Direct and indirect cardiovascular and cardiometabolic sequelae of the combined anti-retroviral therapy on people living with HIV.

With reports of its emergence as far back as the early 1900s, human immunodeficiency virus (HIV) has become one of the deadliest and most difficult viruses to treat in the era of modern medicine. Although not always effective, HIV treatment has evolved and improved substantially over the past few decades. Despite the major advancements in the efficacy of HIV therapy, there are mounting concerns about the physiological, cardiovascular, and neurological sequelae of current treatments. The objective of this review is to (Blattner et al., Cancer Res., 1985, 45(9 Suppl), 4598s-601s) highlight the different forms of antiretroviral therapy, how they work, and any effects that they may have on the cardiovascular health of patients living with HIV, and to (Mann et al., J Infect Dis, 1992, 165(2), 245-50) explore the new, more common therapeutic combinations currently available and their effects on cardiovascular and neurological health. We executed a computer-based literature search using databases such as PubMed to look for relevant, original articles that were published after 1998 to current year. Articles that had relevance, in any capacity, to the field of HIV therapy and its intersection with cardiovascular and neurological health were included. Amongst currently used classes of HIV therapies, protease inhibitors (PIs) and combined anti-retroviral therapy (cART) were found to have an overall negative effect on the cardiovascular system related to increased cardiac apoptosis, reduced repair mechanisms, block hyperplasia/hypertrophy, decreased ATP production in the heart tissue, increased total cholesterol, low-density lipoproteins, triglycerides, and gross endothelial dysfunction. The review of Integrase Strand Transfer Inhibitors (INSTI), Nucleoside Reverse Transcriptase Inhibitors (NRTI), and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) revealed mixed results, in which both positive and negative effects on cardiovascular health were observed. In parallel, studies suggest that autonomic dysfunction caused by these drugs is a frequent and significant occurrence that needs to be closely monitored in all HIV + patients. While still a relatively nascent field, more research on the cardiovascular and neurological implications of HIV therapy is crucial to accurately evaluate patient risk.

Could "cellular exercise" be the missing ingredient in a healthy life? Diets, caloric restriction, and exercise-induced hormesis.

Overnutrition is a poor dietary habit that has been correlated with increased health risks, especially in the developed world. This leads to an imbalance between energy storage and energy breakdown. Many biochemical processes involving hormones are involved in conveying the excess of energy into pathologic states, mainly atherosclerosis, hypertension, cardiovascular diseases, and diabetes. Diverse modalities of regular exercise have been shown to be beneficial, to varying extents, in overcoming the overnutrition comorbidities. Cellular exercises and hormesis are triggered by dietary protocols that could underlie the cellular mechanisms involved in modulating the deleterious effects of overnutrition through activation of specific cellular signal pathways. Of interest are the oxidative stress signaling, nuclear factor erythroid-2, insulin-like growth factor-1, AMP-activated protein kinase as well as sirtuins and nuclear factor-κB. Therefore, the value of intermittent fasting diets as well as different diet regimens inducing hormesis are evaluated in terms of their beneficial effects on health and longevity. In parallel, important effects of diets on the immune system are explored as essential components that can undermine the overall health outcome. Additionally, the subtle but relevant relation between diet and sleep is investigated for its impact on the cardiovascular system and quality of life. The aim of this review is to focus on how calorie restriction triggers multiple molecular pathways that ultimately lead to hormetic effects resulting in cell longevity and resistance to cardiovascular disease, stroke, and cancer.

CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy.

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates ß-adrenergic receptor (ß-AR) signaling and ultimately limits ß-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to ß-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates ß-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.

Alcoholism: A Multi-Systemic Cellular Insult to Organs.

Alcohol abuse can affect more than the heart and the liver. Many observers often do not appreciate the complex and differing aspects of alcohol's effects in pathophysiologies that have been reported in multiple organs. Chronic alcohol abuse is known to be associated with pathophysiological changes that often result in life-threatening clinical outcomes, e.g., breast and colon cancer, pancreatic disease, cirrhosis of the liver, diabetes, osteoporosis, arthritis, kidney disease, immune system dysfunction, hypertension, coronary artery disease, cardiomyopathy, and can be as far-reaching as to cause central nervous system disorders. In this review article, we will discuss the various organs impacted by alcohol abuse. The lack of clear guidelines on the amount and frequency of alcohol intake, complicated by personal demographics, make extrapolations to real-life practices at best difficult for public health policy-makers.

