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Objectives: We hypothesized that women with lower extremity peripheral arterial disease (PAD) would have greater mobility loss and faster functional decline than men with PAD. Background: Whether rates of mobility loss or functional decline differ between men and women with PAD is currently unknown. Methods: Three hundred eighty men and women with PAD completed the 6-min walk, were assessed for mobility disability, and underwent measures of 4-m walking velocity at baseline and annually for up to 4 years. Computed tomography-assessed calf muscle characteristics were measured biannually. Outcomes included becoming unable to walk for 6 min continuously among participants who walked continuously for 6 min at baseline. Mobility loss was defined as becoming unable to walk for a quarter mile or to walk up and down 1 flight of stairs without assistance among those without baseline mobility disability. Results were adjusted for age, race, body mass index, physical activity, the ankle brachial index, comorbidities, and other confounders. Results: At 4 years of follow-up, women were more likely to become unable to walk for 6 min continuously (hazard ratio: 2.30, 95% confidence interval: 1.30 to 4.06, p = 0.004), more likely to develop mobility disability (hazard ratio: 1.79, 95% confidence interval: 1.30 to 3.03, p = 0.030), and had faster declines in walking velocity (p = 0.022) and the distance achieved in the 6-min walk (p = 0.041) compared with men. Sex differences in functional decline were attenuated after additional adjustment for baseline sex differences in calf muscle area. Conclusions: Women with PAD have faster functional decline and greater mobility loss than men with PAD. These sex differences may be attributable to smaller baseline calf muscle area among women with PAD. [ABSTRACT FROM AUTHOR]

Objectives: This study determined whether increased levels of inflammatory blood markers, D-dimer, and homocysteine were associated with smaller calf skeletal muscle area, increased calf muscle percent fat, reduced calf muscle density, and poorer calf strength in persons with lower extremity peripheral arterial disease (PAD). Background: Elevated levels of inflammatory markers and D-dimer are associated with greater functional impairment and functional decline in persons with PAD. Mechanisms of these associations are unknown. Methods: Participants were 423 persons with PAD. Calf muscle area, percent fat, and density were measured with computed tomography. Physical activity levels were measured objectively over 7 days with the Caltrac (Muscle Dynamics Fitness Network, Inc., Rocklin, California) vertical accelerometer. Isometric plantarflexion strength was measured. Analyses were adjusted for age, gender, race, comorbidities, the ankle-brachial index, and other potential confounders. Results: Higher levels of D-dimer (p = 0.014), C-reactive protein (CRP) (p = 0.002), interleukin (IL)-6 (p < 0.001), and soluble vascular cellular adhesion molecule (sVCAM)-1 (p = 0.008) were associated with smaller calf muscle area. Higher sVCAM-1 (p = 0.004) and IL-6 (p = 0.017) were associated with higher calf muscle percent fat. Higher D-dimer (p < 0.001), sVCAM-1 (p < 0.001), and homocysteine (p = 0.014) were associated with lower calf muscle density. These associations were generally unchanged after additional adjustment for physical activity. Higher sVCAM-1 (p = 0.013) was associated with lower calf strength. Conclusions: These data show, for the first time, that higher levels of inflammation, D-dimer, and homocysteine are associated with more adverse calf muscle characteristics in persons with PAD. These associations may contribute to previously established associations between elevated biomarkers and functional impairment and functional decline in PAD. [Copyright &y& Elsevier]

Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel gerotherapeutic approaches, some of which are already used in management of CVD, and explore their potential to transform care and management of CVD. The geroscience paradigm is gaining traction broadly in medical specialties, with potential to mitigate premature aging, reduce health care disparities, and improve population healthspan. [Display omitted] • Reduced efficiency of mechanisms opposing age-related molecular damage increases susceptibility to cardiovascular disease. • Key resilience mechanisms associated with aging have been identified as potential therapeutic targets. • By targeting these mechanisms, geroscience could transform the diagnosis, prevention, treatment, and prognosis of cardiovascular disease in an aging population. [ABSTRACT FROM AUTHOR]

