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Left ventricular hypertrophy detected by echocardiography in HIV-infected patients
European Journal of Internal Medicine 24 (2013) 558–561
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Left ventricular hypertrophy detected by echocardiography in HIV-infected patients Marta Pombo a, Julián Olalla b,⁎, Alfonso Del Arco b, Javier De La Torre b, Daniel Urdiales b, Ana Aguilar b, José Luis Prada b, Javier García-Alegría b, Francisco Ruiz-Mateas a a b
Área de Cardiología, Agencia Hospitalaria Costa del Sol, Marbella, Spain Área de Medicina Interna, Agencia Hospitalaria Costa del Sol, Marbella, Spain
a r t i c l e
i n f o
Article history: Received 13 November 2012 Received in revised form 22 March 2013 Accepted 14 April 2013 Available online 7 May 2013 Keywords: HIV Echocardiography Hypertrophy Left ventricular
a b s t r a c t Background: Left ventricular hypertrophy (LVH) is a predictor of overall mortality in the general population. The most sensitive diagnostic method is transthoracic echocardiography (TTE). In this study, we describe the prevalence of LVH, and the factors associated with it, in a group of patients with HIV infection. Methods: TTE was offered to all patients attending the outpatient clinic of the Hospital Costa del Sol (Marbella, Spain) between 1 December 2009 and 28 February 2011. The corresponding demographic and clinical data were obtained. The left ventricular mass (LVM) was calculated and indexed by height2.7. LVH was defined as LVM >48 g/m2.7 in men or >44 g/m2.7 in women. Results: We examined 388 individuals (75.5% male, mean age 45.38 years). Of these, 76.1% were receiving HAART; 11.9% had hypertension, 6.2% had diabetes mellitus, 23.2% had dyslipidaemia and 53.6% were tobacco users. The risk of cardiovascular disease at 10 years (RV10) was 12.15% (95%CI: 10.99–13.31%). 19.1% of these patients had a high RV10. A total of 69 patients (19.8%) presented high LVM. Age, hypertension, dyslipidaemia, RV10 and the use of nevirapine were associated with a greater presence of LVH in the univariate analysis. In the logistic regression analysis performed, the factors retained in the model were the presence of high RV10 (OR: 2.92, 95%CI: 1.39–6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18–4.14). Conclusions: In this group of patients, the use of nevirapine and the presence of high RV10 were associated with LVH. The use of nevirapine might be related to its prescription for patients with higher RV10. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Following the introduction of highly active antiretroviral therapy (HAART) against human immunodeficiency virus (HIV), AIDSassociated morbidity and mortality have declined continuously [1]. However, cardiovascular morbidity and mortality have presented less improvement during this period, compared with the results achieved for AIDS and liver diseases [2]. It has been reported that both HIV infection and HAART may be involved in the occurrence of events such as acute myocardial infarction [3–5], the progression of carotid atherosclerotic disease [6,7] or heart disease [8,9], and that they also influence other parameters of subclinical involvement such as the ankle-brachial index [10]. This has led to the development of various observational, cross-sectional studies focusing on the safety and security of the different components of HAART. One phenomenon implicated in the pathogenesis of heart disease and the occurrence of cardiovascular events is that of left ventricular hypertrophy (LVH). Increased left ventricular mass (LVM) is a prognostic factor for overall and cardiovascular mortality [11,12], and is the most sensitive method available to diagnose transthoracic echocardiography ⁎ Corresponding author at: Unidad de Medicina Interna, Agencia Hospitalaria Costa del Sol, Carretera Nacional 340, km 187, 29603 Marbella, Spain. Tel.: +34 951976669. E-mail address: [email protected] (J. Olalla).
(TTE). In particular, the presence of LVH, confirmed by TTE, is associated with a relative risk of death from any cause of 1.5–2 compared to patients with normal LVM, and the corresponding value for vascular events is around 2. Increased LVM has been related with gender (higher in women) [13], obesity [14], age [11], hypertension [15] and diabetes mellitus [16], among others. In recent years, some studies have shown that the prevalence of LVH is higher among HIV-infected patients [17,18], regardless of the associated factors in the non-infected population. Also implicated as factors associated with LVH in patients with HIV infection are the use of inhibitors of nucleoside reverse transcriptase [19] and that of protease inhibitors [20]. In this study we investigate the prevalence of LVH diagnosed by TTE in a cohort of patients with chronic HIV infection and presenting the risk factors associated with its occurrence. 2. Material and methods 2.1. Study design Descriptive, cross-sectional study performed in patients who regularly attended the HIV clinic at the Costa del Sol Hospital in Marbella (Spain) between 1 December 2009 and 28 February 2011. TTE was offered in all cases. When consent was given, data were obtained
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M. Pombo et al. / European Journal of Internal Medicine 24 (2013) 558–561
