Sarcopenia and Cardiovascular Diseases.

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.

Longitudinal decline in peak V̇o2 with aging in a healthy population is associated with a reduction in peripheral oxygen utilization but not in cardiac output.

Aging is associated with a significant decline in aerobic capacity assessed by maximal exercise oxygen consumption (V̇o2max). The relative contributions of the specific V̇o2 components driving this decline, namely cardiac output (CO) and arteriovenous oxygen difference (A - V)O2, remain unclear. We examined this issue by analyzing data from 99 community-dwelling participants (baseline age: 21-96 yr old; average follow-up: 12.6 yr old) from the Baltimore Longitudinal Study of Aging, free of clinical cardiovascular disease. V̇o2peak, a surrogate of V̇o2max, was used to assess aerobic capacity during upright cycle ergometry. Peak exercise left ventricular volumes, heart rate, and CO were estimated using repeated gated cardiac blood pool scans. The Fick equation was used to calculate (A - V)O2diff,peak from COpeak and V̇o2peak. In unadjusted models, V̇o2peak, (A - V)O2diff,peak, and COpeak declined longitudinally over time at steady rates with advancing age. In multiple linear regression models adjusting for baseline values and peak workload, however, steeper declines in V̇o2peak and (A - V)O2diff,peak were observed with advanced entry age but not in COpeak. The association between the declines in V̇o2peak and (A - V)O2diff,peak was stronger among those ≥50 yr old compared with their younger counterparts, but the difference between the two age groups did not reach statistical significance. These findings suggest that age-associated impairment of peripheral oxygen utilization during maximal exercise poses a stronger limitation on peak V̇o2 than that of CO. Future studies examining interventions targeting the structure and function of peripheral muscles and their vasculature to mitigate age-associated declines in (A - V)O2diff are warranted.NEW & NOTEWORTHY The age-associated decline in aerobic exercise performance over an average of 13 yr in community-dwelling healthy individuals is more closely associated with decreased peripheral oxygen utilization rather than decreased cardiac output. This association was more evident in older than younger individuals. These findings suggest that future studies with larger samples examine whether these associations vary across the age range and whether the decline in cardiac output plays a greater role earlier in life. In addition, studies focused on determinants of peripheral oxygen uptake by exercising muscle may guide the selection of preventive strategies designed to maintain physical fitness with advancing age.

Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part one: Pleiotropic pro-atherosclerotic effects of PCSK9.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in lipid metabolism, but recent evidence suggests that it may have broader implications due to its diverse tissue expression. OBJECTIVE: This review aims to explore the multifaceted functions of PCSK9, highlighting its pro-atherosclerotic effects, including its impact on circulating lipoprotein variables, non-low-density lipoprotein receptors, and various cell types involved in atherosclerotic plaque development. CONCLUSIONS: PCSK9 exhibits diverse roles beyond lipid metabolism, potentially contributing to atherosclerosis through multiple pathways. Understanding these mechanisms could offer new insights into therapeutic strategies targeting PCSK9 for cardiovascular disease management.

Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part two: Current and emerging concepts in the clinical use of PCSK9 inhibition.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a novel class of drugs with cardioprotective effects through their lipid-lowering effects. OBJECTIVE: This review aims to discuss existing and novel strategies of PCSK9 inhibition, providing an overview of established randomized controlled trials and ongoing outcome trials that assess the efficacy and long-term safety of PCSK9 inhibitors. It also explores the evolving role of PCSK9 beyond lipid metabolism and outlines the pleiotropic actions of PCSK9 inhibition in various disorders and future directions including novel strategies to target PCSK9. CONCLUSION: PCSK9 inhibition shows promise not only in lipid metabolism but also in other disease processes, including atherosclerotic plaque remodeling, acute coronary syndrome, stroke, inflammation, and immune response.

Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.

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 31P 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. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Coronary artery endothelial function and aging in people with HIV and HIV-negative individuals.

