Research Opportunities in Stroke Prevention for Atrial Fibrillation: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study.

Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.

Chronic wound repair and healing in older adults: current status and future research.

The incidence of chronic wounds is increased among older adults, and the impact of chronic wounds on quality of life is particularly profound in this population. It is well established that wound healing slows with age. However, the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The impact of age and accompanying multi-morbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables, lack of standardization in data collection, and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this paper, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify key research questions to guide future study of age-associated changes in chronic wound healing.

Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study.

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-ß (TGF-ß) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-ß and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-ß and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-ß and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-ß and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-ß and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS).

BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited. METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor ß1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years. RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 µg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor ß1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk. CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.

Cardiovascular Disease in the Older Adult: Where Are We 4 Decades Later?

The 1986 Bethesda Conference on Cardiovascular Disease (CVD) in the Elderly, co-chaired by Drs. Nanette Wenger, Frank Marcus, and Robert O'Rourke, delineated the anticipated social, political, ethical, economic and technological impact of an aging population on the incidence, prevalence, and management of CVD in the US and worldwide. In the ensuing 4 decades, older patients have come to comprise an increasingly large proportion of the CVD population, and there has been an explosion of research in all aspects of CVD affecting older adults. Correspondingly, Geriatric Cardiology is now an established field within cardiovascular medicine. In this communication, we provide a focused update on intersections between CVD and geriatrics from basic science to clinical practice, a review of major advances in diagnosis and treatment of older adults with CVD, and a preview of future research directions in the still evolving field of geriatric cardiology.

Associations of total and high-molecular-weight adiponectin with all-cause and cardiovascular mortality in older persons: the Cardiovascular Health Study.

BACKGROUND: Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk). METHODS AND RESULTS: In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality. CONCLUSIONS: Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults.

Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study.

BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD). METHODS AND RESULTS: Among 3710 community-living individuals ≥ 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 ± 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01). CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those ≥ 75 years of age.

Association of body mass index with peripheral arterial disease in older adults: the Cardiovascular Health Study.

The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)(2)) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥ 65 years at baseline (1989-1990 or 1992-1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.

Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women.

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥ 30 kg/m²) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m² was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

Succeeding in Aging Research During the Pandemic: Strategies for Fellows and Junior Faculty.

Fellows and junior faculty conducting aging research have encountered substantial new challenges during the COVID-19 pandemic. They report that they have been uncertain how and whether to modify existing research studies, have faced difficulties with job searches, and have struggled to balance competing pressures including greater clinical obligations and increased responsibilities at home. Many have also wondered if they should shift gears and make COVID-19 the focus of their research. We asked a group of accomplished scientists and mentors to grapple with these concerns and to share their thoughts with readers of this journal.

Increasing Use of Cardiac and Pulmonary Rehabilitation in Traditional and Community Settings: OPPORTUNITIES TO REDUCE HEALTH CARE DISPARITIES.

Although both cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) are recommended by clinical practice guidelines and covered by most insurers, they remain severely underutilized. To address this problem, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the National Institute on Aging (NIA), developed Funding Opportunity Announcements (FOAs) in late 2017 to support phase II clinical trials to increase the uptake of CR and PR in traditional and community settings. The objectives of these FOAs were to (1) test strategies that will lead to increased use of CR and PR in the US population who are eligible based on clinical guidelines; (2) test strategies to reduce disparities in the use of CR and PR based on age, gender, race/ethnicity, and socioeconomic status; and (3) test whether increased use of CR and PR, whether by traditional center-based or new models, is accompanied by improvements in relevant clinical and patient-centered outcomes, including exercise capacity, cardiovascular and pulmonary risk factors, and quality of life. Five NHLBI grants and a single NIA grant were funded in the summer of 2018 for this CR/PR collaborative initiative. A brief description of the research to be developed in each grant is provided.

Cardiovascular Biomarkers and Imaging in Older Adults: JACC Council Perspectives.

Whereas the burgeoning population of older adults is intrinsically vulnerable to cardiovascular disease, the utility of many management precepts that were validated in younger adults is often unclear. Whereas biomarker- and imaging-based tests are a major part of cardiovascular disease care, basic assumptions about their use and efficacy cannot be simply extrapolated to many older adults. Biology, physiology, and body composition change with aging, with important influences on cardiovascular disease testing procedures and their interpretation. Furthermore, clinical priorities of older adults are more heterogeneous, potentially undercutting the utility of testing data that are collected. The American College of Cardiology and the National Institutes on Aging, in collaboration with the American Geriatrics Society, convened, at the American College of Cardiology Heart House, a 2-day multidisciplinary workshop, "Diagnostic Testing in Older Adults with Cardiovascular Disease," to address these issues. This review summarizes key concepts, clinical limitations, and important opportunities for research.