Alcohol-Mediated Organ Damages: Heart and Brain.

Alcohol is one of the most commonly abused substances in the United States. Chronic consumption of ethanol has been responsible for numerous chronic diseases and conditions globally. The underlying mechanism of liver injury has been studied in depth, however, far fewer studies have examined other organs especially the heart and the central nervous system (CNS). The authors conducted a narrative review on the relationship of alcohol with heart disease and dementia. With that in mind, a complex relationship between inflammation and cardiovascular disease and dementia has been long proposed but inflammatory biomarkers have gained more attention lately. In this review we examine some of the consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver. The article reviews the potential role of inflammatory markers such as TNF-α in predicting dementia and/or cardiovascular disease. It was found that TNF-α could promote and accelerate local inflammation and damage through autocrine/paracrine mechanisms. Unraveling the mechanisms linking chronic alcohol consumption with proinflammatory cytokine production and subsequent inflammatory signaling pathways activation in the heart and CNS, is essential to improve our understanding of the disease and hopefully facilitate the development of new remedies.

Fetal Alcohol Exposure: The Common Toll.

Alcohol has always been present in human life, and currently it is estimated that 50% of women of childbearing age consume alcohol. It has become increasingly clear over the last years that alcohol exposure during fetal development can have detrimental effects on various organ systems, and these effects are exerted by alcohol through multiple means, including effects on free radical formation, cellular apoptosis, as well as gene expression. Fetal alcohol exposure can lead to a spectrum of short term as well as long-term problems, with Fetal Alcohol Syndrome being on the more severe end of that spectrum. This syndrome is morbid, yet preventable, and is characterized by midfacial hypoplasia, thin upper lip, widely spaced small eyes, long smooth philtrum and inner epicanthal folds. Other findings include growth restriction as well as various neurodevelopmental abnormalities. This article is the first comprehensive review combining the molecular as well as the gross physiological and anatomical effects of alcohol exposure during pregnancy on various organ systems in the body. Our knowledge of these various mechanisms is crucial for our understanding of how alcohol exposure during fetal development can lead to its detrimental effects.

Alcohol and Apoptosis: Friends or Foes?

Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis with less than 25% survival for more than three years. In contrast, low alcohol consumption has been associated with reduced risk of cardiovascular disease, however the mechanism of this phenomenon remains elusive. The aim of this study was to determine the significance of apoptosis as a mediating factor in cardiac function following chronic high alcohol versus low alcohol exposure. Adult rats were provided 5 mM (low alcohol), 100 mM (high alcohol) or pair-fed non-alcohol controls for 4-5 months. The hearts were dissected, sectioned and stained with cresyl violet or immunohistochemically for caspase-3, a putative marker for apoptosis. Cardiomyocytes were isolated to determine the effects of alcohol exposure on cell contraction and relaxation. High alcohol animals displayed a marked thinning of the left ventricular wall combined with elevated caspase-3 activity and decreased contractility. In contrast, low alcohol was associated with increased contractility and decreased apoptosis suggesting an overall protective mechanism induced by low levels of alcohol exposure.

Alcohol and inflammatory responses: summary of the 2013 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

Loyola University Chicago, Health Sciences Campus in Maywood, Illinois hosted the 18th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting on November 22, 2013. This year's meeting emphasized alcohol's effect on inflammatory responses in diverse disease states and injury conditions. The meeting consisted of three plenary sessions demonstrating the adverse effects of alcohol, specifically, liver inflammation, adverse systemic effects, and alcohol's role in infection and immunology. Researchers also presented insight on modulation of microRNAs and stress proteins following alcohol consumption. Additionally, researchers revealed sex- and concentration-dependent differences in alcohol-mediated pathologies.

Calcitonin Gene-Related Peptide Regulates Cardiomyocyte Survival through Regulation of Oxidative Stress by PI3K/Akt and MAPK Signaling Pathways.

