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Sarcopenia is the loss of muscle strength, mass, and function, which is often exacerbated by chronic comorbidities including cardiovascular diseases, chronic kidney disease, and cancer. Sarcopenia is associated with faster progression of cardiovascular diseases and higher risk of mortality, falls, and reduced quality of life, particularly among older adults. Although the pathophysiologic mechanisms are complex, the broad underlying cause of sarcopenia includes an imbalance between anabolic and catabolic muscle homeostasis with or without neuronal degeneration. The intrinsic molecular mechanisms of aging, chronic illness, malnutrition, and immobility are associated with the development of sarcopenia. Screening and testing for sarcopenia may be particularly important among those with chronic disease states. Early recognition of sarcopenia is important because it can provide an opportunity for interventions to reverse or delay the progression of muscle disorder, which may ultimately impact cardiovascular outcomes. Relying on body mass index is not useful for screening because many patients will have sarcopenic obesity, a particularly important phenotype among older cardiac patients. In this review, we aimed to: (1) provide a definition of sarcopenia within the context of muscle wasting disorders; (2) summarize the associations between sarcopenia and different cardiovascular diseases; (3) highlight an approach for a diagnostic evaluation; (4) discuss management strategies for sarcopenia; and (5) outline key gaps in knowledge with implications for the future of the field.

Cocaine use exacerbates human immunodeficiency virus (HIV)-associated subclinical coronary atherosclerosis. We investigated whether cocaine abstinence or reduced use achieved with contingency management (CM) intervention would retard high-risk coronary plaque progression among cocaine users with HIV and subclinical coronary atherosclerosis.Between March 2014 and August 2017, 76 cocaine users with HIV and coronary plaques were enrolled in a study designed to decrease cocaine use and determine whether doing so impacted progression of subclinical coronary atherosclerosis as measured by coronary artery computed tomography examinations. Of the 76, 7 did not complete the study, resulting in 69 participants. A 12-month cash-based CM intervention was implemented to promote cocaine abstinence or reduced cocaine use. Generalized estimating equation approach was used to perform longitudinal data analyses.During the 12-month CM, all 69 participants reduced cocaine use, and of these, 25 (36%; 95% confidence interval, 25%-49%) achieved cocaine abstinence. After adjusting for potential confounding factors, generalized estimating equation analyses showed that (1) endothelin-1 (ET-1) levels, a proinflammatory biomarker for endothelial dysfunction, at the 6-month and 12-month visits were significantly lower compared with baseline ET-1 (P = 0.001 and P0.001, respectively), and (2) low-attenuation noncalcified coronary plaque volume, a predictor for myocardial infarction, at 12-month visit was significantly lower compared with baseline low-attenuation noncalcified coronary plaque volume (P0.05).The findings of this study have not only demonstrated that CM is effective in achieving a sustained reduction in cocaine use, but also provided compelling evidence that reduction in cocaine use leads to quantifiable cardiovascular health benefits, including concurrent decrease in high-risk plaque burden and ET-1, among cocaine users with HIV-associated coronary atherosclerosis.

BACKGROUND: People living with HIV (PLWH) on antiretroviral therapy (ART) are at increased risk of atherosclerotic disease. Abnormal adipose distribution is common in PLWH and may contribute to atherosclerosis. Because coronary artery endothelial function (CEF) is impaired in early atherosclerosis, predicts future cardiovascular events, and is reduced in PLWH, we investigated associations between body fat distribution and CEF in PLWH. SETTING: Prospective cohort study. METHODS: PLWH on stable ART underwent MRI to quantify CEF, measured as change in coronary cross-sectional area (CSA) from rest to that during isometric handgrip exercise, an endothelial-dependent stressor. Abdominal visceral and subcutaneous fat area (axial L4 level) and liver fat fraction were quantified via MRI. Linear regression was used to determine associations between CEF and independent variables. RESULTS: Among 84 PLWH (52±11 years; 33% women), mean CSA change was 0.74±11.7’%, indicating impaired CEF. On univariable regression analysis, CEF was inversely related to waist circumference (R=−0.31, p =0.014), hip circumference (R=−0.27, p =0.037), and subcutaneous fat area (R=−0.25, p =0.031). We did not observe significant relationships between CEF and liver fat fraction, waist/hip ratio, or visceral fat area. On multivariable regression adjusted for age, sex, and race, CEF was associated with waist circumference, hip circumference, subcutaneous fat, and liver fat fraction. CONCLUSION: Waist and hip circumference, and subcutaneous fat area are associated with impaired CEF, an established metric of abnormal vascular health in PLWH on stable ART, and may contribute to the increased rate of heart disease in this population.