Objectives: This study determined whether greater 2-year declines in Walking Impairment Questionnaire (WIQ) stair climbing, distance, or speed scores were associated with higher all-cause and cardiovascular disease (CVD) mortality among men and women with lower extremity peripheral artery disease (PAD). Background: Associations of decline in the WIQ with mortality among people with PAD are unknown. Methods: Participants were 442 men and women with PAD identified from Chicago area medical centers. The WIQ was completed at baseline and at 2-year follow-up. Cox proportional hazard models were used to assess associations across categories of 2-year changes in WIQ stair climbing, WIQ distance, and WIQ speed scores with subsequent all-cause and CVD mortality, adjusting for age, sex, race, ankle-brachial index, body mass index, smoking, comorbidities, and other covariates. Results: One hundred twenty-three participants (27.8%) died during a median follow-up of 4.7 years after the 2-year change in WIQ score measurements. Forty-five participants died from CVD. Adjusting for covariates, participants with WIQ score declines ≥20.0 points had higher all-cause mortality (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.01 to 3.68 for WIQ stair climbing; HR: 2.34, 95% CI: 1.15 to 4.75 for WIQ distance; and HR: 3.55, 95% CI: 1.57 to 8.04 for WIQ speed, respectively) compared with participants with ≥20.0 point improvement in each of the corresponding WIQ categories. Participants with ≥20.0 point declines in the WIQ distance score had higher CVD mortality (HR: 4.56, 95% CI: 1.30 to 16.01) compared with those with ≥20.0 point improvement in the WIQ distance score. Conclusions: Patients with PAD who experienced ≥20.0 point declines in the WIQ stair climbing, distance, and speed scores had a higher rate of all-cause mortality compared with those with less declines in each WIQ score. [Copyright &y& Elsevier]

Objectives: In participants with peripheral arterial disease (PAD), we determined whether more sedentary behavior and slower outdoor walking speed were associated with faster functional decline and more adverse changes in calf muscle characteristics over time. Background: Modifiable behaviors associated with faster functional decline in lower-extremity PAD are understudied. Methods: Participants were 384 men and women with an ankle brachial index <0.90 followed for a median of 47 months. At baseline, participants reported the number of hours they spent sitting per day and their walking speeds outside their homes. Participants underwent baseline and annual measures of objective functional performance. Calf muscle characteristics were measured with computed tomography at baseline and every 2 years subsequently. Analyses were adjusted for age, sex, race, comorbidities, ankle brachial index, and other confounders. Results: Slower walking speed outside the home was associated with faster annual decline in calf muscle density (brisk/striding pace −0.32 g/cm3, average pace −0.46 g/cm3, casual strolling −1.03 g/cm3, no walking at all −1.43 g/cm3, p trend <0.001). Greater hours sitting per day were associated with faster decline in 6-min walk (<4 h: −35.8 feet/year; 4 to <7 h: −41.1 feet/year; 8 to <11 h: −68.7 feet; ≥12 h: −78.0 feet; p trend = 0.008). Similar associations were observed for greater hours sitting per day and faster declines in fast-paced (p trend = 0.018) and usual-paced (p trend < 0.001) 4-m walking velocity. Conclusions: Greater sedentary hours per day and slower outdoor walking speed are modifiable behaviors that are associated with faster functional decline and greater decline in calf muscle density, respectively, in patients with PAD. [Copyright &y& Elsevier]

Objectives: We hypothesized that a greater 2-year decline in office-based functional performance measures would be associated with greater mobility loss and mortality in people with peripheral arterial disease (PAD). Background: Associations of decline in functional performance with clinically important outcomes in patients with PAD are unknown. Methods: A total of 440 men and women with PAD completed the 6-min walk test and measures of walking velocity at baseline and annually for 2 years. Participants were categorized into tertiles according to their functional decline between baseline and 2-year follow-up and were followed annually after the functional change assessment. Cox proportional hazard models were used to assess relations between the 2-year change in functional performance with later mortality and mobility loss, with adjustments for age, sex, race, ankle brachial index, comorbidities, and other confounders. Results: A total of 102 participants (23.2%) died during a median follow-up of 44.5 months after functional change was assessed. Of 319 participants without baseline mobility disability, 60 (18.8%) developed mobility loss after functional change was assessed. Participants in the tertile with the greatest 6-min walk decline had the highest subsequent mobility loss (hazard ratio [HR]: 3.50; 95% confidence interval [CI]: 1.56 to 7.85; p = 0.002), all-cause mortality (HR: 2.16; 95% CI: 1.28 to 3.64; p = 0.004), and cardiovascular disease mortality (HR: 2.45; 95% CI: 1.08 to 5.54; p = 0.031), compared with those with the smallest 6-min walk decline. Greater declines in fastest-paced 4-m walking velocity were associated with higher mobility loss (p trend = 0.018), all-cause mortality (p trend = 0.01), and cardiovascular mortality (p trend = 0.004). Conclusions: Participants with PAD with declining functional performance are at increased risk for later mobility loss and mortality. [Copyright &y& Elsevier]