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regarding epidemiological and clinical parameters, as well as for traditional cardiovascular risk factors and variables associated with their HIV infection status. Patients were classed as hypertensive when this was stated in their clinical background, or when their systolic blood pressure exceeded 140 mm Hg or when their diastolic blood pressure was greater than 90 mm Hg, measured on two separate occasions at least three months apart, or when they were receiving antihypertensive treatment. Patients were considered diabetic when this was stated in their clinical background, when they had fasting plasma glucose levels above 126 mg/dl measured on two separate occasions at least three months apart, or when they were receiving treatment with antidiabetic oral agents or insulin. Patients were considered dyslipidaemic when this was stated in their clinical background, when they had LDL cholesterol levels above 160 mg/dl or triglycerides equal to or greater than 150 mg/dl, or when they were receiving treatment with hypolipidaemic drugs. Patients were considered HBV co-infected if they had antibodies to HBV core antigen (AntiHbcAc), and HCV co-infected if they presented positive ELISA for HCV. We calculated the duration of HIV infection assuming its onset to be the first serology (Western blot analysis) positively reflected in the patient's medical history. Ten years cardiovascular risk was estimated by the Framingham equation, which is shown in the European AIDS Clinical Society web site, available in: http://www.cphiv. dk/TOOLS/Framingham/tabid/302/Default.aspx. Risk was classified as follows: b 10% low risk, 10–20% intermediate risk and >20% high risk. Medical histories in our hospital are computerized, so every patient's report was reviewed considering medication prescribed in each visit. For this purpose, a team of antiretroviral therapy experienced doctors was designed, with extensive knowledge of available drug combinations. TTE was performed by a single expert echocardiographer, using a Siemens Acuson Sequoia C256 with 3.5 MHz transducer. Measurements were performed on the parasternal long axis, using the 2D-guided M mode, and recording the following parameters: LV diastolic and systolic diameter (LVDD and LVSD, respectively), interventricular septal thickness (IVS) and posterior wall (PW) thickness, ejection fraction and left atrial volume, following the guidelines of the American Society of Echocardiography (ASE) [21]. LVM was measured by the following formula: LVM (ASE) = 0.8 × {1.04 [(LVDD + IVS + PW) 3 − (LVDD)3]} + 0.6 g, adjusting for height2.7 to avoid underestimating the prevalence of LVH in obese or overweight patients. The normal range bounds specified by the ASE were used to establish the presence or otherwise of LVH in men and women (>48 g/m 2.7 and >44 g/m 2.7 respectively).
was via heterosexual transmission (38.4%). The average duration of HIV infection was 9.13 years (95%CI: 8.5–9.8). Only 13.9% of patients were naive to antiretroviral therapy (ART); of those who received ART, the average exposure was 6.20 years (95%CI: 5.7–6.7). 25.3% presented AIDS-associated parameters. The mean count of CD4 lymphocytes was 650/μl (95%CI: 616–685), with a mean nadir of 286 cells/μl (95%CI: 263–309). Viral load values were obtained for 98.2% of the participants, and remained below 50 copies/mL in 65.5% of the patients. 32.2% of the patients were co-infected with HCV. The average body mass index (BMI) was 24.9 kg/m2 (95%CI: 24.4–27.3). Regarding the classical cardiovascular risk factors, 11.9% of the patients were hypertensive, 6.2% had diabetes mellitus, 23.2% dyslipidaemia and 53.6% consumed tobacco. The 10-year risk of cardiovascular disease (RV10) was 12.15% (95%CI: 11–13.3). 19.1% of the patients had a high RV10. Nineteen patients were under antithrombotic therapy (4.8%), 23 (5.8%) received betablocker, 16 (4%) ACE inhibitors, 12 (3%) Angiotensin II receptor blocker, 5 (1.3%) dihydropyridines, 2 (0.5%) doxazosin, 8 (2%) diuretics, 45 (11.3%) statins, 20 (5%) fibrates, 1 (0.3%) ezetimibe, 4 (1%) fatty acids, 16 (4.1%) oral antidiabetic and 4 (1%) insulin.
2.2. Statistical analysis
3.3. Factors associated with LVH
Data were compiled directly into SPSS 15.0 (Statistical Package for Social Sciences, Inc. Chicago, Illinois, USA). The quantitative variables were described using the mean, with a 95% confidence interval (95%CI), and the qualitative variables are given as percentages. The quantitative variables were compared using Student's t test, after verifying the normality of the samples; when this condition was not met, the Mann–Whitney test was used. The qualitative variables were compared using the χ2 test. In the initial analysis, the dependent variable was taken as the presence of LVH, according to the criteria stipulated above. The variables that presented a statistical association with LVH (p b 0.05) were included in the logistic regression analysis, using a forward stepwise method. The odds ratio (OR) was calculated at 95%CI and statistical significance was set at p b 0.05. At the decision of the investigator, the antiretrovirals (ARVs) that were not given to at least five patients in each group (normal and elevated LVM) were omitted from the logistic regression analysis.