Aims Lipoprotein(a) [Lp(a)] levels are generally constant throughout an individual’s lifetime, and current guidelines recommend that a single measurement is sufficient to assess the risk of coronary artery disease (CAD). However, it is unclear whether a single measurement of Lp(a) in individuals with acute myocardial infarction (MI) is indicative of the Lp(a) level six months following the event. Methods and results Lp(a) levels were obtained from individuals with non–ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI) (n = 99) within 24 h of hospital admission and after six months, who were enrolled in two randomized trials of evolocumab and placebo, and in individuals with NSTEMI or STEMI (n = 9) who enrolled in a small observation arm of the two protocols and did not receive study drug, but whose levels were obtained at the same time points. Median Lp(a) levels increased from 53.5 nmol/L (19, 165) during hospital admission to 58.0 nmol/L (14.8, 176.8) six months after the acute infarction (P = 0.02). Subgroup analysis demonstrated no difference in the baseline, six-month, or change between the baseline and six-month Lp(a) values between the STEMI and NSTEMI groups and between the group which received evolocumab and the group that did not. Conclusion This study demonstrated that Lp(a) levels in individuals with acute MI are significantly higher six months after the initial event. Therefore, a single measurement of Lp(a) in the peri-infarction setting is not sufficient to predict the Lp(a)-associated CAD risk in the post-infarction period. Registration Evolocumab in Acute Coronary Syndrome Trial [EVACS I] NCT03515304, Evolocumab in Patients with Acute Myocardial Infarction [EVACS II], NCT04082442

Lipoprotein(a), or Lp(a), levels and the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on Lp(a) during the peri-infarction and early postinfarction period are not well characterized. This study aimed to describe the trajectory of Lp(a), as well as the effect of PCSK9 inhibition on that trajectory during the peri-infarction and early postinfarction period. Lp(a) levels were obtained within 24 hours of hospital admission as well as within 24 hours of hospital discharge and at 30 days from 74 participants who presented with a NSTEMI (troponin I5 ng/ml) or with a STEMI and were enrolled in 2 randomized, double-blind trials of evolocumab and placebo (Evolocumab in Acute Coronary Syndrome [EVACS I]; ClinicalTrials.gov, NCT03515304 and Evolocumab in Patients With STEMI [EVACS II]; ClinicalTrials.gov Identifier: NCT04082442). There was a significant increase from the pretreatment level in the placebo-treated patients, from 64 (41,187) nmol/L to 80 (47, 172) nmol/L at hospital discharge and to 82 (37, 265) at 30 days. This was primarily driven by the results from participants with high Lp(a) at hospital admission (75 nmol/L) in whom the median increase was 28% as compared with a 10% increase in those with pretreatment Lp(a) of75 nmol/L. In contrast, there was no significant change from the pretreatment level in the evolocumab-treated patients regardless of pretreatment Lp(a) levels. In conclusion, Lp(a) rises during the peri-infarction and early postinfarction period in patients with acute myocardial infarction. The increase was prevented by a single dose of subcutaneous evolocumab given within 24 hours of hospital admission.

Background: Mitochondrial DNA copy number (mtDNA-CN) is a surrogate measure of mitochondrial function that is independently associated with increased cardiovascular disease risk. Individuals with obesity and cardiometabolic risk factors have lower mtDNA-CN levels. However, the modifiability of mtDNA-CN following a weight loss intervention has remained largely unexplored. Hypothesis: Bariatric surgery-induced weight loss is associated with longitudinal increases in circulating mtDNA-CN levels. Methods: In the BARI-Heart prospective cohort of bariatric surgery patients, we quantified mtDNA-CN from whole blood samples collected at three visits: 3 to 6 months prior to surgery, 2-4 weeks prior to surgery, and 6 months post-surgery. We used linear mixed models with random effects to assess changes in mtDNA-CN after bariatric surgery, with the pre-surgery visits while awaiting bariatric surgery serving as the control period. We used multivariable linear regression to evaluate the dose-response association between weight loss and change in mtDNA-CN. Results: We included 71 participants (mean age 45 years, 74% female, 88% White). While mtDNA-CN levels did not change significantly during the pre-surgery period (V1 to V2), mtDNA-CN significantly increased after bariatric surgery (V2 to V3) (Figure). In linear mixed models adjusting for age, sex, and smoking, mtDNA-CN was higher after bariatric surgery than immediately prior to bariatric surgery (Table: ß=0.141, p < 0.001). This increase in mtDNA-CN remained significant following further adjustment for changes in cardiometabolic risk factors (ß=0.116, p < 0.01). In linear regression, each 10% greater weight loss was associated with a 1.6% increase in mtDNA-CN. Conclusions: Weight loss via bariatric surgery is associated with significant increases in mtDNA-CN, independent of cardiometabolic risk factors. Improvements in mitochondrial function may mediate some of the cardiovascular benefits of significant weight loss.

