Cardiovascular complications are more common in human immunodeficiency virus—infected individuals than in age-matched uninfected individuals. Antiretroviral therapy reduces the risk of cardiovascular ...complications, suggesting that viral replication directly or indirectly causes vascular disease. Long-term effective antiretroviral therapy does not fully restore vascular health, and treated adults continue to have higher-than-expected rates of disease progression. Although this excess risk during therapy is likely due to multiple factors, a growing body of evidence suggests that chronic inflammation, which persists during effective antiretroviral therapy, is directly and causally associated with vascular dysfunction and the accelerated development of atherosclerosis.
Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix ...(ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.
HIV-seropositive patients are at higher risk for atherosclerosis than HIV-seronegative persons. This has been variably attributed to antiretroviral drug toxicity, immunodeficiency, and/or ...HIV-associated inflammation. To evaluate the contributions of these factors to HIV-associated atherosclerosis, we assessed carotid artery intima-media thickness in a diverse cohort of HIV-seronegative and seropositive adults, including a unique group of HIV-infected patients who were untreated, had undetectable viral loads, and had preserved CD4 T-cell counts (HIV controllers).
Carotid intima-media thickness was measured in 494 participants, including 33 HIV controllers and 93 HIV-seronegative controls. HIV controllers had higher intima-media thickness than seronegative controls even after adjustment for traditional risk factors (P = 0.003). Intima-media thickness in controllers was similar to antiretroviral-untreated patients with detectable viremia. Across all participants, intima-media thickness was strongly associated with the presence of HIV disease rather than viral load or CD4 T-cell count. C-reactive protein was higher in HIV controllers than HIV-seronegative persons. Antiretroviral drug exposure was also associated with higher intima-media thickness.
Increased atherosclerosis with HIV infection can occur in the absence of antiretroviral therapy, detectable viremia, or overt immunodeficiency. Chronic inflammation - which is higher in controllers than in HIV-uninfected persons - may account for early atherosclerosis in these patients.
Lipid abnormalities are prevalent among persons living with HIV infection and contribute to increasing the risk of cardiovascular events. Antiretroviral therapy (ART) is associated with lipid ...abnormalities, most commonly hypertriglyceridemia, but also increases in low-density lipoprotein cholesterol and total cholesterol. Different classes of ART, and different drugs within classes, have differing effects on lipid levels, but in general newer drugs have more favourable effects compared with older ones. Low-level inflammation and chronic immune activation act on lipids through a variety of mechanisms to make them more atherogenic. As a consequence, risk is higher than would be expected for any given cholesterol level. Clinical outcome trials of cholesterol-lowering therapies have not yet been completed in people living with HIV, so that treatment decisions depend on extrapolation from studies in uninfected populations. Traditional risk assessment tools underestimate cardiovascular risk in individuals with HIV. Statins are the mainstay of lipid-lowering drug treatment; however, drug–drug interactions with ART must be considered. Simvastatin and lovastatin are contraindicated in patients taking protease inhibitors, and the dose of atorvastatin and rosuvastatin should be limited to 40 mg and 10 mg/d with some ART combinations. Switching from older forms of ART to lipid-friendly newer ones is a useful strategy as long as virologic suppression is maintained, but adding a statin lowers low-density lipoprotein cholesterol more effectively. Studies indicate that lipid abnormalities are not treated as aggressively in individuals living with HIV as they are in uninfected people, making this an opportunity to improve care.
Les anomalies lipidiques sont répandues chez les personnes qui vivent avec le VIH et contribuent à l’augmentation du risque d’événements cardiovasculaires. Le traitement antirétroviral (TARV) est associé aux anomalies lipidiques, plus fréquemment à l’hypertriglycéridémie, mais aussi à l’augmentation du cholestérol à lipoprotéines de basse densité et du cholestérol total. Les différentes classes de TARV et les différents médicaments parmi ces classes ont des effets distincts sur les taux de lipides, mais en général les nouveaux médicaments ont des effets plus favorables que les anciens médicaments. L’inflammation de faible degré et l’activation chronique du système immunitaire agissent sur les lipides par divers mécanismes pour les rendre plus athérogènes. Par conséquent, le risque est supérieur à ce que l’on s’attendrait pour tout taux de cholestérol donné. Les études sur les résultats cliniques des traitements hypocholestérolémiants chez les personnes atteintes du VIH n’étant pas encore achevées, les décisions en matière de traitement dépendent donc de l’extrapolation des résultats des études auprès des populations non infectées. Les outils traditionnels d’évaluation des risques sous-estiment les risques cardiovasculaires chez les individus infectés par le VIH. Les statines constituent le pilier du traitement par hypolipidémiants. Toutefois, les interactions médicamenteuses avec le TARV doivent être considérées. La simvastatine et la lovastatine sont contre-indiquées chez les patients qui prennent des inhibiteurs de protéase, et la dose respective d’atorvastatine et de rosuvastatine devrait être limitée à 40 mg et à 10 mg/j avec certaines combinaisons de TARV. Le passage des anciens TARV vers les nouveaux TARV dont les effets sur le profil lipidique sont favorables est une stratégie utile pourvu que la suppression virologique soit maintenue, mais l’utilisation supplémentaire d’une statine abaisse plus efficacement le cholestérol à lipoprotéines de faible densité. Les études montrent que les anomalies des lipides ne sont pas traitées aussi énergiquement chez les individus qui vivent avec le VIH qu’elles le sont chez les personnes non infectées et offrent une occasion d’amélioration des soins.