Coronary artery disease (CAD) is a common comorbidity in people with human immunodeficiency virus (HIV) (PWH) and impaired coronary endothelial function (CEF) plays a central role in the pathogenesis of CAD. Age-related impaired CEF among PWH, however, is not well characterized. We investigated the association between CEF and age in males and females with and without HIV using 3-T magnetic resonance imaging (MRI). We measured the changes in coronary cross-sectional area (CSA) and coronary blood flow during isometric handgrip exercise (IHE), an established endothelial-dependent stressor with smaller increases in CSA and coronary blood flow indicative of impaired CEF. We included 106 PWH and 82 individuals without HIV. Differences in demographic and clinical characteristics between PWH and individuals without HIV were explored using Pearson's χ2 test for categorical variables and Welch's t test for continuous variables. Linear regression models were used to examine the association between CEF and age. CEF was significantly lower in PWH as compared with individuals without HIV. Coronary endothelial dysfunction was also present at younger ages in PWH than in the individuals without HIV and there were significant differences in CEF between the PWH and individuals without HIV across age groups. Among the individuals without HIV, the percent changes in CSA were inversely related to age in unadjusted and adjusted models. There was no significant association between CEF and age in PWH. To the best of our knowledge, this is the first study to examine the relationship between age and CEF in PWH, and our results suggest that factors other than age significantly impair CEF in PWH across the life span.NEW & NOTEWORTHY This is the first study to examine the relationship between age and coronary endothelial function (CEF) in people with human immunodeficiency virus (HIV) (PWH). CEF was assessed using magnetic resonance imaging (MRI) in people with and without HIV. Although age and CEF were significantly inversely related in individuals without HIV, there was no association between age and CEF in PWH.

Diabetes Duration and Subclinical Myocardial Injury: The Atherosclerosis Risk in Communities Study (ARIC).

BACKGROUND: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT). METHODS: We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used multinomial logistic regression to determine the association of diabetes duration with increased (≥14 ng/L) or detectable (≥6 ng/L) Visit 4 hs-cTnT, relative to undetectable hs-cTnT, adjusted for demographics and cardiovascular risk factors. RESULTS: The prevalence of increased Visit 4 hs-cTnT was higher in persons with longer diabetes duration, from 12% for those with diabetes 0 to <5 years up to 31% among those with diabetes for ≥15 years (P for trend <0.0001). New onset diabetes at Visit 4 was associated with 1.92× higher relative risk (95% CI, 1.27-2.91) of increased hs-cTnT than no diabetes. Longer diabetes duration was associated with greater myocardial injury, with duration ≥15 years associated with 9.29× higher risk (95% CI, 5.65-15.29) for increased hs-cTnT and 2.07× (95% CI, 1.24-3.16) for detectable hs-cTnT, compared to no diabetes. CONCLUSIONS: Longer diabetes duration is strongly associated with subclinical myocardial injury. Interventional studies are needed to assess whether the prevention and delay of diabetes onset can mitigate early myocardial damage.

Deep learning-based atherosclerotic coronary plaque segmentation on coronary CT angiography.

OBJECTIVES: Volumetric evaluation of coronary artery disease (CAD) allows better prediction of cardiac events. However, CAD segmentation is labor intensive. Our objective was to create an open-source deep learning (DL) model to segment coronary plaques on coronary CT angiography (CCTA). METHODS: Three hundred eight individuals' 894 CCTA scans with 3035 manually segmented plaques by an expert reader (considered as ground truth) were used to train (186/308, 60%), validate (tune, 61/308, 20%), and test (61/308, 20%) a 3D U-net model. We also evaluated the model on an external test set of 50 individuals with vulnerable plaques acquired at a different site. Furthermore, we applied transfer learning on 77 individuals' data and re-evaluated the model's performance using intra-class correlation coefficient (ICC). RESULTS: On the test set, DL outperformed the currently used minimum cost approach method to quantify total: ICC: 0.88 [CI: 0.85-0.91] vs. 0.63 [CI: 0.42-0.76], noncalcified: 0.84 [CI: 0.80-0.88] vs. 0.45 [CI: 0.26-0.59], calcified: 0.99 [CI: 0.98-0.99] vs. 0.96 [CI: 0.94-0.97], and low attenuation noncalcified: 0.25 [CI: 0.13-0.37] vs. -0.01 [CI: -0.13 to 0.11] plaque volumes. On the external dataset, substantial improvement was observed in DL model performance after transfer learning, total: 0.62 [CI: 0.01-0.84] vs. 0.94 [CI: 0.87-0.97], noncalcified: 0.54 [CI: -0.04 to 0.80] vs. 0.93 [CI: 0.86-0.96], calcified: 0.91 [CI:0.85-0.95] vs. 0.95 [CI: 0.91-0.97], and low attenuation noncalcified 0.48 [CI: 0.18-0.69] vs. 0.86 [CI: 0.76-0.92]. CONCLUSIONS: Our open-source DL algorithm achieved excellent agreement with expert CAD segmentations. However, transfer learning may be required to achieve accurate segmentations in the case of different plaque characteristics or machinery. KEY POINTS: • Deep learning 3D U-net model for coronary segmentation achieves comparable results with expert readers' volumetric plaque quantification. • Transfer learning may be needed to achieve similar results for other scanner and plaque characteristics. • The developed deep learning algorithm is open-source and may be implemented in any CT analysis software.