The patients with high LVH presented a higher average age (49 vs. 44.6 years, p = 0.001). There were no significant differences in immunovirological status. The proportion of patients with HCV co-infection was lower among the patients with high LVH (22.4% vs. 34.3%) without reaching statistical significance (p = 0.058). The latter also had a higher BMI (27.4 vs. 24.4 kg/m 2). LVH was more frequent among hypertensive patients (19.1 vs. 10.4%, p = 0.04) and those with dyslipidaemia (34.8% vs. 20.7%, p = 0.012). RV10 was greater among patients with LVH (16.7% vs. 11.1%, p = 0.001), and moreover there was a higher proportion of patients with high RV among those with LVH (32.4% vs. 16.2%, p = 0.001). With respect to the use of ARVs, a history of nevirapine use was more frequent among patients with LVH (17.6% vs. 33.3%, p = 0. 003), as was also the case with maraviroc, although in this case, there were only six patients. We also observed an association between the current use of maraviroc and a lower cumulative exposure to enfuvirtide. We performed a logistic regression analysis (Table 2), which included the duration of ART (assessed by the researcher), hypertension, dyslipidaemia, RV10 (categorised as low, medium or high) and the use of nevirapine in the patient's clinical history. The factors retained in the model were the presence of high RV10 (OR 2.92,
3. Results TTE was performed on a total of 388 patients (Table 1) of whom the majority were male (75.5%). The average age of the study participants was 45.38 years (95%CI: 44.4-46.3). The main route of virus acquisition
3.1. Prevalence of high LVM A total of 69 patients (19.8%) presented LVH. The average LVM value was 39.6 g/m 2.7 (95%CI 38.3–40.7). 3.2. Use of ART The antiretroviral (ARV) most frequently used, according to the patients' clinical histories, was tenofovir (61.1%). Among nonnucleoside reverse transcriptase inhibitors (NNRTI), efavirenz was the most used (55.2%), and among protease inhibitors (PI) lopinavir–ritonavir was the most widely used (18.6%). With respect to the accumulated use of ARV, lamivudine had been used for longest (62.2 months, 95%CI: 56.4–68.07). Among nucleoside reverse transcriptase inhibitors, zidovudine had the longest accumulated use (50.3 months, CI95%: 44.2–56.5); nevirapine had the longest accumulated use among NNRTI (51 months, CI95%: 41.4-60.8) and fosamprenavir–ritonavir among PI (28 months, CI95%: 19.2–36.9). At the time of data compilation, again tenofovir was the most commonly used (54.1%), followed by efavirenz (52.3%).
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M. Pombo et al. / European Journal of Internal Medicine 24 (2013) 558–561
Table 1 Characteristics of the patients. All patients N = 388 Male gender Age (years) Transmission route Heterosexual Homosexual Injection drug user AIDS Duration of infection (years) Viral load b50 copies/mL CD4 cell counts (cells/μL) Nadir CD4 cell counts (cells/μL) Use of ART Duration use of ART (years) HCV Hypertension Dyslipidaemia Diabetes mellitus Smokers Body mass index (kg/m2) RV10 (%) RV10 Low Moderate High Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) Glomerular filtration MDRD-4 (mL/minute)
With LVH N = 69
No LVH N = 319
297 (75.5) 45.4 (44.4–46.3)
52 (75.4) 49 (46.6–51.4)
245 (76.8) 44.6 (43.6–45.6)
149 (38.4) 121 (31.2) 102 (26.3) 98 (25.2) 9.1 (8.5–9.8) 254 (65.5) 650 (616–685) 286 (263–309) 334 (86.1) 6.2 (5.7–6.7) 122 (32.2) 46 (11.9) 90 (23.2) 24 (6.2) 208 (53.6) 24.9 (24.4–27.3) 12.2 (11–13.3)
30 (43.5) 24 (34.8) 12 (17.4) 21 (30.4) 9.8 (8.1–11.5) 45 (70.3) 711 (627–795) 301 (232–371) 60 (87) 7.3 (5.9–8.8) 15 (22.4) 13 (19.1) 34 (34.8) 3 (4.3) 32 (46.4) 27.4 (26.1–28.7) 16.7 (13.3–20)
119 (37.3) 97 (30.4) 90 (28.2) 77 (24.1) 9 (8.2–9.7) 209 (65.9) 637 (599–675) 283 (259–307) 274 (85.9) 6 (5.4–6.5) 107 (34.3) 33 (10.4) 66 (20.7) 21 (6.6) 176 (55.2) 24.4 (23.9–24.8) 11.1 (10–12.3)
198 (53.4) 102 (27.5) 71 (19.1) 191.8 (187.5–196.3) 46.9 (45.5–48.4) 114.9 (111.3–118.4) 165.6 (153.7–177.4) 106.7 (104.1–109.4)
24 22 22 199.1 45.4 120.3 181.2 111.1
(35.3) (32.4) (32.4) (187.4–210.7) (41.8–49.01) (110.8–129.8) (150.2–212.3) (102.7–117.6)
174 (57.4) 80 (26.4) 49 (16.2) 190.3 (185.5–195.1) 47.3 (45.7–48.9) 113.6 (109.8–117.4) 162.1 (149.3– 174.9) 106 (103.2–108.9)
p 0.8 0.001 0.5
0.27 0.43 0.49 0.17 0.72 0.82 0.1 0.058 0.04 0.01 0.48 0.18 b0.0005 0.001 0.001
0.13 0.35 0.15 0.22 0.27
Categoric variables are stated as integers (%); continuous variables are stated as the mean (95%CI).