Due to the aging and increasingly complex nature of our patients, frailty has become a high-priority theme in cardiovascular medicine. Despite the recognition of frailty as a pivotal element in the evaluation of older adults with cardiovascular disease (CVD), there has yet to be a road map to facilitate its adoption in routine clinical practice. Thus, we sought to synthesize the existing body of evidence and offer a perspective on how to integrate frailty into clinical practice. Frailty is a biological syndrome that reflects a state of decreased physiological reserve and vulnerability to stressors. Upward of 20 frailty assessment tools have been developed, with most tools revolving around the core phenotypic domains of frailty—slow walking speed, weakness, inactivity, exhaustion, and shrinking—as measured by physical performance tests and questionnaires. The prevalence of frailty ranges from 10% to 60%, depending on the CVD burden, as well as the tool and cutoff chosen to define frailty. Epidemiological studies have consistently demonstrated that frailty carries a relative risk of >2 for mortality and morbidity across a spectrum of stable CVD, acute coronary syndromes, heart failure, and surgical and transcatheter interventions. Frailty contributes valuable prognostic insights incremental to existing risk models and assists clinicians in defining optimal care pathways for their patients. Interventions designed to improve outcomes in frail elders with CVD such as multidisciplinary cardiac rehabilitation are being actively tested. Ultimately, frailty should not be viewed as a reason to withhold care but rather as a means of delivering it in a more patient-centered fashion. [Copyright &y& Elsevier]

Objectives: This study analyzed whether lower calf muscle density and poorer upper and lower extremity strength are associated with higher mortality rates in men and women with peripheral arterial disease (PAD). Background: Men and women with lower extremity PAD have lower calf muscle density and reduced lower extremity strength compared with individuals without PAD. Methods: At baseline, participants underwent measurement of calf muscle density with computed tomography in addition to knee extension power and isometric knee extension, plantar flexion, and hand grip strength measures. Participants were followed up annually for up to 4 years. Results were adjusted for age, sex, race, body mass index, ankle-brachial index, smoking, physical activity, and comorbidities. Results: Among 434 PAD participants, 103 (24%) died during a mean follow-up of 47.6 months. Lower calf muscle density was associated with higher all-cause mortality (lowest density tertile hazard ratio [HR]: 1.80 [95% confidence interval (CI): 1.07 to 3.03], second tertile HR: 0.91 (95% CI: 0.51 to 1.62); highest density tertile HR: 1.00; p trend = 0.020) and higher cardiovascular disease mortality (lowest density tertile HR: 2.39 [95% CI: 0.90 to 6.30], second tertile HR: 0.85 [95% CI: 0.27 to 2.71]; highest density tertile HR: 1.00; p trend = 0.047). Poorer plantar flexion strength (p trend = 0.004), lower baseline leg power (p trend = 0.046), and poorer handgrip (p trend = 0.005) were associated with higher all-cause mortality. Conclusions: These data demonstrate that lower calf muscle density and weaker plantar flexion strength, knee extension power, and hand grip were associated with increased mortality in these participants with PAD, independently of the ankle-brachial index and other confounders. [ABSTRACT FROM AUTHOR]