CGRP and specific CGRP receptors are found in the heart where they produce positive-inotropic and anti-apoptotic effects, key adaptations to exercise and cardiovascular disease. PI3K/Akt and MAPK signaling imbalances are associated with cardiomyocyte pathologies; however, the effects of CGRP on these pathways are unclear. Therefore, we hypothesized that CGRP modulates inotropic and apoptotic adaptations of cardiomyocytes by regulating PI3K/Akt and MAPK/ERK signaling balances. We treated cardiomyocytes with combinations of CGRP, PI3K/Akt and MAPK signaling agonists and antagonists. We evaluated expression of the mRNA and proteins levels of survival signaling molecules related to the PI3K/Akt and MAPK and measured apoptosis by caspase 3/7 activity. CGRP1-37 decreased Akt, NFκB, SOD-3 and increased ERK1/2 and p38 MAPK expressions, which was antagonized by CGRP8-37. Akt-negative construct transfection, Ad.Akt(K179M), inhibited the CGRP1-37-induced increment in MAPK expressions. A PI3K-antagonist treatment with LY294002 or CGRP1-37/Ad.Akt(K179M) co-treatment alleviated the CGRP-increased caspase activity and -decrements in SOD-3. These findings demonstrate a CGRP negative effect on the PI3K/Akt signaling pathway and CGRP receptor-induced crosstalk between PI3K/Akt and MAPK in normal cardiomyocytes. Future studies to differentiate CGRP effects on intracellular signal transduction mechanisms in pathological conditions will elucidate the significance of CGRP in, and provide novel therapeutic targets for, heart failure.

Effects of Nitrate Supplementation on Cardiovascular and Autonomic Reactivity in African-American Females.

Previous studies have shown that beetroot juice (BJ) decreases systolic blood pressure (SBP) and oxygen demand. This study tests the hypothesis that a beetroot juice (BJ) treatment increases heart rate variability (HRV) measured by the average standard deviation of normal-normal electrocardiogram RR intervals (SDNN) and the low frequency (LF), mainly sympathetic, fast Fourier transform spectral index of HRV. The subjects were 13 healthy young adult African-American females. Placebo control orange juice (OJ) and BJ treatments were given on separate days. Blood nitric oxide [NO], SBP and RR intervals were measured at rest and at constant workloads set to 40% and 80% of the predetermined VO2peak. Two hours after ingestion the BJ treatment increased [NO] and decreased SBP. BJ also increased SDNN at rest and at the 40% VO2peak workload, without significant effects on LF. SDNN was significantly greater after the BJ than after the OJ treatment, across the two physical activity conditions and SDNN was (negatively) correlated with SBP. These results suggest that BJ decreases SBP and increases HRV at rest and during aerobic exercise. Similar results in subjects with prehypertension or hypertension could translate to a dietary nitrate treatment for hypertension.

Acute alcohol modulates cardiac function as PI3K/Akt regulates oxidative stress.

BACKGROUND: Clinical manifestations of alcohol abuse on the cardiac muscle include defective contractility with the development of heart failure. Interestingly, low alcohol consumption has been associated with reduced risk of cardiovascular disease. Although several hypotheses have been postulated for alcoholic cardiomyopathy and for the low-dose beneficial cardiovascular effects, the precise mechanisms and mediators remain largely undefined. We hypothesize that modulation of oxidative stress by PI3K/Akt plays a key role in the cardiac functional outcome to acute alcohol exposure. METHODS: Thus, acutely exposed rat cardiac tissue and cardiocytes to low (LA: 5 mM), moderate (MA: 25 mM), and high (HA: 100 mM) alcohol were assessed for markers of oxidative stress in the presence and absence of PI3K/Akt activators (IGF-1 0.1 µM or constitutively active PI3K: Ad.BD110 transfection) or inhibitor (LY294002 1 µM or Akt-negative construct Ad.Akt(K179M) transfection). RESULTS: Acute LA reduced Akt, superoxide dismutase (SOD-3) and NFκB, ERK1, and p38 MAPK gene expression. Acute HA only increased that of SOD-3 and NFκB. These effects were generally inhibited by Ad.Akt(K179M) and enhanced with Ad.BD110 transfection. In parallel, LA reduced but HA enhanced Akt activity, which was reversed by IGF-1 and inhibited by Ad.Akt(K179M), respectively. Also, LA reduced caspase 3/7 activity and oxidative stress, while HA increased both. The former was blocked, while the latter effect was enhanced by Ad.Akt(K179M). The reverse was true with PI3K/Akt activation. This translated into reduced viability with HA, with no effect with LA. On the functional level, acute LA improved cardiac output and ejection fraction, mainly through increased stroke volume. This was accompanied with enhanced end-systolic pressure-volume relationship and preload recruitable stroke work. Opposite effect was recorded for HA. LA and HA in vivo functional effects were alleviated by LY and enhanced by IGF-1 treatment. CONCLUSIONS: Acute LA and HA seem to oppositely affect cardiac function through modulation of oxidative stress where PI3K/Akt plays a pivotal role.