Introduction: Adipokine levels are strongly linked to diabetes and metabolic syndrome, with higher adiponectin having protective associations and higher leptin having harmful associations. Little is known about how past changes in adipokine levels relate to current metabolic risk. Methods: Among ARIC Visit 3 (1993-1995) participants, we examined the association of past changes in adiponectin and leptin levels over the 3-year period from ARIC Visit 2 (1990-1992) to Visit 3 with prevalent diabetes and metabolic syndrome at Visit 3. Adipokines were measured using aptamer technology (correlated 0.9x with immunoassay) and analyzed categorically as >50% increase, >50% decrease and 2 ) status. Results: Among 9,287 Visit 3 participants, the mean age was 61 years with 56% female and 19% Black adults. Relative to stable levels, a >50% increase in adiponectin over the past 3 years was associated with higher odds of prevalent diabetes (OR 1.62; 95% CI: 1.29-2.03) and metabolic syndrome (OR 1.45; 95% CI: 1.22-1.72). Past increases in leptin were associated with lower odds of diabetes (OR 0.64; 95% CI: 0.53-0.77) and metabolic syndrome (OR 0.70; 95% CI: 0.62-0.77) (Table). Compared to stable levels, >50% decrease in adiponectin over time was associated with lower likelihood of diabetes and metabolic syndrome. Decreasing leptin had nonsignificant associations. Patterns were largely consistent in obesity stratified analyses, with the principal difference being that adiponectin increase was only associated with increased metabolic risk in those without obesity. Conclusion: Recent changes in adipokine levels are linked to current metabolic status. A past increase in adiponectin has direct associations, while increasing leptin has inverse associations. The underlying mechanisms and implications for metabolic risk in older age should be further studied.

Background: Adipokines mediate many metabolic effects of adipose tissue. While regional body composition is associated with metabolic risk, it is unclear if metabolic risk associations differ for adipokine expression in visceral and subcutaneous tissue and adipokine concentrations in the circulation. Methods: We obtained visceral and subcutaneous fat samples, and pre-surgical serum samples from Geisinger Obesity Registry patients undergoing bariatric surgery. We used real-time PCR to quantify mRNA expression of adipokines (adiponectin, leptin, leptin/adiponectin ratio) in fat samples, and targeted assays (ELISA) to measure serum adipokines. Using multivariable linear regression, we evaluated the individual and combined associations of visceral, subcutaneous and serum adipokines (per-1-SD and tertiles) with a metabolic syndrome (MetS) severity Z-score. Results: 181 participants (mean age 45 years, mean BMI 47 kg/m 2 , 85% female) with available fat and serum samples were included. Visceral, subcutaneous and serum adipokines were all weakly correlated (all ρ Conclusion: Visceral, but not subcutaneous, adipokine expression provides complementary information to serum adipokines on metabolic risk. This indicates significant differences in the physiologic impact of regional adipose tissue and highlights adipokines as a potential target for modifying cardiometabolic risk.

