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Importance: In the Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a novel 12-week rehabilitation intervention demonstrated significant improvements in validated measures of physical function, quality of life, and depression, but no significant reductions in rehospitalizations or mortality compared with a control condition during the 6-month follow up. The economic implications of these results are important given the increasing pressures for cost containment in health care., Objective: To report the economic outcomes of the REHAB-HF trial and estimate the potential cost-effectiveness of the intervention., Design, Setting, Participants: The multicenter REHAB-HF trial randomized 349 patients 60 years or older who were hospitalized for acute decompensated heart failure to rehabilitation intervention or a control group; patients were enrolled from September 17, 2014, through September 19, 2019. For this preplanned secondary analysis of the economic outcomes, data on medical resource use and quality of life (via the 5-level EuroQol 5-Dimension scores converted to health utilities) were collected. Medical resource use and medication costs were estimated using 2019 US Medicare payments and the Federal Supply Schedule, respectively. Cost-effectiveness was estimated using the validated Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model, which uses an individual-patient simulation model informed by the prospectively collected trial data. Data were analyzed from March 24, 2019, to December 1, 2020., Interventions: Rehabilitation intervention or control., Main Outcomes and Measures: Costs, quality-adjusted life-years (QALYs), and the lifetime estimated cost per QALY gained (incremental cost-effectiveness ratio)., Results: Among the 349 patients included in the analysis (183 women [52.4%]; mean [SD] age, 72.7 [8.1] years; 176 non-White [50.4%] and 173 White [49.6%]), mean (SD) cumulative costs per patient were $26 421 ($38 955) in the intervention group (excluding intervention costs) and $27 650 ($30 712) in the control group (difference, -$1229; 95% CI, -$8159 to $6394; P = .80). The mean (SD) cost of the intervention was $4204 ($2059). Quality of life gains were significantly greater in the intervention vs control group during 6 months (mean utility difference, 0.074; P = .001) and sustained beyond the 12-week intervention. Incremental cost-effectiveness ratios were estimated at $58 409 and $35 600 per QALY gained for the full cohort and in patients with preserved ejection fraction, respectively., Conclusions and Relevance: These analyses suggest that longer-term benefits of this novel rehabilitation intervention, particularly in the subgroup of patients with preserved ejection fraction, may yield good value to the health care system. However, long-term cost-effectiveness is currently uncertain and dependent on the assumption that benefits are sustained beyond study follow-up, which needs to be corroborated in future trials in this patient population.

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets., Competing Interests: Funding Support and Author Disclosures The workshop “A Gero-centric Approach to Exercise Intolerance and Heart Failure with Preserved Ejection Fraction (HFpEF) in Older Adults: Elucidating and Targeting Extra-cardiac Contributors” was funded by the National Institute on Aging. The contents of this paper are solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Dr Pandey is supported by the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics; has served on the advisory board for Roche Diagnostics; and has received nonfinancial support from Pfizer and Merck. Dr Butler has served as a consultant for Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sequana Medical, V-Wave Limited, and Vifor. Dr Kellogg Jr is supported by NIH grants P30 AG044271 and K01AG059837. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. Dr Forman is funded by NIH grants R01AG060499, R01AG058883, R01AG051376, and P30AG024827. Dr Borlaug is funded by NIH grant RO1 HL128526. Dr Simon has received grant support from Aadi; and has served as a consultant for Acceleron, Actelion, and United Therapeutics. Dr Chirinos is supported by NIH grants R01-HL 121510, R33-HL-146390, R01-AG058969, 1R01-HL104106, P01-HL094307, R03-HL146874, R56-HL136730, and 1R01HL153646-01; has served as a consultant for Bayer, Sanifit, Fukuda-Denshi, Bristol Myers Squibb, Johnson & Johnson, Edwards Lifesciences, Merck, and the Galway-Mayo Institute of Technology; is named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction; has received University of Pennsylvania research grants from National Institutes of Health, Fukuda-Denshi, Bristol