95%CI: 1.39–6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18– 4.14). 4. Discussion Our study revealed a LVH prevalence of 19.8%, in contrast to the 4–6% reported by studies that calculated LVM after indexing it by body surface area [18,19]. However, studies of LVM indexed by height2.7 show a LVH prevalence similar to that in our series [22,23], but indexing LVM by body surface area rather than by height2.7 produces an underestimate [24]. Other studies [25] found no patients with LVH, but excluded patients with diabetes, hypertension or dyslipidaemia, as well as those presenting an abnormal electrocardiogram. In our series, these exclusion criteria were not adopted; rather, we aimed to establish the prevalence among all patients who attended the clinic regularly. We corroborate the findings of other studies that LVH is associated with the presence of diabetes mellitus and hypertension [18,19]. These same risk factors were confirmed in patients with and without HIV infection. In patients with HIV infection, there is an increased risk of coronary events, while vascular events are a major cause of mortality after AIDS events [2,3]. A recent retrospective study [26] claimed that sudden deaths were responsible for 13% of total mortalities in a cohort of patients infected with HIV, 4.5 times more than expected. It is true that these patients more frequently had a history of ischaemic heart disease or heart failure, but among the deceased who had had an ECG, about 33%
Table 2 Logistic regression analysis. Parameter
OR
95%CI
P
Use of nevirapine RV10 Low Moderate High
2.20
1.18–4.14
0.013
Reference 1.94 2.92
0.96–3.91 1.39–6.15
0.062 b0.0005
(accounting for 25% of the sudden deaths) presented signs of LVH. Some of these heart-related sudden deaths may have been provoked by an increase in LVM. The latter is involved not only in elevated overall mortality, but also specifically in the increased incidence of sudden death and ventricular arrhythmias [27]. One factor that is specific to HIV infection is ART. Previous studies have indicated that the use of protease inhibitors [20] or nucleoside analogues [19,23] may be associated with a LVH. Others have found such a relationship, not with any specific component of the ART, but with receiving ART compared with non-infected patients [18]. It has been argued that this increase would be mediated either through greater dyslipidaemia or through direct mitochondrial damage, in the case of nucleoside analogues [28]. In our study, no such association was found. However, the use of nevirapine was associated with LVH. Although in the logistic regression analysis the use of this drug was retained in the model, together with moderate and high RV10, there may be an indication bias regarding this drug. It has long been known that nevirapine has a good metabolic profile. Its long-term use has been associated with a protective effect against the development of diabetes, according to the D:A:D study [29], and with a very evident elevation of HDL cholesterol [30]. This could have encouraged the medical staff in our study to recommend this ART to patients with high RV. We found no association between the protease inhibitors most commonly used today (atazanavir, darunavir) with the presence of LVH. Other protease inhibitors, tested previously, and for which such an association was found, are not currently used, as they require an uncomfortably high dosage and produce stronger metabolic effects. The fact that diseases normally more prevalent among older patients, such as coronary heart disease, osteoporosis or kidney failure, affect younger patients with HIV infection [31] should also alert us to the increase in other markers of cardiovascular disease such as LVH, especially when increasing numbers of prevalent and incident cases of HIV infection occur among older patients [32,33]. The presence of a chronic inflammatory state, characteristic of HIV infection, which is not completely reversed even with highly effective ART [34], can contribute to a greater presence of LVH, as has been observed in other chronic
M. Pombo et al. / European Journal of Internal Medicine 24 (2013) 558–561
inflammatory processes [35]. The greater the similarity between patients with HIV infection and the non-infected population, the greater the tendency for cardiovascular mortality to be the leading cause of death, as occurs among non-infected persons [36]. It is not insignificant that different series have reflected a prevalence of LVH between 15% and 19%. The association of a high RV10 to the presence of LVI endorse it as a good tool in the evaluation of our patients. It seems reasonable to perform a TTE in those patients with a high RV10 in order to detect LVH. Learning points • Left ventricular mass is an independent risk factor for death. • Prevalence of left ventricular hypertrophy (LVH) is high among people with HIV infection. • Vascular risk is in relationship with LVH. Conflict of interests All the authors declare having no conflict of interest. References [1] Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853–60. [2] Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law M, et al. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS 2010;24:1537–48. [3] Islam F, Wu J, Jansson J, Wilson D. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med 2012;13:453–68. [4] Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007;356:1723–35. [5] El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355: 2283–96. [6] van Vonderen MG, Smulders YM, Stehouwer CD, Danner SA, Gundy CM, Vos F, et al. Carotid intima-media thickness and arterial stiffness in HIV-infected patients: the role of HIV, antiretroviral therapy, and lipodystrophy. J Acquir Immune Defic Syndr 2009;50:153–61. [7] Hsue PY, Ordovas K, Lee T, Reddy G, Gotway M, Schnell A, et al. Carotid intima-media thickness among human immunodeficiency virus-infected patients without coronary calcium. Am J Cardiol 2012;109:742–7. [8] Butt AA, Chang CC, Kuller L, Goetz MB, Leaf D, Rimland D, et al. Risk of heart failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart disease. Arch Intern Med 2011;171:737–43. [9] Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011;25:1289–98. [10] Olalla J, Salas D, Del Arco A, De la Torre J, Prada J, Machin-Hamalainen S, et al. Ankle-branch index and HIV: the role of antiretrovirals. HIV Med 2009;10:1–5. [11] Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561–6. [12] Kardys I, Deckers JW, Stricker BH, Vletter WB, Hofman A, Witteman JC. Echocardiographic parameters and all-cause mortality: the Rotterdam Study. Int J Cardiol 2009;133:198–204. [13] Savage DD, Garrison RJ, Kannel WB, Levy D, Anderson SJ, Stokes III J, et al. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987;75:I26–33. [14] de Simone G, Palmieri V, Bella JN, Celentano A, Hong Y, Oberman A, et al. Association of left ventricular hypertrophy with metabolic risk factors: the HyperGEN study. J Hypertens 2002;20:323–31.