Objectives This study assessed the association of diabetes duration with incident heart failure (HF). Background Diabetes increases HF risk. However, the independent effect of diabetes duration on incident HF is unknown. Methods We included 9,734 participants (mean age 63 years, 58% women, 22% Black) at ARIC (Atherosclerosis Risk In Communities) Visit 4 (1996-1998) without HF or coronary heart disease. We calculated diabetes duration at Visit 4 (baseline), utilizing diabetes status at the first 4 ARIC visits spaced 3 years apart, and self-reported diagnosis date for those with diabetes diagnosed before Visit 1. We used Cox regression to estimate associations of diabetes duration with incident HF, accounting for intercurrent coronary heart disease and other risk factors. We performed analyses stratified by age ( Results Over 22.5 years of follow-up, there were 1,968 HF events. Compared to those without diabetes, HF risk rose with longer diabetes duration, with the highest risk among those with ≥15 y diabetes duration (HR: 2.82; 95% CI: 2.25-3.63). Each 5-year increase in diabetes duration was associated with a 17% (95% CI: 11-22) relative increase in HF risk. Similar results were observed across HF subtypes. The HF and diabetes duration associations were stronger among those aged Conclusions Delaying diabetes onset may augment HF prevention efforts, and therapies to improve HF outcomes might target those with long diabetes duration.

BACKGROUND: Various cardiovascular risk factors are thought to modify atherosclerosis in a similar fashion (ie, by increasing the magnitude of coronary artery disease [CAD]). However, coronary CT angiography allows precision phenotyping of plaque characteristics through use of radiomics. PURPOSE: To assess whether different cardiovascular risk factors have distinctive contributions to the changes in plaque morphologic features over time. MATERIALS AND METHODS: Individuals with or without HIV infection and cocaine use and without cardiovascular symptoms underwent coronary CT angiography between May 2004 and August 2015. In the current HIPAA-compliant study, the effects of cocaine use, HIV infection, and atherosclerotic cardiovascular disease (ASCVD) risk on the temporal changes (mean ± standard deviation, 4.0 years ± 2.3 between CT angiographic examinations) in CAD structure were analyzed by using radiomic analysis. The changes in radiomic features were analyzed by using linear mixed models, with correction for factors that may change plaque structure: high‐sensitivity C‐reactive protein level, statin use, positive family history of CAD, and total plaque volume to account for any potential intrinsic correlation between volume and morphologic features. Clusters among significant radiomic features were identified by using hierarchical clustering. Bonferroni-corrected P values less than .00004 (.05 divided by 1276) were considered to indicate significant differences. RESULTS: Of 1429 participants, 300 with CAD confirmed at coronary CT angiography were randomly selected (mean age, 48 years ± 7; 210 men, 226 people infected with HIV, 174 people who use cocaine) and 1276 radiomic features were quantified for each plaque. Cocaine use was significantly associated with 23.7% (303 of 1276) of the radiomic features, HIV infection was significantly associated with 1.3% (17 of 1276), and elevated ASCVD risk was significantly associated with 8.2% (104 of 1276) (P < .00004 for all). Parameters associated with elevated ASCVD risk or cocaine use and HIV infection did not overlap. There were 13 clusters among the 409 parameters, eight of which were affected only by cocaine use and three of which were affected only by ASCVD risk. CONCLUSION: Radiomics-based precision phenotyping indicated that conventional risk factors, cocaine use, and HIV infection each had different effects on CT angiographic morphologic changes in coronary atherosclerosis over 4 years. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Schoepf and Emrich in this issue.

Although mechanical energy transfer between the heart and arterial system, referred to as arterial-ventricular (AV) coupling, is an important determinant of cardiovascular performance, how AV coupling changes over time within and among individuals as they age has not been fully explored. We studied 129 participants (baseline age 21–96) of the Baltimore Longitudinal Study of Aging, free of clinical CVD. Participants underwent repeated multigated cardiac blood pool scans to estimate left ventricular (LV) volumes (SV, EDV, and ESV). Total systemic vascular resistance (TSVR), total arterial compliance (TAC), effective arterial elastance (Ea), and end-systolic LV elastance (Elv) were calculated using LV volumes and brachial BP measurements; calculated Ea/Elv was the measure of AV coupling. Linear mixed-effects models were used to estimate person-specific rates of change (Change) for each variable. The rate at which Ea increased over time was faster than the rate at which Elv increased, resulting in AV uncoupling (increased Ea/Elv) over time that was significantly greater in women than in men. Loss of arterial compliance was the main determinant of (Ea/Elv)(Change), which was negatively associated with changes in SV and EDV but positively with changes in ESV. Progressive AV uncoupling occurred with aging and was more pronounced in women than men. While Ea change did not differ by sex, Elv increased at a slower rate in women than in men. AV uncoupling was inversely associated with EDV and SV rates of change and a directly associated with an increase in ESV rate of change. Additional studies are needed to explore the functional consequences of AV uncoupling in healthy individuals with respect to the emergence of age-associated clinical cardiovascular diseases, such as heart failure with preserved ejection fraction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-020-00321-x.