Cardiorespiratory function associated with dietary nitrate supplementation.

The advent of medical nutrition therapy and nutritional physiology affords the opportunity to link diet to specific cardiovascular mechanisms, suggesting novel treatments for cardiovascular disease. This study tests the hypothesis that beetroot juice increases the plasma nitric oxide (NO) concentration, which is associated with improvements in cardiorespiratory function at rest and during submaximal aerobic exercise. The subjects were 12 healthy, young adult, normotensive African-American females, with a body mass of 61 ± 2 kg, body fat of 28% ± 4%, and peak oxygen consumption of 26 ± 3 mL·kg(-1)·min(-1). The subjects were studied at rest and during cycle ergometer exercise at 40%, 60%, and 80% of peak oxygen consumption. Plasma NO concentration, respiratory quotient (RQ), minute ventilation, systolic and diastolic blood pressure (SBP and DBP), heart rate, and oxygen consumption were compared between isocaloric, isovolumetric placebo control orange juice and experimental beetroot juice treatments on separate days. The beetroot juice treatment increased plasma NO concentration and decreased oxygen consumption, SBP, and the heart rate-SBP product at rest and at 40%, 60%, and 80% of peak oxygen consumption in the absence of significant effects on RQ, minute ventilation, heart rate, and DBP. These findings suggest that, in healthy subjects, beetroot juice treatments increase plasma NO concentration and decrease cardiac afterload and myocardial oxygen demand at rest and during 3 submaximal levels of aerobic exercise. Future studies should determine the cellular and molecular mechanisms responsible for the improvement in cardiorespiratory function associated with dietary nitrate supplementation and whether they translate into better cardiovascular function and exercise tolerance in individuals with a compromised cardiovascular system.

Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart.

Previous studies have demonstrated positive-inotropic effects of calcitonin gene-related peptide (CGRP), but the mechanisms remain unclear. Therefore, two experiments were performed to determine the physiological correlates of the positive-inotropic effects of CGRP. Treatments designed to antagonize the effects of physiologically active CGRP1₋37 included posttreatment with CGRP8₋37 and pretreatment with LY-294002 (LY, an inhibitor of phosphatidylinositol 3-kinase), 17ß-estradiol (E), and progesterone (P) were also used to modulate the effects of CGRP1₋37. Experiment 1 was in vitro studies on sarcomeres and cells of isolated adult rat cardiac myocytes. CGRP1₋37, alone and in combination with E and P, decreased sarcomere shortening velocities and increased shortening percentages, effects that were antagonized by CGRP8₋37, but not by LY. CGRP1₋37 increased resting intracellular calcium ion concentrations and Ca(2+) influxes, effects that were also antagonized by both CGRP8₋37 and LY. Experiment 2 was in vivo studies on left ventricular pressure-volume (PV) loops. CGRP1₋37 increased end-systolic pressure, ejection fraction, and velocities of contraction and relaxation while decreasing stroke volume, cardiac output, stroke work, PV area, and compliance. After partial occlusion of the vena cava, CGRP1₋37 increased the slope of the end-systolic PV relationship. CGRP8₋37 and LY attenuated most of the CGRP-induced changes. These findings suggest that CGRP-induced positive-inotropic effects may be increased by treatments with estradiol and progesterone and inhibited by LY. The physiological correlates of CGRP-induced positive inotropy observed in rat sarcomeres, cells, and intact hearts are likely to reveal novel mechanisms of heart failure in humans.

The good, the bad, and the ugly with alcohol use and abuse on the heart.

Since its advent, alcohol has been utilized throughout history socially, for rituals, worship, and for its therapeutic, antibacterial, and analgesic properties. In moderation, alcohol consumption and its use are generally viewed as clinically beneficial. Excessive alcohol consumption on the other hand has been recognized as having several adverse implications. Excessive use increases the risk of liver and heart disease, metabolic disturbances, nutritional deficiencies, certain cancers, brain damage, dementia, neuropathy, as well as other facets of morbidity and mortality. This review targets the sequelae of alcohol consumption on the heart, specifically on myocardial contractility, calcium channel signaling, and intracellular signaling pathways. With the incidence of alcohol-induced cardiac abnormalities being higher than previously thought, it is of increasing importance to elucidate the mechanisms behind them. Here, the cardiac effects of alcohol were not discussed in isolation but in conjunction with other important factors, such as high- and low-density lipoprotein levels and vascular dilatory influences. We explore these mechanisms, in particular, the oxidative stress as the major contributor, as well as pathways that may prove to be cardioprotective. As such, we demonstrate the involvement of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/NRF2) as well as AKT that act as regulators of oxidative balance during oxidative stress responses. Thus, alcohol consumption may confer a cardioprotective effect when used in moderation through an AKT/NRF2-dependent mechanism.