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Left ventricular hypertrophy detected by echocardiography in HIV-infected patients Marta Pombo a, Julián Olalla b,⁎, Alfonso Del Arco b, Javier De La Torre b, Daniel Urdiales b, Ana Aguilar b, José Luis Prada b, Javier García-Alegría b, Francisco Ruiz-Mateas a a b
Área de Cardiología, Agencia Hospitalaria Costa del Sol, Marbella, Spain Área de Medicina Interna, Agencia Hospitalaria Costa del Sol, Marbella, Spain
a r t i c l e
i n f o
Article history: Received 13 November 2012 Received in revised form 22 March 2013 Accepted 14 April 2013 Available online 7 May 2013 Keywords: HIV Echocardiography Hypertrophy Left ventricular
a b s t r a c t Background: Left ventricular hypertrophy (LVH) is a predictor of overall mortality in the general population. The most sensitive diagnostic method is transthoracic echocardiography (TTE). In this study, we describe the prevalence of LVH, and the factors associated with it, in a group of patients with HIV infection. Methods: TTE was offered to all patients attending the outpatient clinic of the Hospital Costa del Sol (Marbella, Spain) between 1 December 2009 and 28 February 2011. The corresponding demographic and clinical data were obtained. The left ventricular mass (LVM) was calculated and indexed by height2.7. LVH was defined as LVM >48 g/m2.7 in men or >44 g/m2.7 in women. Results: We examined 388 individuals (75.5% male, mean age 45.38 years). Of these, 76.1% were receiving HAART; 11.9% had hypertension, 6.2% had diabetes mellitus, 23.2% had dyslipidaemia and 53.6% were tobacco users. The risk of cardiovascular disease at 10 years (RV10) was 12.15% (95%CI: 10.99–13.31%). 19.1% of these patients had a high RV10. A total of 69 patients (19.8%) presented high LVM. Age, hypertension, dyslipidaemia, RV10 and the use of nevirapine were associated with a greater presence of LVH in the univariate analysis. In the logistic regression analysis performed, the factors retained in the model were the presence of high RV10 (OR: 2.92, 95%CI: 1.39–6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18–4.14). Conclusions: In this group of patients, the use of nevirapine and the presence of high RV10 were associated with LVH. The use of nevirapine might be related to its prescription for patients with higher RV10. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Following the introduction of highly active antiretroviral therapy (HAART) against human immunodeficiency virus (HIV), AIDSassociated morbidity and mortality have declined continuously [1]. However, cardiovascular morbidity and mortality have presented less improvement during this period, compared with the results achieved for AIDS and liver diseases [2]. It has been reported that both HIV infection and HAART may be involved in the occurrence of events such as acute myocardial infarction [3–5], the progression of carotid atherosclerotic disease [6,7] or heart disease [8,9], and that they also influence other parameters of subclinical involvement such as the ankle-brachial index [10]. This has led to the development of various observational, cross-sectional studies focusing on the safety and security of the different components of HAART. One phenomenon implicated in the pathogenesis of heart disease and the occurrence of cardiovascular events is that of left ventricular hypertrophy (LVH). Increased left ventricular mass (LVM) is a prognostic factor for overall and cardiovascular mortality [11,12], and is the most sensitive method available to diagnose transthoracic echocardiography ⁎ Corresponding author at: Unidad de Medicina Interna, Agencia Hospitalaria Costa del Sol, Carretera Nacional 340, km 187, 29603 Marbella, Spain. Tel.: +34 951976669. E-mail address: [email protected] (J. Olalla).
(TTE). In particular, the presence of LVH, confirmed by TTE, is associated with a relative risk of death from any cause of 1.5–2 compared to patients with normal LVM, and the corresponding value for vascular events is around 2. Increased LVM has been related with gender (higher in women) [13], obesity [14], age [11], hypertension [15] and diabetes mellitus [16], among others. In recent years, some studies have shown that the prevalence of LVH is higher among HIV-infected patients [17,18], regardless of the associated factors in the non-infected population. Also implicated as factors associated with LVH in patients with HIV infection are the use of inhibitors of nucleoside reverse transcriptase [19] and that of protease inhibitors [20]. In this study we investigate the prevalence of LVH diagnosed by TTE in a cohort of patients with chronic HIV infection and presenting the risk factors associated with its occurrence. 2. Material and methods 2.1. Study design Descriptive, cross-sectional study performed in patients who regularly attended the HIV clinic at the Costa del Sol Hospital in Marbella (Spain) between 1 December 2009 and 28 February 2011. TTE was offered in all cases. When consent was given, data were obtained
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M. Pombo et al. / European Journal of Internal Medicine 24 (2013) 558–561