Temporal assessment of lesion morphology on radiological images beyond lesion volumes-a proof-of-principle study.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. KEY POINTS: • 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.

Frailty and cardiovascular outcomes in the National Health and Aging Trends Study.

AIMS: Physical frailty is a commonly encountered geriatric syndrome among older adults without coronary heart disease (CHD). The impact of frailty on the incidence of long-term cardiovascular outcomes is not known.We aimed to evaluate the long-term association of frailty, measured by the Fried frailty phenotype, with all-cause-mortality and MACE among older adults without a history of CHD at baseline in the National Health and Aging Trends Study. METHODS AND RESULTS: We used the National Health and Aging Trends Study, a prospective cohort study linked to a Medicare sample. Participants with a prior history of CHD were excluded. Frailty was measured during the baseline visit using the Fried physical frailty phenotype. Cardiovascular outcomes were assessed during a 6-year follow-up.Of the 4656 study participants, 3259 (70%) had no history of CHD 1 year prior to their baseline visit. Compared to those without frailty, subjects with frailty were older (mean age 82.1 vs. 75.1 years, P < 0.001), more likely to be female (68.3% vs. 54.9%, P < 0.001), and belong to an ethnic minority. The prevalence of hypertension, falls, disability, anxiety/depression, and multimorbidity was much higher in the frail and pre-frail than the non-frail participants. In a Cox time-to-event multivariable model and during 6-year follow-up, the incidences of death and of each individual cardiovascular outcomes were all significantly higher in the frail than in the non-frail patients including major adverse cardiovascular event (MACE) [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.53, 2.06], death (HR 2.70, 95% CI 2.16, 3.38), acute myocardial infarction (HR 1.95, 95% CI 1.31, 2.90), stroke (HR 1.71, 95% CI 1.34, 2.17), peripheral vascular disease (HR 1.80, 95% CI 1.44, 2.27), and coronary artery disease (HR 1.35, 95% CI 1.11, 1.65). CONCLUSION: In patients without CHD, frailty is a risk factor for the development of MACEs. Efforts to identify frailty in patients without CHD and interventions to limit or reverse frailty status are needed and, if successful, may limit subsequent adverse cardiovascular events.

Contribution of Risk Factors to the Development of Coronary Atherosclerosis as Confirmed via Coronary CT Angiography: A Longitudinal Radiomics-based Study.

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.

Cardiovascular risk factors and illicit drug use may have a more profound effect on coronary atherosclerosis progression in people living with HIV.