Introduction: Obesity is associated with a varying spectrum of metabolic risk, from the metabolically healthy obesity (MHO) phenotype, to metabolically unhealthy obesity (MUO) with the development of metabolic syndrome (MetS) and diabetes (DM). The longitudinal association of metabolic risk with CVD phenotypes (CHD, HF) has not been well characterized. Hypothesis: Persistent MHO is independently associated with heart failure (HF) but not coronary heart disease (CHD), and regression from MUO to MHO mitigates CVD risk. Methods: We conducted a prospective analysis of 10,011 Visit 4 (1996-98) ARIC participants free of HF and CHD (mean age 63, 21% Black, 56% female). Metabolic risk among those with obesity (BMI ≥ 30 kg/m 2 ) was categorized as MHO (no MetS or DM), MUO (MetS present) and MUO with DM, with same categorizations among those without obesity. We used Cox regression models to estimate associations of cross-categories of metabolic risk status at Visit 2 (1990-92) and Visit 4 with risk of HF and CHD after Visit 4 through 12/21/19. (Reference: persistent metabolically healthy normal weight). Results: Between Visits 2 and 4, 56% of those with MHO transitioned to MUO. There were 2212 HF and 1648 CHD events, median follow-up of 20.5 years. Persistent MHO status was associated with increased risk for HF (HR:1.59, 95% CI: 1.19-2.13) but not CHD (HR: 1.08, 95% CI: 0.74-1.58) (Table). Persistent MUO with DM had the highest risk for HF (HR: 5.30, 95% CI: 4.38-6.41) and CHD (HR: 3.77, 95% CI: 3.00-4.74). Among those with MUO at Visit 2, progression to MUO with DM at Visit 4 was linked to greater risk for HF and CHD, while regression to MHO was associated with an attenuated risk for CVD. Similar patterns were seen for those without obesity (data not shown). Conclusions: Transitions in metabolic risk status are common and associated with divergent patterns of CVD risk. Progression from MHO to MUO and even persistent MHO are linked to HF risk, whereas regression from MUO to MHO may attenuate CVD risk. Primordial prevention of obesity is warranted to stave off HF.

High lipoprotein(a) [Lp(a)] levels are associated with the development of atherosclerotic cardiovascular disease (ASCVD) and with calcific aortic valve stenosis (CAVS) both observationally and causally from human genetic studies. The mechanisms are not well characterized but likely involve its role as a carrier of oxidized phospholipids (OxPLs), which are known to be increased in pro-inflammatory states, to induce pro-inflammatory changes in monocytes leading to plaque instability, and to impair vascular endothelial cell function, a driver of acute and recurrent ischemic events. In addition, Lp(a) itself has prothrombotic activity. Current lipid-lowering strategies do not sufficiently lower Lp(a) serum levels. Lp(a)-specific-lowering drugs, targeting apolipoprotein(a) synthesis, lower Lp(a) by up to 90% and are being evaluated in ongoing clinical outcome trials. This review summarizes the current knowledge on the associations of Lp(a) with ASCVD and CAVS, the current role of Lp(a) assessment in the clinical setting, and emerging Lp(a)-specific-lowering therapies.

To develop a general framework to assess temporal changes in lesion morphology on radiological images beyond volumetric changes and to test whether cocaine abstinence changes coronary plaque structure on serial coronary CT angiography (CTA).Chronic cocaine users with human immunodeficiency virus (HIV) infection were prospectively enrolled to undergo cash-based contingency management to achieve cocaine abstinence. Participants underwent coronary CTA at baseline and 6 and 12 months following recruitment. We segmented all coronary plaques and extracted 1103 radiomic features. We implemented weighted correlation network analysis to derive consensus eigen radiomic features (named as different colors) and used linear mixed models and mediation analysis to assess whether cocaine abstinence affects plaque morphology correcting for clinical variables and plaque volumes and whether serum biomarkers causally mediate these changes. Furthermore, we used Bayesian hidden Markov network changepoint analysis to assess the potential rewiring of the radiomic network.Sixty-nine PLWH (median age 55 IQR: 52-59 years, 19% female) completed the study, of whom 26 achieved total abstinence. Twenty consensus eigen radiomic features were derived. Cocaine abstinence significantly affected the pink and cyan eigen features (-0.04 CI: [-0.06; -0.02], p = 0.0009; 0.03 CI: [0.001; 0.04], p = 0.0017, respectively). These effects were mediated through changes in endothelin-1 levels. In abstinent individuals, we observed significant rewiring of the latent radiomic signature network.Using our proposed framework, we found 1 year of cocaine abstinence to significantly change specific latent coronary plaque morphological features and rewire the latent morphologic network above and beyond changes in plaque volumes and clinical characteristics.• We propose a general methodology to decompose the latent morphology of lesions on radiological images using a radiomics-based systems biology approach. • As a proof-of-principle, we show that 1 year of cocaine abstinence results in significant changes in specific latent coronary plaque morphologic features and rewiring of the latent morphologic network above and beyond changes in plaque volumes and clinical characteristics. • We found endothelin-1 levels to mediate these structural changes providing potential pathological pathways warranting further investigation.