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regarding epidemiological and clinical parameters, as well as for traditional cardiovascular risk factors and variables associated with their HIV infection status. Patients were classed as hypertensive when this was stated in their clinical background, or when their systolic blood pressure exceeded 140 mm Hg or when their diastolic blood pressure was greater than 90 mm Hg, measured on two separate occasions at least three months apart, or when they were receiving antihypertensive treatment. Patients were considered diabetic when this was stated in their clinical background, when they had fasting plasma glucose levels above 126 mg/dl measured on two separate occasions at least three months apart, or when they were receiving treatment with antidiabetic oral agents or insulin. Patients were considered dyslipidaemic when this was stated in their clinical background, when they had LDL cholesterol levels above 160 mg/dl or triglycerides equal to or greater than 150 mg/dl, or when they were receiving treatment with hypolipidaemic drugs. Patients were considered HBV co-infected if they had antibodies to HBV core antigen (AntiHbcAc), and HCV co-infected if they presented positive ELISA for HCV. We calculated the duration of HIV infection assuming its onset to be the first serology (Western blot analysis) positively reflected in the patient's medical history. Ten years cardiovascular risk was estimated by the Framingham equation, which is shown in the European AIDS Clinical Society web site, available in: http://www.cphiv. dk/TOOLS/Framingham/tabid/302/Default.aspx. Risk was classified as follows: b 10% low risk, 10–20% intermediate risk and >20% high risk. Medical histories in our hospital are computerized, so every patient's report was reviewed considering medication prescribed in each visit. For this purpose, a team of antiretroviral therapy experienced doctors was designed, with extensive knowledge of available drug combinations. TTE was performed by a single expert echocardiographer, using a Siemens Acuson Sequoia C256 with 3.5 MHz transducer. Measurements were performed on the parasternal long axis, using the 2D-guided M mode, and recording the following parameters: LV diastolic and systolic diameter (LVDD and LVSD, respectively), interventricular septal thickness (IVS) and posterior wall (PW) thickness, ejection fraction and left atrial volume, following the guidelines of the American Society of Echocardiography (ASE) [21]. LVM was measured by the following formula: LVM (ASE) = 0.8 × {1.04 [(LVDD + IVS + PW) 3 − (LVDD)3]} + 0.6 g, adjusting for height2.7 to avoid underestimating the prevalence of LVH in obese or overweight patients. The normal range bounds specified by the ASE were used to establish the presence or otherwise of LVH in men and women (>48 g/m 2.7 and >44 g/m 2.7 respectively).
was via heterosexual transmission (38.4%). The average duration of HIV infection was 9.13 years (95%CI: 8.5–9.8). Only 13.9% of patients were naive to antiretroviral therapy (ART); of those who received ART, the average exposure was 6.20 years (95%CI: 5.7–6.7). 25.3% presented AIDS-associated parameters. The mean count of CD4 lymphocytes was 650/μl (95%CI: 616–685), with a mean nadir of 286 cells/μl (95%CI: 263–309). Viral load values were obtained for 98.2% of the participants, and remained below 50 copies/mL in 65.5% of the patients. 32.2% of the patients were co-infected with HCV. The average body mass index (BMI) was 24.9 kg/m2 (95%CI: 24.4–27.3). Regarding the classical cardiovascular risk factors, 11.9% of the patients were hypertensive, 6.2% had diabetes mellitus, 23.2% dyslipidaemia and 53.6% consumed tobacco. The 10-year risk of cardiovascular disease (RV10) was 12.15% (95%CI: 11–13.3). 19.1% of the patients had a high RV10. Nineteen patients were under antithrombotic therapy (4.8%), 23 (5.8%) received betablocker, 16 (4%) ACE inhibitors, 12 (3%) Angiotensin II receptor blocker, 5 (1.3%) dihydropyridines, 2 (0.5%) doxazosin, 8 (2%) diuretics, 45 (11.3%) statins, 20 (5%) fibrates, 1 (0.3%) ezetimibe, 4 (1%) fatty acids, 16 (4.1%) oral antidiabetic and 4 (1%) insulin.
2.2. Statistical analysis
3.3. Factors associated with LVH
Data were compiled directly into SPSS 15.0 (Statistical Package for Social Sciences, Inc. Chicago, Illinois, USA). The quantitative variables were described using the mean, with a 95% confidence interval (95%CI), and the qualitative variables are given as percentages. The quantitative variables were compared using Student's t test, after verifying the normality of the samples; when this condition was not met, the Mann–Whitney test was used. The qualitative variables were compared using the χ2 test. In the initial analysis, the dependent variable was taken as the presence of LVH, according to the criteria stipulated above. The variables that presented a statistical association with LVH (p b 0.05) were included in the logistic regression analysis, using a forward stepwise method. The odds ratio (OR) was calculated at 95%CI and statistical significance was set at p b 0.05. At the decision of the investigator, the antiretrovirals (ARVs) that were not given to at least five patients in each group (normal and elevated LVM) were omitted from the logistic regression analysis.
