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Silent cardiac dysfunction and exercise intolerance in HIV+ men receiving combined antiretroviral therapies
  [Research Letters]
AIDS:Volume 22(18)30 November 2008p 2537-2540
Thoni, Gilles Ja,b; Schuster, Irisb,c; Walther, Guillaumea; Nottin, Stephanea; Vinet, Agnesa; Boccara, Franckd; Mauboussin, Jean-Marce; Rouanet, Isabellee; Ederhy, Stephaned; Dauzat, Michelc; Messner-Pellenc, Patickb,c; Obert, Philippea aEA 4278, Faculty of Sciences, Avignon, France
bCardiology Department, University Hospital, France
cEA 2992, Montpellier-Nimes Faculty of Medicine, Nimes, France
dCardiology Department, Saint-Antoine University and Medical School, Assistance
Publique - Hopitaux de Paris and Pierre & Marie Curie University, Paris, France
eInfectious diseases department, University Hospital, Nimes, France.
Resting and exercise cardiac function, skeletal muscle oxygenation and whole-body aerobic exercise capacities were evaluated prospectively in cardiac symptom-free HIV+ men receiving antiretroviral therapies and in healthy controls matched for age, physical activity, smoking and body surface area. HIV+ patients showed resting cardiac dysfunction, altered cardiac responses to exercise and depressed exercise tolerance. Exercise stroke volume kinetics and muscle oxygenation were impaired in HIV+ patients, especially in those with resting diastolic dysfunction.
Aerobic exercise intolerance in HIV+ patients receiving highly-active antiretroviral therapy (HAART) has been attributed to chronic-disease-related deconditioning, anemia, smoking, or nucleoside reverse transcriptase inhibitor (NRTI)-related peripheral oxidative dysfunction [1,2]. We recently reported silent resting cardiac abnormalities in HAART-experienced men [3] and investigated here the involvement of cardiac dysfunction in their exercise limitations.
White, nonobese (BMI < 30 kg/m2) men, aged 30-50 years, without cardiovascular history or symptoms, were recruited. Sixteen HIV+ patients in a steady clinical and immunovirological state, infected for 11 ± 4 years; receiving HAART for at least 2 years (8 ± 3 years in mean; viral load 2.2 ± 0.9 log10copies/ml, undetectable in 2/3 of patients; CD4 cell count 503 ± 175/μl, without value <200/μl), and without recent infectious event or weight loss, were compared with 21 healthy uninfected controls, matched for age (43 ± 4 vs. 41 ± 6 years), body surface area (1.9 ± 0.1 m2 for both), smoking habits (former/current smokers, actual packs/day, cumulated smoking: 18.6 ± 9.5 vs. 14.8 ± 9.8 packs years), and physical activity (current type/amount of training, Baecke questionnaire index 8.6 ± 1.5 vs. 9.1 ± .1.2). At inclusion, all patients were receiving at least one NRTI (cumulative duration: 172 ± 44 months, mean ± SD); two patients had only NRTIs. HAART included thymidine analogues in 56% (for 62 ± 30 months), nucleotide analogues in 37% (for 18 ± 8 months), protease inhibitors in 37% (for 48 ± 35 months), and NNRTI in 31% (for 31 ± 23 months).
Resting echocardiography was performed as previously described [3]. Patients presented resting echocardiographic abnormalities (Fig. 1a), with a greater prevalence of left ventricular diastolic dysfunction (i.e. relaxation/filling abnormalities, 56 vs. 14% in controls, P ≦ 0.01), consistent with previous data obtained in larger cohorts [4]. Patients had impaired left ventricular longitudinal contraction as evidenced by reduced peak systolic velocity on tissue Doppler imaging (TDI) (Fig. 1a), whereas their left ventricular ejection fraction was preserved (all values >50%). Similar findings have been reported by others in patients infected for a shorter duration [5]. Our patients had higher (but normal) resting pulmonary artery systolic pressure than controls (Fig. 1a).