Effects of dietary nitrates on systemic and cerebrovascular hemodynamics.

Cerebral blood flow dysregulation is often associated with hypertension. We hypothesized that a beetroot juice (BRJ) treatment could decrease blood pressure and cerebrovascular resistance (CVR). We subjected 12 healthy females to control and BRJ treatments. Cerebrovascular resistance index (CVRI), systolic blood pressure (SBP), total vascular resistance (TVR), and the heart rate-systolic pressure product (RPP) measured at rest and at two exercise workloads were lower after the BRJ treatment. CVRI, SBP, and RPP were lower without a lower TVR at the highest exercise level. These findings suggest improved systemic and cerebral hemodynamics that could translate into a dietary treatment for hypertension.

Oxygen Consumption at 30 W of Exercise Is Surrogate for Peak Oxygen Consumption in Evaluation of Cardiorespiratory Fitness in Young-Adult African-American Females.

Body mass index (BMI) is negatively correlated with cardiorespiratory fitness, measured by maximal or peak oxygen consumption (VO2peak). VO2peak measurements require heavy aerobic exercise to near exhaustion which increases the potential for adverse cardiovascular events. This study tests the hypothesis that VO2 measured at a fixed submaximal workload of 30 W is a surrogate for VO2peak. We studied 42 normotensive African-American female university students, 18-25 years of age. We measured VO2peak, blood pressure, and VO2 at a 30 W exercise workload and computed BMI. We found significant negative correlations between BMI and VO2peak (r = -0.41, P < 0.01) and between BMI and VO2 at 30 W (r = -0.53, P < 0.001). Compared to VO2peak, VO2 at 30 W increased the significance of the negative correlation with BMI. The heart rate-systolic pressure product at 30 W was positively correlated with BMI (r = 0.36, P < 0.01) and negatively correlated with VO2peak (r = -0.38, P < 0.001). The positive correlation between BMI and the heart rate-systolic pressure product and the greater negative correlation between VO2 and BMI at 30 W of exercise than that at exercise to fatigue suggest that normalized measurements of VO2 at the fixed exercise workload of 30 W could be useful surrogates for measurements of VO2peak.

Effects of IGF-1 on I(K) and I(K1) Channels via PI3K/Akt Signaling in Neonatal Cardiac Myocytes.

Previous studies suggest that sarcolemmal potassium currents play important roles in cardiac hypertrophy. IGF-1 contributes to cardiac hypertrophy via activation of PI3K/Akt signaling. However, the relationships between IGF-1, PI3K/Akt signaling and sarcolemmal potassium currents remain unknown. Therefore, we tested the hypothesis that IGF-1 and PI3K/Akt signaling, independently, decrease sarcolemmal potassium currents in cardiac myocytes of neonatal rats. We compared the delayed outward rectifier (I(K)) and the inward rectifier (I(K)) current densities resulting from IGF-1 treatments to those resulting from simulation of PI3K/Akt signaling using adenoviral (Ad) BD110 and wild-type Akt and to those resulting from inhibition of PI3K signaling by LY294002. Ad.BD110 and Ad.Akt decreased I(K) and these decrements were attenuated by LY 294002. The IGF-1 treatments decreased both I(K) and I(K1) but only the I(K) decrement was attenuated by LY294002. These findings demonstrate that IGF-1 may contribute to cardiac hypertrophy by PI3K/Akt signal transduction mechanisms in neonatal rat cardiomyocytes. Failure of LY294002 to effectively antagonize IGF-1 induced decrements in I(K1) suggests that a signal pathway adjunct to PI3K/Akt contributes to IGF-1 protection against arrhythmogenesis in these myocytes. Our findings imply that sarcolemmal outward and inward rectifier potassium channels are substrates for IGF-1/PI3K/Akt signal transduction molecules.