## 3 Pathophysiologic Mechanisms  
The multiple phenotypes of HIV-cardiomyopathy are associated with numerous pathophysiologic mechanisms, which seem to have changed over time according to the more nuanced types of myocardial involvement. The proposed causes include direct myocardial injury from HIV-1 (with or without myocarditis), opportunistic infections, nutritional deficiencies, autoimmune reactions, and drug toxicity [10]. One of the earliest theories linked HIV-1 infection directly to myocardial damage, particularly in relation to systolic dysfunction. Interestingly, some studies suggest that cardiomyocytes themselves are not the main target, but rather macrophages. This is likely because cardiac myocytes lack HIV-1 receptor proteins [11]. In a study by Twuet et al., researchers analyzed 18 hearts from AIDS patients (with and without cardiomyopathy) and found that those with cardiomyopathy had significantly higher levels of gp120 and tumor necrosis factor-alpha (TNF-\(\alpha\)), both of which were associated with cardiomyopathyocyte apoptosis. Both extrinsic and intrinsic apoptotic pathways were involved, as indicated by elevated caspase-9 fragments (linked to mitochondrial activation) and Fas ligand (a TNF superfamily member). Gp120 was highly expressed in macrophages and T cells but was either low or absent in cardiac myocytes. Additionally, experiments showed that while HIV-1 could enter rat cardiac myocytes via macropinocytosis in vitro, it was unable to replicate within them [12]. Beyond triggering cardiomyocyte apoptosis, TNF-\(\alpha\) also impairs heart contractility by disrupting calcium-induced calcium release, as demonstrated by Yokoyama [13]. Furthermore, proinflammatory cytokines such as TNF-alfa trigger expression of nitric oxide synthase (iNOS), which has been recognized as being involved in cardiac myocyte depression [14; 15]. This suggests that proinflammatory cytokines play a central role in the development of HIV-cardiomyopathy. However, other cardiotropic viruses have the ability to invade cardiac myocytes, leading to myocarditis through localized cytokine release. The agents incriminated were frequently represented by Coxsackie B3 virus, Epstein-Barr virus, and cytomegalovirus [16]. Moreover, nonviral opportunistic agents were shown to be responsible for the development of myocarditis, especially in late stages of AIDS [3]. Autoimmune processes may further contribute to heart disease in HIV and AIDS patients. Specific cardiac autoantibodies, such as anti-alpha-myosin, have been detected in HIV-positive individuals. Viral infections, both opportunistic and common, might trigger autoimmunity by exposing cardiac surface epitopes. In a study by Currie et al., researchers compared 74 HIV-positive patients (both with and without structural heart disease) to HIV-negative controls. They found higher levels of anti-alpha-myosin autoantibodies in HIV-positive individuals, regardless of heart disease presence. However, within the HIV-positive group, those with structural heart disease had higher antibody concentrations (43%) compared to those without cardiac abnormalities (19%) [17]. Finally, while HAART has significantly improved HIV patient survival, it may also contribute to cardiac disease. Certain drug classes, such as protease inhibitors and some nucleoside reverse transcriptase inhibitors (NRTIs), have been associated with adverse cardiovascular effects, raising concerns about long-term heart health in HIV patients. The use of zidovudine, a reverse nucleoside transcriptase inhibitor, was associated with focal myocardial necrosis, mainly through mitochondrial damage, but studies have failed to acknowledge the exact role of zidovudine in the pathogenesis of HIV-cardiomyopathy [18]. All four classes were associated with metabolic disturbances, such as lipopolysaccharide, hypertriglyceridemia, and insulin resistance. Nelson et al.