Myers Squibb, Microsoft, and Abbott; has received payments for editorial roles from the American Heart Association, the American College of Cardiology, and Wiley; and has received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. Dr Sam is supported by NIH grant R01HL145985. Dr Molina is supported by NIH grant R21 AG051077. Dr Pipinos is supported by R01AG062198. Dr Lewis has received research funding from the National Institutes of Health R01-HL 151841, R01-HL131029, American Heart Association 15GPSGC-24800006, and Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and Sonivie in relation to projects that are distinct from this work; has received honoraria outside of the current study from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and receives royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Bertoni is partially supported by NIH grant 1R01HL127028-01; and has consulted with Premier/Merck on a diabetes quality improvement project. Dr Justice has received support from NIH grants K01AG059837 and P30AG021332. Dr Hummel is supported by NIH grants R01AG062582 and R01HL139813, and by VA grant I01CX001636. Dr Kitzman is supported in part by NIH grants R01AG18915, R01AG045551, P30AG021332, and U24AG059624, and by the Kermit G. Phillips Endowed Chair in Cardiovascular Medicine; has received honoraria outside the present study as a consultant for AbbVie, Bayer, Merck, Medtronic, Relypsa, Merck, Corvia Medical, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Novartis; has received grant funding outside the present study from Novartis, Bayer, Novo Nordisk, and AstraZeneca; and has stock ownership in Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is upregulated in congestive heart failure (CHF), contributing to electrical, structural, and functional remodeling. CaMKII inhibition is known to improve CHF, but its direct cardiac effects in CHF remain unclear. We hypothesized that CaMKII inhibition improves cardiomyocyte function, [Ca 2+ ] i regulation, and β -adrenergic reserve, thus improving advanced CHF. In a 16-week study, we compared plasma neurohormonal levels and left ventricular (LV)- and myocyte-functional and calcium transient ([Ca 2+ ] iT ) responses in male Sprague-Dawley rats (10/group) with CHF induced by isoproterenol (170 mg/kg sq for 2 days). In rats with CHF, we studied the effects of the CaMKII inhibitor KN-93 or its inactive analog KN-92 ( n = 4) (70 µg/kg per day, mini-pump) for 4 weeks. Compared with controls, isoproterenol-treated rats had severe CHF with 5-fold-increased plasma norepinephrine and about 50% decreases in ejection fraction (EF) and LV contractility [slope of LV end-systolic pressure-LV end-systolic volume relation (E ES )] but increased time constant of LV relaxation ( τ ). They also showed significantly reduced myocyte contraction [maximum rate of myocyte shortening (dL/dt max )], relaxation (dL/dt max ), and [Ca 2+ ] iT Isoproterenol superfusion caused significantly fewer increases in dL/dt max and [Ca 2+ ] iT KN-93 treatment prevented plasma norepinephrine elevation, with increased basal and acute isoproterenol-stimulated increases in EF and E ES and decreased τ in CHF. KN-93 treatment preserved normal myocyte contraction, relaxation, [Ca 2+ ] iT , and β -adrenergic reserve, whereas KN-92 treatment failed to improve LV and myocyte function, and plasma norepinephrine remained high in CHF. Thus, chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system, restoring normal LV and cardiomyocyte basal and β -adrenergic-stimulated contraction, relaxation, and [Ca 2+ ] iT , thereby playing a rescue role in advanced CHF. SIGNIFICANCE STATEMENT: We investigated the therapeutic efficacy of late initiation of chronic Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) inhibition on progression of advanced congestive heart failure (CHF). Chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system and restored normal intrinsic cardiomyocyte basal and β -adrenergic receptor-stimulated relaxation, contraction, and [Ca 2+ ] i regulation, leading to reversal of CHF progression. These data provide new evidence that CaMKII inhibition is able and sufficient to rescue a failing heart, and thus cardiac CaMKII inhibition is a promising target for improving CHF treatment., Competing Interests: No conflicts of interest, financial or otherwise, are declared by the authors., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Increasing evidence shows that cognition and gait speed are associated and are important measures of health among older adults. However, previous studies have used different methods to assess these 2 outcomes and lack sufficient sample size to examine heterogeneity among subgroups. This study examined how the relationship