The patients with high LVH presented a higher average age (49 vs. 44.6 years, p = 0.001). There were no significant differences in immunovirological status. The proportion of patients with HCV co-infection was lower among the patients with high LVH (22.4% vs. 34.3%) without reaching statistical significance (p = 0.058). The latter also had a higher BMI (27.4 vs. 24.4 kg/m 2). LVH was more frequent among hypertensive patients (19.1 vs. 10.4%, p = 0.04) and those with dyslipidaemia (34.8% vs. 20.7%, p = 0.012). RV10 was greater among patients with LVH (16.7% vs. 11.1%, p = 0.001), and moreover there was a higher proportion of patients with high RV among those with LVH (32.4% vs. 16.2%, p = 0.001). With respect to the use of ARVs, a history of nevirapine use was more frequent among patients with LVH (17.6% vs. 33.3%, p = 0. 003), as was also the case with maraviroc, although in this case, there were only six patients. We also observed an association between the current use of maraviroc and a lower cumulative exposure to enfuvirtide. We performed a logistic regression analysis (Table 2), which included the duration of ART (assessed by the researcher), hypertension, dyslipidaemia, RV10 (categorised as low, medium or high) and the use of nevirapine in the patient's clinical history. The factors retained in the model were the presence of high RV10 (OR 2.92,
3. Results TTE was performed on a total of 388 patients (Table 1) of whom the majority were male (75.5%). The average age of the study participants was 45.38 years (95%CI: 44.4-46.3). The main route of virus acquisition
3.1. Prevalence of high LVM A total of 69 patients (19.8%) presented LVH. The average LVM value was 39.6 g/m 2.7 (95%CI 38.3–40.7). 3.2. Use of ART The antiretroviral (ARV) most frequently used, according to the patients' clinical histories, was tenofovir (61.1%). Among nonnucleoside reverse transcriptase inhibitors (NNRTI), efavirenz was the most used (55.2%), and among protease inhibitors (PI) lopinavir–ritonavir was the most widely used (18.6%). With respect to the accumulated use of ARV, lamivudine had been used for longest (62.2 months, 95%CI: 56.4–68.07). Among nucleoside reverse transcriptase inhibitors, zidovudine had the longest accumulated use (50.3 months, CI95%: 44.2–56.5); nevirapine had the longest accumulated use among NNRTI (51 months, CI95%: 41.4-60.8) and fosamprenavir–ritonavir among PI (28 months, CI95%: 19.2–36.9). At the time of data compilation, again tenofovir was the most commonly used (54.1%), followed by efavirenz (52.3%).
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Table 1 Characteristics of the patients. All patients N = 388 Male gender Age (years) Transmission route Heterosexual Homosexual Injection drug user AIDS Duration of infection (years) Viral load b50 copies/mL CD4 cell counts (cells/μL) Nadir CD4 cell counts (cells/μL) Use of ART Duration use of ART (years) HCV Hypertension Dyslipidaemia Diabetes mellitus Smokers Body mass index (kg/m2) RV10 (%) RV10 Low Moderate High Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) Glomerular filtration MDRD-4 (mL/minute)
With LVH N = 69
No LVH N = 319
297 (75.5) 45.4 (44.4–46.3)
52 (75.4) 49 (46.6–51.4)
245 (76.8) 44.6 (43.6–45.6)
149 (38.4) 121 (31.2) 102 (26.3) 98 (25.2) 9.1 (8.5–9.8) 254 (65.5) 650 (616–685) 286 (263–309) 334 (86.1) 6.2 (5.7–6.7) 122 (32.2) 46 (11.9) 90 (23.2) 24 (6.2) 208 (53.6) 24.9 (24.4–27.3) 12.2 (11–13.3)
30 (43.5) 24 (34.8) 12 (17.4) 21 (30.4) 9.8 (8.1–11.5) 45 (70.3) 711 (627–795) 301 (232–371) 60 (87) 7.3 (5.9–8.8) 15 (22.4) 13 (19.1) 34 (34.8) 3 (4.3) 32 (46.4) 27.4 (26.1–28.7) 16.7 (13.3–20)
119 (37.3) 97 (30.4) 90 (28.2) 77 (24.1) 9 (8.2–9.7) 209 (65.9) 637 (599–675) 283 (259–307) 274 (85.9) 6 (5.4–6.5) 107 (34.3) 33 (10.4) 66 (20.7) 21 (6.6) 176 (55.2) 24.4 (23.9–24.8) 11.1 (10–12.3)
198 (53.4) 102 (27.5) 71 (19.1) 191.8 (187.5–196.3) 46.9 (45.5–48.4) 114.9 (111.3–118.4) 165.6 (153.7–177.4) 106.7 (104.1–109.4)
24 22 22 199.1 45.4 120.3 181.2 111.1
(35.3) (32.4) (32.4) (187.4–210.7) (41.8–49.01) (110.8–129.8) (150.2–212.3) (102.7–117.6)
174 (57.4) 80 (26.4) 49 (16.2) 190.3 (185.5–195.1) 47.3 (45.7–48.9) 113.6 (109.8–117.4) 162.1 (149.3– 174.9) 106 (103.2–108.9)
p 0.8 0.001 0.5
0.27 0.43 0.49 0.17 0.72 0.82 0.1 0.058 0.04 0.01 0.48 0.18 b0.0005 0.001 0.001
0.13 0.35 0.15 0.22 0.27
Categoric variables are stated as integers (%); continuous variables are stated as the mean (95%CI).