Objectives: We studied associations of borderline and low normal ankle-brachial index (ABI) values with functional decline over a 5-year follow-up. Background: The associations of borderline and low normal ABI with functional decline are unknown. Methods: The 666 participants included 412 with peripheral arterial disease (PAD). Participants were categorized as follows: severe PAD (ABI <0.50), moderate PAD (ABI 0.50 to 0.69), mild PAD (ABI 0.70 to 0.89), borderline ABI (0.90 to 0.99), low normal ABI (1.00 to 1.09), and normal ABI (ABI 1.10 to 1.30). Outcomes were assessed annually for 5 years. Mobility loss was defined as loss of the ability to walk one-quarter mile or walk up and down 1 flight of stairs without assistance among participants without baseline mobility impairment. Becoming unable to walk for 6 min continuously was defined as stopping during the 6-min walk at follow-up among those who walked for 6 min continuously at baseline. Results were adjusted for age, sex, race, comorbidities, and other confounders. Results: Hazard ratios (HRs) for mobility loss according to ABI category were as follows: severe PAD, HR: 4.16 (95% confidence interval [CI]: 1.58 to 10.92); moderate PAD, HR: 3.82 (95% CI: 1.66 to 8.81); mild PAD, HR: 3.22 (95% CI: 1.43 to 7.21); borderline ABI, HR: 3.07 (95% CI: 1.21 to 7.84); and low normal ABI, HR: 2.61 (95% CI: 1.08 to 6.32; p trend = 0.0018). Similar associations were observed for becoming unable to walk for 6 min continuously (p trend < 0.0001). Conclusions: At 5-year follow-up, persons with borderline ABI values have a higher incidence of mobility loss and becoming unable to walk for 6 min continuously compared with persons who have a normal baseline ABI. A low normal ABI is associated with an increased incidence of mobility loss compared with persons who have a normal ABI. [Copyright &y& Elsevier]

Objectives: Among persons with lower extremity peripheral artery disease (PAD), we determined whether objective measures of walking performance predict mortality independently of the ankle brachial index (ABI). Background: The ability of office-based functional performance measures to predict mortality in patients with PAD is unknown. Methods: Participants were 444 persons with PAD followed prospectively for 4.8 years. The 6-min walk and 4-m walks at usual and fastest pace were measured at baseline. Cox proportional hazard models were used to assess relations between baseline measures of lower extremity performance with mortality, adjusting for confounders. Results: One hundred twenty-seven patients (28.6%) died during follow-up. Adjusting for age, gender, race, comorbidities, ABI, and other confounders, participants in the poorest baseline quartile of 6-min walk performance had significantly increased total mortality (hazard ratio [HR] 2.36 [95% confidence interval (CI) 1.33 to 4.18]) and cardiovascular mortality (HR 5.59 [95% CI 1.97 to 15.9]) compared with the best quartile of baseline performance. Participants in the poorest baseline quartile of normal-paced 4-m walking speed had significantly increased total mortality (HR 1.86 [95% CI 1.06 to 3.29]) and cardiovascular mortality (HR 2.55 [95% CI 1.01 to 6.46]) compared with the best quartile of baseline performance. Conclusions: This study demonstrates for the first time that performance-based measures, which can be administered in an office setting, provide prognostic information regarding mortality in persons with PAD beyond that provided by the ABI. [Copyright &y& Elsevier]

Objectives: This study sought to evaluate whether pulse wave velocity (PWV), a noninvasive index of arterial stiffness, is a predictor of the longitudinal changes in systolic blood pressure (SBP) and of incident hypertension. Background: Although arterial stiffness is believed to underlie, in part, the age-associated changes in SBP, particularly at older ages, few longitudinal studies in humans have examined the relationship between arterial stiffness and blood pressure. Methods: Pulse wave velocity was measured at baseline in 449 normotensive or untreated hypertensive volunteers (age 53 ± 17 years). Repeated measurements of blood pressure were performed during an average follow-up of 4.9 ± 2.5 years. Results: After adjusting for covariates including age, body mass index, and mean arterial pressure, linear mixed effects regression models showed that PWV was an independent determinant of the longitudinal increase in SBP (p = 0.003 for the interaction term with time). In a subset of 306 subjects who were normotensive at baseline, hypertension developed in 105 (34%) during a median follow-up of 4.3 years (range 2 to 12 years). By stepwise Cox proportional hazards models, PWV was an independent predictor of incident hypertension (hazard ratio 1.10 per 1 m/s increase in PWV, 95% confidence interval 1.00 to 1.30, p = 0.03) in individuals with a follow-up duration greater than the median. Conclusions: Pulse wave velocity is an independent predictor of the longitudinal increase in SBP and of incident hypertension. This suggests that PWV could help identify normotensive individuals who should be targeted for the implementation of interventions aimed at preventing or delaying the progression of subclinical arterial stiffening and the onset of hypertension. [Copyright &y& Elsevier]