All patients performed a maximal exercise test [3], without clinical or electrical evidence of myocardial ischemia. As frequently described [1-3], our patients had reduced exercise tolerance (Fig. 1b) although both groups were matched on physical activity and smoking habits and had similar hemoglobin (14.1 ± 1.4 vs. 14.5 ± 0.7 mmol/l) and hematocrit (41.9 ± 3.7 vs. 42.7 ± 2.2%). Throughout exercise, stroke volume (SV) and cardiac output (CO) were estimated from the ascending aortic blood flow, reached from the suprasternal notch with a 2.0-MHz continuous wave Doppler transducer [6]. CO increased linearly with exercise intensity in controls, whereas it tended to level off near exhaustion in patients (Fig. 1c) who had maximal values 14% lower (P ≦ 0.05, Fig. 1b). Heart rate (HR) rose similarly throughout exercise in both groups (Fig. 1c), with peak values lower in patients (-6%, Fig. 1b), as frequently reported [2]. Nevertheless, maximal HR reached at least 90% of age-predicted values in all patients that did not support the 'autonomic dysfunction' hypothesis. As patients had a thigh circumference (a surrogate of lower-limb muscle mass) 8% lower than controls (P ≦ 0.05), a premature peripheral fatigue might explain the between-group difference observed in maximal HR. As usually described in healthy adults [6], SV increased from rest to moderate intensity in both groups, then plateaued up to exhaustion in controls. In contrast, it gradually declined from moderate intensity to exhaustion in patients (Fig. 1c). Interestingly, this specific SV pattern was observed only in HIV+ patients with resting left ventricular diastolic dysfunction (Fig. 1d), suggesting a key contribution of exercise relaxation/filling abnormalities. Impaired myocardial contractility and pulmonary hypertension during exercise might be two other potential shareholders in patients' exercise intolerance as the TDI index of longitudinal systolic function and pulmonary artery pressure were significantly altered in our patients at rest. Systemic vascular resistance declined regularly during exercise in both patients and controls with similar submaximal and peak exercise values (not shown). Therefore, differences in cardiac after-load conditions could not explain the SV drop observed in patients.
Transcutaneous thigh oxygenation, an index of oxygen delivery/utilization imbalance measured by near-infrared spectroscopy (Niro-300TM, Hamamatsu Photonics, Japan), decreased during exercise in both groups with values significantly lower in patients from rest to exhaustion (Fig. 1b, c), although patients and controls had similar hemoglobin and hematocrit values. In fact, muscle oxygenation was significantly depressed at rest and at exhaustion only in patients with resting diastolic dysfunction (Fig. 1d), suggesting that central cardiac dysfunction might have compromised peripheral oxygen delivery. As arteriovenous oxygen difference during exercise was similar in our patients and controls (not shown), global skeletal muscle oxidative dysfunction was unlikely. Nonetheless, in the absence of exercise-induced myocardial ischemia, NRTI (especially thymidine analogues)-related mitochondrial toxicity on cardiomyocytes [7,8] and HAART adverse effects on myocardial metabolism [9] should be investigated.
Our limited sample was quite heterogeneous regarding HIV/HAART history, hepatitis B virus/hepatitis C virus coinfection (50% of our patients), and previous intravenous drug abuse (37%). Cardiac abnormalities might result from complex interactions between HIV-infection itself, HAART medications and other HIV-unrelated cofactors such as coinfection or behavioral factors (smoking, alcohol/drug abuse, substitutive therapies, sedentary lifestyle, etc.). Studies on larger cohorts of strictly selected patients will be needed to assess the multifactorial pathogenesis of cardiac dysfunction in HAART-experienced patients. Diastolic dysfunction and altered aerobic capacities, expected to worsen with aging, are independent cardiovascular risk factors in seronegative individuals [10-12]. The prognostic values of subclinical cardiac abnormalities, (i.e. the risk for developing symptomatic disease) remains to be established in the specific HIV+ HAART-experienced population.
In conclusion, our patients had resting cardiac (mainly diastolic) dysfunction, impaired cardiac responses to exercise, reduced peripheral muscle oxygenation and exercise intolerance. This contrasts with previous studies, which attributed aerobic limitations in HIV+ patients receiving HAART exclusively to peripheral muscle dysfunction [2]. Cardiovascular risk assessment and regular cardiac screening (including echocardiography, ECG, and exercise testing) should be considered in multitreated HIV+ patients for early detection, prevention and follow-up. Pharmacologic treatments in preclinical diastolic dysfunction are being debated in the general population [13], preventive strategies in HIV+ patients might include treatments of coexisting risk factors (diabetes, hypertension, dyslipidemia, and atherosclerosis) and lifestyle interventions [14,15]. Safe and effective management strategies counteracting cardiac dysfunction in HAART-experienced HIV+ patients should be evaluated and implemented.
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