95%CI: 1.39–6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18– 4.14). 4. Discussion Our study revealed a LVH prevalence of 19.8%, in contrast to the 4–6% reported by studies that calculated LVM after indexing it by body surface area [18,19]. However, studies of LVM indexed by height2.7 show a LVH prevalence similar to that in our series [22,23], but indexing LVM by body surface area rather than by height2.7 produces an underestimate [24]. Other studies [25] found no patients with LVH, but excluded patients with diabetes, hypertension or dyslipidaemia, as well as those presenting an abnormal electrocardiogram. In our series, these exclusion criteria were not adopted; rather, we aimed to establish the prevalence among all patients who attended the clinic regularly. We corroborate the findings of other studies that LVH is associated with the presence of diabetes mellitus and hypertension [18,19]. These same risk factors were confirmed in patients with and without HIV infection. In patients with HIV infection, there is an increased risk of coronary events, while vascular events are a major cause of mortality after AIDS events [2,3]. A recent retrospective study [26] claimed that sudden deaths were responsible for 13% of total mortalities in a cohort of patients infected with HIV, 4.5 times more than expected. It is true that these patients more frequently had a history of ischaemic heart disease or heart failure, but among the deceased who had had an ECG, about 33%
Table 2 Logistic regression analysis. Parameter
OR
95%CI
P
Use of nevirapine RV10 Low Moderate High
2.20
1.18–4.14
0.013
Reference 1.94 2.92
0.96–3.91 1.39–6.15
0.062 b0.0005
(accounting for 25% of the sudden deaths) presented signs of LVH. Some of these heart-related sudden deaths may have been provoked by an increase in LVM. The latter is involved not only in elevated overall mortality, but also specifically in the increased incidence of sudden death and ventricular arrhythmias [27]. One factor that is specific to HIV infection is ART. Previous studies have indicated that the use of protease inhibitors [20] or nucleoside analogues [19,23] may be associated with a LVH. Others have found such a relationship, not with any specific component of the ART, but with receiving ART compared with non-infected patients [18]. It has been argued that this increase would be mediated either through greater dyslipidaemia or through direct mitochondrial damage, in the case of nucleoside analogues [28]. In our study, no such association was found. However, the use of nevirapine was associated with LVH. Although in the logistic regression analysis the use of this drug was retained in the model, together with moderate and high RV10, there may be an indication bias regarding this drug. It has long been known that nevirapine has a good metabolic profile. Its long-term use has been associated with a protective effect against the development of diabetes, according to the D:A:D study [29], and with a very evident elevation of HDL cholesterol [30]. This could have encouraged the medical staff in our study to recommend this ART to patients with high RV. We found no association between the protease inhibitors most commonly used today (atazanavir, darunavir) with the presence of LVH. Other protease inhibitors, tested previously, and for which such an association was found, are not currently used, as they require an uncomfortably high dosage and produce stronger metabolic effects. The fact that diseases normally more prevalent among older patients, such as coronary heart disease, osteoporosis or kidney failure, affect younger patients with HIV infection [31] should also alert us to the increase in other markers of cardiovascular disease such as LVH, especially when increasing numbers of prevalent and incident cases of HIV infection occur among older patients [32,33]. The presence of a chronic inflammatory state, characteristic of HIV infection, which is not completely reversed even with highly effective ART [34], can contribute to a greater presence of LVH, as has been observed in other chronic
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inflammatory processes [35]. The greater the similarity between patients with HIV infection and the non-infected population, the greater the tendency for cardiovascular mortality to be the leading cause of death, as occurs among non-infected persons [36]. It is not insignificant that different series have reflected a prevalence of LVH between 15% and 19%. The association of a high RV10 to the presence of LVI endorse it as a good tool in the evaluation of our patients. It seems reasonable to perform a TTE in those patients with a high RV10 in order to detect LVH. Learning points • Left ventricular mass is an independent risk factor for death. • Prevalence of left ventricular hypertrophy (LVH) is high among people with HIV infection. • Vascular risk is in relationship with LVH. Conflict of interests All the authors declare having no conflict of interest. References [1] Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853–60. [2] Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law M, et al. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS 2010;24:1537–48. [3] Islam F, Wu J, Jansson J, Wilson D. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med 2012;13:453–68. [4] Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007;356:1723–35. [5] El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355: 2283–96. [6] van Vonderen MG, Smulders YM, Stehouwer CD, Danner SA, Gundy CM, Vos F, et al. Carotid intima-media thickness and arterial stiffness in HIV-infected patients: the role of HIV, antiretroviral therapy, and lipodystrophy. J Acquir Immune Defic Syndr 2009;50:153–61. [7] Hsue PY, Ordovas K, Lee T, Reddy G, Gotway M, Schnell A, et al. Carotid intima-media thickness among human immunodeficiency virus-infected patients without coronary calcium. Am J Cardiol 2012;109:742–7. [8] Butt AA, Chang CC, Kuller L, Goetz MB, Leaf D, Rimland D, et al. Risk of heart failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart disease. Arch Intern Med 2011;171:737–43. [9] Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011;25:1289–98. [10] Olalla J, Salas D, Del Arco A, De la Torre J, Prada J, Machin-Hamalainen S, et al. Ankle-branch index and HIV: the role of antiretrovirals. HIV Med 2009;10:1–5. [11] Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561–6. [12] Kardys I, Deckers JW, Stricker BH, Vletter WB, Hofman A, Witteman JC. Echocardiographic parameters and all-cause mortality: the Rotterdam Study. Int J Cardiol 2009;133:198–204. [13] Savage DD, Garrison RJ, Kannel WB, Levy D, Anderson SJ, Stokes III J, et al. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987;75:I26–33. [14] de Simone G, Palmieri V, Bella JN, Celentano A, Hong Y, Oberman A, et al. Association of left ventricular hypertrophy with metabolic risk factors: the HyperGEN study. J Hypertens 2002;20:323–31.
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