HIV-infection, certain antiretroviral drug classes, especially protease inhibitors (PI), and obesity are associated with increased ischaemic heart disease (IHD) risk. However, the effect of PI-free fixed dose combination (FDC) antiretroviral therapy (ART) on hearts exposed to ischaemia-reperfusion injury (I/R) is unknown, particularly in obesity. This is becoming relevant as World Health Organisation guidelines recommend a FDC ART containing (non-) nucleoside reverse transcriptase inhibitors (tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV)) as first-line HIV treatment. Additionally, obesity rates are rising in HIV-infected populations, not only in ART-experienced individuals, but also at the time of ART initiation, which may further increase the risk of IHD. Therefore, we investigated the effects of PI-free FDC ART in myocardial I/R-exposed hearts from obese rats. Obesity was induced in male wistar rats via a 16-week high calorie diet. At week 10, treatment with a FDC ART drug containing TDF/FTC/EFV was initiated. Biometric and metabolic parameters, as well as myocardial functional recovery and infract size (IS), and myocardial signalling proteins following I/R were assessed after 16 weeks. Obese rats presented with increased body and intraperitoneal fat mass, elevated triglyceride and TBARS levels, whilst the hearts responded to I/R with impaired functional performance and increased IS. The FDC ART treatment did not alter biometric and metabolic parameters in obese rats. In a novel finding, ART protected obese hearts against I/R as shown by improved functional performance and smaller IS vs. untreated obese hearts. Cardioprotection was underscored by increased myocardial phosphorylated endothelial nitric oxide synthase (eNOS) and reduced AMP-kinase levels. In conclusion, these results demonstrate for the first time, that 6-weeks treatment of obese rats with a FDC ART drug specifically containing TDF/FTC/EFV conferred cardioprotection against I/R. The FDC ART-induced cardioprotection was seemingly unrelated to metabolic changes, but rather due to direct cardiac mechanisms including the up-regulation of myocardial eNOS.
Highlights
People living with HIV/AIDS are at higher risk of developing ischaemic heart disease and experiencing a future cardiac event compared to the general population [1,2,3,4]
At the end of the 16-week feeding programme, the high calorie diet- (HCD) and HCD+antiretroviral therapy (ART) rats were ~9.9% and ~10% heavier compared to their respective lean controls; ART did not affect body mass measurements in either the control of HCD animals (Fig 2 and Table 1)
In the HCD-induced obese rats, treatment with the ART drug resulted in increased % liver mass compared to untreated obese rats; ART was associated with reduced serum TC and increased TG levels compared to control group (Control) +ART rats, and with reduced CD levels compared to untreated HCD rats (Table 1)
Summary
People living with HIV/AIDS are at higher risk of developing ischaemic heart disease and experiencing a future cardiac event compared to the general population [1,2,3,4]. Obesity, a recognised modifiable ischaemic heart disease risk factor, is increasingly observed in HIV-infected populations, as a consequence of ARTinduced reversal of HIV/AIDS associated weight loss [6,7,8,9], but interestingly in HIVinfected individuals at the time of diagnosis before the initiation of ART [10,11] These findings suggest that obesity rates in HIV-infected populations are either approaching or already mirroring those of the general population [7,8,12], which may pose an additional cardiac risk in such individuals. These knowledge gaps are becoming clinically relevant, both in terms of the rising obesity rates posing potential additional cardiovascular risk, and recent World Health Organisation (WHO) guidelines that strongly recommend the use of once daily first-line FDC drugs consisting of two NRTI’s: Tenofovir (TDF) plus Lamivudine or Emtricitabine (FTC), and one NNRTI: Efavirenz (EFV) [16]
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