Use of Functional Assessment to Define Therapeutic Goals and Treatment.

This article summarizes the presentations and discussions from a workshop, "Using Functional Assessment to Define Therapeutic Goals and Treatment," which took place on November 30 to December 1, 2017. This workshop brought together transdisciplinary leaders in the fields of function and disability and clinical investigators engaged in research on geriatric populations to outline opportunities and challenges for incorporating measures of function in clinical research. Topics addressed included reliable and clinically feasible measures of function and key domains of health (eg, musculoskeletal, cognitive, and sensory) that are most strongly associated with patients' perceptions of well-being, independence, and quality of life across a wide array of diseases and interventions. The workshop also focused on the importance of function in medical decision making to inform communications between specialty physicians and patients about prognosis and goals of care. Workshop participants called for more research on the role of function as a predictor of an intervention's effectiveness and an important treatment outcome. Such research would be facilitated by development of a core set of simple, short, functional measures that can be used by all specialties in the clinical setting to allow "big data" analytics and a pragmatic research. J Am Geriatr Soc 67:1782-1790, 2019.

Pathways, Contributors, and Correlates of Functional Limitation Across Specialties: Workshop Summary.

Traditional clinical care models focus on the measurement and normalization of individual organ systems and de-emphasize aspects of health related to the integration of physiologic systems. Measures of physical, cognitive and sensory, and psychosocial or emotional function predict important health outcomes like death and disability independently from the severity of a specific disease, cumulative co-morbidity, or disease severity measures. A growing number of clinical scientists in several subspecialties are exploring the utility of functional assessment to predict complication risk, indicate stress resistance, inform disease screening approaches and risk factor interpretation, and evaluate care. Because a substantial number of older adults in the community have some form of functional limitation, integrating functional assessment into clinical medicine could have a large impact. Although interest in functional implications for health and disease management is growing, the science underlying functional capacity, functional limitation, physical frailty, and functional metrics is often siloed among different clinicians and researchers, with fragmented concepts and methods. On August 25-26, 2016, participants at a trans-disciplinary workshop, supported by the National Institute on Aging and the John A. Hartford Foundation, explored what is known about the pathways, contributors, and correlates of physical, cognitive, and sensory functional measures across conditions and disease states; considered social determinants and health disparities; identified knowledge gaps, and suggested priorities for future research. This article summarizes those discussions.

Multimorbidity in Older Adults With Cardiovascular Disease.

Multimorbidity occurs in adults of all ages, but the number and complexity of comorbid conditions commonly increase with advancing age such that cardiovascular disease (CVD) in older adults typically occurs in a context of multimorbidity. Current clinical practice and research mainly target single disease-specific care that does not embrace the complexities imposed by concurrent conditions. In this paper, emerging concepts regarding CVD in combination with multimorbidity are reviewed, including recommendations for incorporating multimorbidity into clinical decision making, critical knowledge gaps, and research priorities to optimize care of complex older patients.

Statins for Primary Prevention in Older Adults-Moving Toward Evidence-Based Decision-Making.

OBJECTIVES: To determine the efficacy and safety of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) events in older adults, especially those aged 80 and older and with multimorbidity. METHODS: The National Institute on Aging and the National Heart, Lung and Blood Institute convened A multidisciplinary expert panel from July 31 to August 1, 2017, to review existing evidence, identify knowledge gaps, and consider whether statin safety and efficacy data in persons aged 75 and older without ASCVD are sufficient; whether existing data can inform the feasibility, design, and implementation of future statin trials in older adults; and clinical trial options and designs to address knowledge gaps. This article summarizes the presentations and discussions at that workshop. RESULTS: There is insufficient evidence regarding the benefits and harms of statins in older adults, especially those with concomitant frailty, polypharmacy, comorbidities, and cognitive impairment; a lack of tools to assess ASCVD risk in those aged 80 and older; and a paucity of evidence of the effect of statins on outcomes of importance to older adults, such as statin-associated muscle symptoms, cognitive function, and incident diabetes mellitus. Prospective, traditional, placebo-controlled, randomized clinical trials (RCTs) and pragmatic RCTs seem to be suitable options to address these critical knowledge gaps. Future trials have to consider greater representation of very old adults, women, underrepresented minorities, and individuals of differing health, cognitive, socioeconomic, and educational backgrounds. Feasibility analyses from existing large healthcare networks confirm appropriate power for death and cardiovascular outcomes for future RCTs in this area. CONCLUSION: Existing data cannot address uncertainties about the benefits and harms of statins for primary ASCVD prevention in adults aged 75 and older, especially those with comorbidities, frailty, and cognitive impairment. Evidence from 1 or more RCTs could address these important knowledge gaps to inform person-centered decision-making. J Am Geriatr Soc 66:2188-2196, 2018.