BACKGROUND: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF., METHODS: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance P-31 spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice., RESULTS: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling., CONCLUSIONS: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF.

Introduction: Impaired coronary endothelial function (CEF) is a known predictor of cardiovascular (CV) events and occurs in people living with HIV. HIV+ women compared to men have worse CV outcomes, but prior studies include very few women. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to endothelial cell inflammation and is elevated in HIV+ men. CEF and PCSK9 are not well studied in women with HIV. Hypothesis: We hypothesize that HIV+ women have worse CEF and higher PCSK9 levels compared to risk factor matched HIV- women, and that CEF will be associated with PCSK9 in HIV+ women, similar to prior findings in HIV+ men. Methods: A total of 34 HIV+ women and 75 HIV+ men on stable highly active antiretroviral therapy and 17 HIV- women and 8 HIV- men underwent MRI to measure CEF (%change in coronary artery cross-sectional area (%CSA) and coronary blood flow (CBF) during isometric handgrip exercise, an endothelial dependent stressor). Serum PCSK9 samples were obtained on the day of MRI. Comparisons were performed using student’s t-test for normally distributed and Kruskal-Wallis test for data not normally distributed. Robust regression was used for the association of PCSK9 with CEF. Results: CEF was significantly reduced in HIV+ women compared to age-, race- and BMI-matched HIV- women (p Conclusions: Coronary endothelial dysfunction is present among HIV+ women as compared to risk factor matched HIV- women. HIV+ women have similarly depressed CEF as HIV+ men. With HIV, PCSK9 is not significantly associated with CEF, suggesting potential alternative mechanisms of impaired CEF in men and women with HIV.

Our objective was to assess whether human immunodeficiency virus (HIV)-infection directly or indirectly promotes the progression of clinical characteristics of coronary artery disease (CAD). 300 African Americans with asymptomatic CAD (210 male; age: 48.0 ± 7.2 years; 226 HIV-infected) who underwent coronary CT angiography at two time points (mean follow-up: 4.0 ± 2.3 years) were randomly selected from 1429 participants of a prospective epidemiological study between May 2004 and August 2015. We calculated Agatston-scores, number of coronary plaques and segment stenosis score (SSS). Linear mixed models were used to assess the effects of HIV-infection, atherosclerotic cardiovascular disease (ASCVD) risk, years of cocaine use on CAD. There was no significant difference in annual progression rates between HIV-infected and—uninfected regarding Agatston-scores (10.8 ± 25.1/year vs. 7.2 ± 17.8/year, p = 0.17), the number of plaques (0.2 ± 0.3/year vs. 0.3 ± 0.5/year, p = 0.11) or SSS (0.5 ± 0.8/year vs. 0.5 ± 1.3/year, p = 0.96). Multivariately, HIV-infection was not associated with Agatston-scores (8.3, CI: [− 37.2–53.7], p = 0.72), the number of coronary plaques (− 0.1, CI: [− 0.5–0.4], p = 0.73) or SSS (− 0.1, CI: [− 1.0–0.8], p = 0.84). ASCVD risk scores and years of cocaine-use significantly increased all CAD outcomes among HIV-infected individuals, but not among HIV-uninfected. Importantly, none of the HIV-medications were associated with any of the CAD outcomes. HIV-infection is not directly associated with CAD and therefore HIV-infected are not destined to have worse CAD profiles. However, HIV-infection may indirectly promote CAD progression as risk factors may have a more prominent role in the acceleration of CAD in these patients.