Objectives: We compared rates of mobility loss among persons with versus without peripheral arterial disease (PAD). Associations between baseline functional performance and mobility loss in persons with and without PAD were studied. Background: Persons with PAD have poorer functional performance than persons without PAD. The prognostic value of poorer performance in persons with PAD is unknown. Methods: Participants were 398 persons with and 240 without PAD who were free of mobility impairment at baseline. Participants were followed for a median of 50 months. Baseline measures included the 6-min walk and the Short Physical Performance Battery score. Mobility status, assessed annually, was defined as the self-reported loss of the ability to walk one-quarter mile or walk up and down one flight of stairs without assistance. Results: Adjusting for age and gender, we found that PAD participants had a greater rate of mobility loss than persons without PAD (hazard ratio [HR] 1.63; 95% confidence interval [CI] 1.03 to 2.56). This difference was not statistically significant after additional adjustment for baseline performance. Among PAD participants, risk of mobility loss in the lowest versus the 2 highest quartiles of baseline performance were as follows: HR 9.65 (95% CI 3.35 to 27.77, p < 0.001) for the 6-min walk and HR 12.84 (95% CI 4.64 to 35.55, p < 0.001) for the Short Physical Performance Battery when adjusting for confounders. Conclusions: Persons with PAD experience greater mobility loss than persons without PAD. This association was explained by poorer baseline functional performance among participants with PAD. Poorer lower extremity performance predicts increased mobility loss in persons with and without PAD. [Copyright &y& Elsevier]

Objectives: We investigated the secular trend in white blood cell (WBC) count and the relationship between WBC count and mortality between 1958 and 2002. Background: The WBC count is a clinical marker of inflammation and a strong predictor of mortality. Limited data exist on the WBC count secular trend and the relationship between WBC and mortality. Methods: One thousand eighty-three women and 1,720 men were evaluated longitudinally in the Baltimore Longitudinal Study of Aging. Blood samples and medical information were collected at the study entry and every 2 years during follow-up visits. The WBC count and all-cause, cardiovascular, and cancer mortality were assessed. Results: A downward trend in WBC count was observed from 1958 to 2002. The secular downward trend was independent of age, gender, race, smoking, body mass index, and physical activity. The WBC count was nonlinearly associated with all-cause mortality and almost linearly associated with cardiovascular mortality. Participants with baseline WBC <3,500 cells/mm3 and WBC >6,000 cells/mm3 had higher mortality than those with 3,500 to 6,000 WBC/mm3. Within each WBC group, age-adjusted mortality rates declined in successive cohorts from the 1960s to the 1990s. Participants who died had higher WBC than those who survived, and the difference was statistically significant within 5 years before death. Conclusions: Our study provides evidence for a secular downward trend in WBC count over the period from 1958 to 2002. Higher WBC counts are associated with higher mortality in successive cohorts. We found no evidence that the decline of age-specific mortality rates that occurred from 1960 to 2000 was attributable to a secular downward trend in WBC. [Copyright &y& Elsevier]

Objectives: We determined whether statin use (vs. non-use) is associated with less annual decline in lower-extremity functioning in patients with and without lower-extremity peripheral arterial disease (PAD) over three-year follow-up. Background: It is unclear whether statin use is associated with less functional decline in patients with PAD. Methods: Participants included 332 men and women with an ankle brachial index (ABI) <0.90 and 212 with ABI 0.90 to 1.50. Functional outcomes included 6-min walk distance and usual and rapid-pace 4-m walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for five repeated chair rises into an ordinal score ranging from 0 to 12 (12 = best). Results: Adjusting for age, race, gender, comorbidities, education, health insurance, total cholesterol/high-density lipoprotein level, body mass index, pack-years of smoking, leg symptoms, immediately previous year functioning, statin use/non-use, ABI, and change in ABI, the PAD participants using statins had less annual decline in usual-pace walking velocity (0.002 vs. −0.024 m/s/year, p = 0.013), rapid-pace walking velocity (−0.006 vs. −0.042 m/s/year, p = 0.006), 6-min walk performance (−34.5 vs. −57.9 feet/year, p = 0.088), and the summary performance score (−0.152 vs. −0.376, p = 0.067) compared with non-users. These associations were attenuated slightly by additional adjustment for high-sensitivity C-reactive protein levels. Among non-PAD participants, there were no significant associations between statin use and functional decline. Conclusions: The PAD patients on statins have less annual decline in lower-extremity performance than PAD patients who are not taking statins. [Copyright &y& Elsevier]