OBJECTIVES: To assess whether HIV infection directly or indirectly promotes coronary artery disease (CAD) volume progression in a longitudinal study of African Americans. METHODS: We randomly selected 300 individuals with subclinical CAD (210 male; age: 48.0 ± 7.2 years; 226 HIV infected, 174 cocaine users) from 1429 cardiovascularly asymptomatic participants of a prospective epidemiological study between May 2004 and August 2015. Individuals underwent coronary CT angiography at two time points (mean follow-up: 4.0 ± 2.3 years). We quantified noncalcified (NCP: -100-350HU), low-attenuation noncalcified (LA-NCP: -100-30HU), and calcified (CP: ≥ 351 HU) plaque volumes. Linear mixed models were used to assess the effects of HIV infection, atherosclerotic cardiovascular disease (ASCVD) risk, and years of cocaine use on plaque volumes. RESULTS: There was no significant difference in annual progression rates between HIV-infected and HIV-uninfected regarding NCP (8.7 [IQR: 3.0-19.4] mm3/year vs. 4.9 [IQR: 1.5-18.3] mm3/year, p = 0.14), LA-NCP (0.2 [IQR: 0.0-1.6] mm3/year vs. 0.2 [IQR: 0.0-0.9] mm3/year, p = 0.07) or CP volumes (0.3 [IQR: 0.0-3.4] mm3/year vs. 0.1 [IQR: 0.0-3.2] mm3/year, p = 0.30). Multivariately, HIV infection was not associated with NCP (-6.9mm3, CI: [-32.8-19.0], p = 0.60), LA-NCP (-0.1mm3, CI: [-2.6-2.4], p = 0.92), or CP volumes (-0.3mm3, CI: [-9.3-8.6], p = 0.96). However, each percentage of ASCVD and each year of cocaine use significantly increased total, NCP, and CP volumes among HIV-infected individuals, but not among HIV-uninfected. Importantly, none of the HIV-associated medications had any effect on plaque volumes (p > 0.05 for all). CONCLUSIONS: The more profound adverse effect of risk factors in HIV-infected individuals may explain the accelerated progression of CAD in these people, as HIV infection was not independently associated with any coronary plaque volume. KEY POINTS: • Human immunodeficiency virus-infected individuals may have similar subclinical coronary artery disease, as the infection is not independently associated with coronary plaque volumes. • However, cardiovascular risk factors and illicit drug use may have a more profound effect on atherosclerosis progression in those with human immunodeficiency virus infection, which may explain the accelerated progression of CAD in these people. • Nevertheless, through rigorous prevention and abstinence from illicit drugs, these individuals may experience similar cardiovascular outcomes as -uninfected individuals.

Sarcopenia and health-related quality of life in older adults after transcatheter aortic valve replacement.

BACKGROUND: Skeletal muscle wasting, or sarcopenia, affects a significant proportion of patients undergoing transcatheter aortic valve replacement (TAVR). However, its influence on post-TAVR recovery and 1-year health-related quality of life (HR-QOL) remains unknown. We examined the relationship between skeletal muscle index (SMI), post-TAVR length of hospital stay (LOS), and 1-year QOL. METHODS: The study sample consisted of 300 consecutive patients undergoing TAVR from 2012 to 2018 who had pre-TAVR computed tomographic scans suitable for analysis of body composition. Skeletal muscle mass was quantified as cm2 of skeletal mass per m2 of body surface area from the cross-sectional computed tomographic image at the third lumbar vertebra. Sarcopenia was defined using established sex-specific cutoffs (women: SMI < 39 cm2/m2; men: < 55 cm2/m2). Multivariable linear regression analysis was used to determine the relationship between SMI, LOS, and HR-QOL using the Kansas City Cardiomyopathy Questionnaire. RESULTS: Sarcopenia was present in most (59%) patients and associated with older age (82 vs 76 years; P < .001) and lower body mass index (27 vs 33 kg/m2; P < .001). There were no other differences in baseline clinical or echocardiographic characteristics among the 4 quartiles of SMI. SMI was positively correlated with LOS and 1-year QOL. After adjusting for age, gender, race, and body mass index, SMI remained a significant predictor of both LOS (P = .01) and 1-year QOL (P = .012). For every 10 cm2/m2 higher SMI, there was an 8-point increase in Kansas City Cardiomyopathy Questionnaire score, a difference that is clinically meaningful. CONCLUSIONS: Sarcopenia is prevalent in TAVR patients. Higher SMI is associated with shorter LOS and better 1-year HR-QOL. To achieve optimal TAVR benefits, further study into how body composition influences post-TAVR recovery and durable improvement in QOL is warranted.

Six-Year Changes in Physical Activity and the Risk of Incident Heart Failure: ARIC Study.