Age-related differences in stem-cell potency contribute to variable outcomes in clinical stem cell trials. To help understand the effect of age on stem cell potency, bone marrow-derived mesenchymal stem cells (MSCs) were isolated from young (6 weeks) and old (18–24 months) mice. HUVEC tubule formation (TF) induced by the old and young MSCs and ELISA of conditioned media were compared to one another, and to old MSCs after 7 d in indirect co-culture with young MSCs. Old MSCs induced less TF than did young (1.56 ± 0.11 vs 2.38 ± 0.17, p = 0.0003) and released lower amounts of VEGF (p = 0.009) and IGF1 (p = 0.037). After 7 d in co-culture with young MSCs, TF by the old MSCs significantly improved (to 2.09 ± 0.18 from 1.56 ± 0.11; p = 0.013), and was no longer different compared to TF from young MSCs (2.09 ± 0.18 vs 2.38 ± 0.17; p = 0.27). RNA seq of old MSCs, young MSCs, and old MSCs following co-culture with young MSCs revealed that the age-related differences were broadly modified by co-culture, with the most significant changes associated with lysosomal pathways. These results indicate that the age-associated decreased paracrine-mediated effects of old MSCs are improved following indirect co-culture with young MSC. The observed effect is associated with broad transcriptional modification, suggesting potential targets to both assess and improve the therapeutic potency of stem cells from older patients.

With the aging of the world's population, a large proportion of patients seen in cardiovascular practice are older adults, but many patients also exhibit signs of physical frailty. Cardiovascular disease and frailty are interdependent and have the same physiological underpinning that predisposes to the progression of both disease processes. Frailty can be defined as a phenomenon of increased vulnerability to stressors due to decreased physiological reserves in older patients and thus leads to poor clinical outcomes after cardiovascular insults. There are various pathophysiologic mechanisms for the development of frailty: cognitive decline, physical inactivity, poor nutrition, and lack of social supports; these risk factors provide opportunity for various types of interventions that aim to prevent, improve, or reverse the development of frailty syndrome in the context of cardiovascular disease. There is no compelling study demonstrating a successful intervention to improve a global measure of frailty. Emerging data from patients admitted with heart failure indicate that interventions associated with positive outcomes on frailty and physical function are multidimensional and include tailored cardiac rehabilitation. Contemporary cardiovascular practice should actively identify patients with physical frailty who could benefit from frailty interventions and aim to deliver these therapies in a patient-centered model to optimize quality of life, particularly after cardiovascular interventions.

Older adults ≥75 years of age carry an increased risk of mortality after ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock.The purpose of this study was to examine the use of percutaneous coronary intervention (PCI) in older adults with STEMI and shock and its influence on in-hospital mortality.We used a large publicly available all-payer inpatient health care database sponsored by the Agency for Healthcare Research and Quality between 1999 and 2013. The primary outcome was in-hospital mortality. The influence of PCI on in-hospital mortality was assessed by quintiles of propensity score (PS).Of the 317,728 encounters with STEMI and shock in the United States, 111,901 (35%) were adults age ≥75 years. Of these, 53% were women and 83% were Caucasians. The median number of chronic conditions was 8 (interquartile range: 6 to 10). The diagnosis of STEMI and cardiogenic shock in older patients decreased significantly over time (proportion of older adults with STEMI and shock: 1999: 42% vs. 2013: 29%). Concomitantly, the rate of PCI utilization in older adults increased (1999: 27% vs. 2013: 56%, p 0.001), with declining in-hospital mortality rates (1999: 64% vs. 2013: 46%; p 0.001). Utilizing PS matching methods, PCI was associated with a lower risk of in-hospital mortality across quintiles of propensity score (Mantel-Haenszel odds ratio: 0.48; 95% confidence interval [CI]: 0.45 to 0.51). This reduction in hospital mortality risk was seen across the 4 different U.S. census bureau regions (adjusted odds ratio: Northeast: 0.41; 95% CI: 0.36 to 0.47; Midwest: 0.49; 95% CI: 0.42 to 0.57; South: 0.51; 95% CI: 0.46 to 0.56; West: 0.46; 95% CI: 0.41 to 0.53).This large and contemporary analysis shows that utilization of PCI in older adults with STEMI and cardiogenic shock is increasing and paralleled by a substantial reduction in mortality. Although clinical judgment is critical, older adults should not be excluded from early revascularization based on age in the absence of absolute contraindications.