Objectives The aim of this study was to determine the incidence and clinical characteristics of sudden cardiac death (SCD) in patients with human immunodeficiency virus (HIV) infection. Background As ...the HIV-infected population ages, cardiovascular disease prevalence and mortality are increasing, but the incidence and features of SCD have not yet been described. Methods The records of 2,860 consecutive patients in a public HIV clinic in San Francisco between April 2000 and August 2009 were examined. Identification of deaths, causes of death, and clinical characteristics were obtained by search of the National Death Index and/or clinic records. SCDs were determined using published retrospective criteria: 1) the International Classification of Diseases-10th Revision, code for all cardiac causes of death; and (2) circumstances of death meeting World Health Organization criteria. Results Of 230 deaths over a median of 3.7 years of follow-up, 30 (13%) met SCD criteria, 131 (57%) were due to acquired immune deficiency syndrome (AIDS), 25 (11%) were due to other (natural) diseases, and 44 (19%) were due to overdoses, suicides, or unknown causes. SCDs accounted for 86% of all cardiac deaths (30 of 35). The mean SCD rate was 2.6 per 1,000 person-years (95% confidence interval: 1.8 to 3.8), 4.5-fold higher than expected. SCDs occurred in older patients than did AIDS deaths (mean 49.0 vs. 44.9 years, p = 0.02). Compared with AIDS and natural deaths combined, SCDs had a higher prevalence of prior myocardial infarction (17% vs. 1%, p < 0.0005), cardiomyopathy (23% vs. 3%, p < 0.0005), heart failure (30% vs. 9%, p = 0.004), and arrhythmias (20% vs. 3%, p = 0.003). Conclusions SCDs account for most cardiac and many non-AIDS natural deaths in HIV-infected patients. Further investigation is needed to ascertain underlying mechanisms, which may include inflammation, antiretroviral therapy interruption, and concomitant medications.
Abstract
Background
The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown.
Methods
We measured ...soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)–attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods.
Results
During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor–α (1.14-fold higher mean ratio 95% confidence interval {CI}, 1.01–1.28; P = .028) and interferon-γ–induced protein 10 (1.28-fold higher mean ratio 95% CI, 1.01–1.62; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio 95% CI, .98–1.70; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio 95% CI, 1.11–1.86; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms.
Conclusions
Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.
Compared to individuals reporting full recovery, individuals with symptoms for >90 days following COVID-19 had subtle elevations in levels of certain markers of immune activation. Further characterization of these processes might identify therapeutic targets for those experiencing postacute sequelae of SARS-CoV-2tion.
Recent reports indicate that stimulant-related deaths are increasing dramatically. People who die from acute stimulant toxicity have high rates of pre-existing cardiovascular disease (CVD), much of ...which is undiagnosed. Moreover, people who use stimulants with CVD often remain asymptomatic until presenting to an emergency department with an acute event. Prior research shows that symptoms of stimulant toxicity may occur on a regular basis, and that people who die from stimulant toxicity are older than those who die of opioid toxicity. Taken collectively, the existing evidence suggests that death from acute stimulant toxicity is often an outcome of long-term, cumulative exposure leading to cardiovascular dysfunction rather than acute intoxication. Strategies tailored to the distinct etiology of stimulant overdose are needed. We propose a three-part approach including (1) implementing stimulant use interventions that promote not only abstinence, but also use reduction, (2) treating ongoing stimulant use as a chronic cardiovascular condition, and (3) making stimulant toxicity interventions relevant to the populations most affected, which includes people outside of the traditional health-care system. In short, to reduce stimulant-related fatality, we need to transform our approach in ways that are tailored to address its natural history.
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