BACKGROUND: Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown. METHODS: We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993-1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987-1989) and third ARIC visits and HF risk. RESULTS: During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63-0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ≈30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82-0.96). CONCLUSIONS: Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF.

The influence of febuxostat on coronary artery endothelial dysfunction in patients with coronary artery disease: A phase 4 randomized, placebo-controlled, double-blind, crossover trial.

BACKGROUND: The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial. METHODS: CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period. RESULTS: Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P<.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods. CONCLUSIONS: In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.

Weight History and Subclinical Myocardial Damage.

BACKGROUND: Excess weight is associated with subclinical myocardial damage, as reflected by high-sensitivity cardiac troponin T (hs-cTnT) concentrations, which portends high heart failure risk. However, the association between weight history and myocardial damage is unknown. METHODS: We evaluated 9062 Atherosclerosis Risk in Communities (ARIC) visit 4 (1996-1999) participants with a body mass index (BMI) ≥ 18.5 kg/m2 and no previous cardiovascular disease. We cross-tabulated visit 4 ("current") BMI categories of normal weight, overweight, and obese with those at visit 1 (1987-1989) and with BMI categories calculated from self-reported weight at age 25 years. Duration of obesity was calculated in years. A cumulative weight measure of "excess BMI-years" was also calculated [product of mean BMI (centered at 25 kg/m2) over all ARIC time points × follow-up duration]. We used logistic regression to estimate associations of weight history metrics with increased hs-cTnT (≥14 ng/L) at visit 4. RESULTS: Overall, 623 individuals (7%) had increased hs-cTnT at visit 4. Within each current BMI category, previous excess weight was associated with increased hs-cTnT, with the strongest associations for those with past and current obesity [odds ratio (OR), 3.85; 95% CI, 2.51-5.90 for obesity at age 25 years and visit 4]. Each 10-year longer obesity duration was associated with increased hs-cTnT (OR, 1.26; 95% CI, 1.17-1.35). Each 100 higher excess BMI-years was also progressively associated with increased hs-cTnT (OR, 1.21; 95% CI, 1.14-1.27). CONCLUSIONS: Previous obesity and greater cumulative weight from young adulthood increase the likelihood of myocardial damage, indicating long-term toxic effects of adiposity on the myocardium and the need for weight maintenance strategies targeting the entire life span.

Cardiac work is related to creatine kinase energy supply in human heart failure: a cardiovascular magnetic resonance spectroscopy study.

BACKGROUND: It has been hypothesized that the supply of chemical energy may be insufficient to fuel normal mechanical pump function in heart failure (HF). The creatine kinase (CK) reaction serves as the heart's primary energy reserve, and the supply of adenosine triphosphate (ATP flux) it provides is reduced in human HF. However, the relationship between the CK energy supply and the mechanical energy expended has never been quantified in the human heart. This study tests whether reduced CK energy supply is associated with reduced mechanical work in HF patients. METHODS: Cardiac mechanical work and CK flux in W/kg, and mechanical efficiency were measured noninvasively at rest using cardiac pressure-volume loops, magnetic resonance imaging and phosphorus spectroscopy in 14 healthy subjects and 27 patients with mild-to-moderate HF. RESULTS: In HF, the resting CK flux (126 ± 46 vs. 179 ± 50 W/kg, p < 0.002), the average (6.8 ± 3.1 vs. 10.1 ± 1.5 W/kg, p  <0.001) and the peak (32 ± 14 vs. 48 ± 8 W/kg, p < 0.001) cardiac mechanical work-rates, as well as the cardiac mechanical efficiency (53% ± 16 vs. 79% ± 3, p < 0.001), were all reduced by a third compared to healthy subjects. In addition, cardiac CK flux correlated with the resting peak and average mechanical power (p < 0.01), and with mechanical efficiency (p = 0.002). CONCLUSION: These first noninvasive findings showing that cardiac mechanical work and efficiency in mild-to-moderate human HF decrease proportionately with CK ATP energy supply, are consistent with the energy deprivation hypothesis of HF. CK energy supply exceeds mechanical work at rest but lies within a range that may be limiting with moderate activity, and thus presents a promising target for HF treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00181259 .

Long-term HIF-1α transcriptional activation is essential for heat-acclimation-mediated cross tolerance: mitochondrial target genes.

An important adaptive feature of heat acclimation (HA) is the induction of cross tolerance against novel stressors (HACT) Reprogramming of gene expression leading to enhanced innate cytoprotective features by attenuating damage and/or enhancing the response of "help" signals plays a pivotal role. Hypoxia-inducible factor-1α (HIF-1α), constitutively upregulated by HA (1 mo, 34°C), is a crucial transcription factor in this program, although its specific role is as yet unknown. By using a rat HA model, we studied the impact of disrupting HIF-1α transcriptional activation [HIF-1α:HIF-1ß dimerization blockade by intraperitoneal acriflavine (4 mg/kg)] on its mitochondrial gene targets [phosphoinositide-dependent kinase-1 (PDK1), LON, and cyclooxygenase 4 (COX4) isoforms] in the HA rat heart. Physiological measures of cardiac HACT were infarct size after ischemia-reperfusion and time to rigor contracture during hypoxia in cardiomyocytes. We show that HACT requires transcriptional activation of HIF-1α throughout the course of HA and that this activation is accompanied by two metabolic switches: 1) profound upregulation of PDK1, which reduces pyruvate entry into the mitochondria, consequently increasing glycolytic lactate production; 2) remodeling of the COX4 isoform ratio, inducing hypoxic-tolerant COX4.2 dominance, and optimizing electron transfer and possibly ATP production during the ischemic and hypoxic insults. LON and COX4.2 transcript upregulation accompanied this shift. Loss of HACT despite elevated expression of the cytoprotective protein heat shock protein-72 concomitantly with disrupted HIF-1α dimerization suggests that HIF-1α is essential for HACT. The role of a PDK1 metabolic switch is well known in hypoxia acclimation but not in the HA model and its ischemic setting. Remodeling of COX4 isoforms by environmental acclimation is a novel finding.

Local coronary wall eccentricity and endothelial function are closely related in patients with atherosclerotic coronary artery disease.

BACKGROUND: Coronary endothelial function (CEF) in patients with coronary artery disease (CAD) varies among coronary segments in a given patient. Because both coronary vessel wall eccentricity and coronary endothelial dysfunction are predictors of adverse outcomes, we hypothesized that local coronary endothelial dysfunction is associated with local coronary artery eccentricity. METHODS: We used 3 T coronary CMR to measure CEF as changes in coronary cross-sectional area (CSA) and coronary blood flow (CBF) during isometric handgrip exercise (IHE), a known endothelial-dependent stressor, in 29 patients with known CAD and 16 healthy subjects. Black-blood MRI quantified mean coronary wall thickness (CWT) and coronary eccentricity index (EI) and CEF was determined in the same segments. RESULTS: IHE-induced changes in CSA and CBF in healthy subjects (10.6 ± 6.6% and 38.3 ± 29%, respectively) were greater than in CAD patients 1.3 ± 7.7% and 6.5 ± 19.6%, respectively, p < 0.001 vs. healthy for both measures), as expected. Mean CWT and EI in healthy subjects (1.1 ± 0.3 mm 1.9 ± 0.5, respectively) were less than those in CAD patients (1.6 ± 0.4 mm, p < 0.0001; and 2.6 ± 0.6, p = 0.006 vs. healthy). In CAD patients, we observed a significant inverse relationship between stress-induced %CSA change and both EI (r = -0.60, p = 0.0002), and CWT (r = -0.54, p = 0.001). Coronary EI was independently and significantly related to %CSA change with IHE even after controlling for mean CWT (adjusted r = -0.69, p = 0.0001). For every unit increase in EI, coronary CSA during IHE is expected to change by -6.7 ± 9.4% (95% confidence interval: -10.3 to -3.0, p = 0.001). CONCLUSION: There is a significant inverse and independent relationship between coronary endothelial macrovascular function and the degree of local coronary wall eccentricity in CAD patients. Thus anatomic and physiologic indicators of high-risk coronary vascular pathology are closely related. The noninvasive identification of coronary eccentricity and its relationship with underlying coronary endothelial function, a marker of vascular health, may be useful in identifying high-risk patients and culprit lesions.