between global cognitive function and gait speed are influenced by age, gender, and race utilizing an integrated data analysis approach., Method: Data on cognition (Montreal Cognitive Assessment [MoCA], Mini-Mental Status Examination [MMSE], and Modified Mini-Mental State Examination [3MSE]) and gait speed (range: 4-400 m) were acquired and harmonized from 25 research studies (n = 2802) of adults aged 50+ from the Wake Forest Older American Independence Center. Multilevel regression models examined the relationship between predicted values of global cognitive function (MoCA) and gait speed (4-m walk), including heterogeneity by age, race, and gender., Results: Global cognitive function and gait speed exhibited a consistent positive relationship among whites with increasing age, while this was less consistent for African Americans. That is, there was a low correlation between global cognitive function and gait speed among African Americans aged 50-59, a positive correlation in their 60s and 70s, then a negative correlation thereafter., Conclusion: Global cognition and gait speed exhibited a curvilinear U-shaped relationship among whites; however, the association becomes inverse in African Americans. More research is needed to understand this racial divergence and could aid in identifying interventions to maintain cognitive and gait abilities across subgroups., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Modified Mini-Mental State Examination (3MSE) and the Mini-Mental State Examination (MMSE) are two commonly used instruments for assessing cognitive function. Although conversion between 3MSE and MMSE is useful in applications such as integrative data analysis, there are limited published reports on the topic. Our objective is to provide a dual tool: (1) an item-level conversion tool to score responses for deriving both 3MSE and MMSE measures, and (2) cross-walk tables to facilitate quick conversion between 3MSE and MMSE., Methods: An SAS program tool allows scoring of 3MSE item-level responses into MMSE score. Using integrated data sets (n = 8346), actual 3MSE and MMSE scores obtained from the same individuals were linked to form cross-walk tables., Results: An SAS conversion program was made available. Cross-walk tables were derived. Validation sample shows bias is -0.11 (standard deviation = 1.02) in 3MSE→MMSE; the converse had substantially large bias., Discussion: The 3MSE→MMSE conversion table can be used in clinical practice and legacy system data., Competing Interests: The authors have no conflicts to report., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Heart failure (HF) risk is highest in late life, and impaired pulmonary vascular function is a risk factor for HF development. However, data regarding the contributors to and prognostic importance of pulmonary vascular dysfunction among HF-free elders in the community are limited and largely restricted to pulmonary hypertension. Our objective was to define the prevalence and correlates of abnormal pulmonary pressure, resistance, and compliance and their association with incident HF and HF phenotype (left ventricular [LV] ejection fraction [LVEF] ≥ or < 50%) independent of LV structure and function., Methods and Findings: We performed cross-sectional and time-to-event analyses in a prospective epidemiologic cohort study, the Atherosclerosis Risk in Communities study. This is an ongoing, observational study that recruited 15,792 persons aged 45-64 years between 1987 and 1989 (visit 1) from four representative communities in the United States: Minneapolis, Minnesota; Jackson, Mississippi; Hagerstown, Maryland; and Forsyth County, North Carolina. The current analysis included 2,810 individuals aged 66-90 years, free of HF, who underwent echocardiography at the fifth study visit (June 8, 2011, to August 28, 2013) and had measurable tricuspid regurgitation by spectral Doppler. Echocardiography-derived pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR), and pulmonary arterial compliance (PAC) were measured. The main outcome was incident HF after visit 5, and key secondary end points were incident HF with preserved LVEF (HFpEF) and incident HF with reduced LVEF (HFrEF). The mean ± SD age was 76 ± 5 years, 66% were female, and 21% were black. Mean values of PASP, PVR, and PAC were 28 ± 5 mm Hg, 1.7 ± 0.4 Wood unit, and 3.4 ± 1.0 mL/mm Hg, respectively, and were abnormal in 18%, 12%, and 14%, respectively, using limits defined from the 10th and 90th percentile limits in 253 low-risk participants free of cardiovascular disease or risk factors. Left heart dysfunction was associated with abnormal PASP and PAC, whereas a restrictive ventilatory deficit was associated with abnormalities of PASP, PVR, and PAC. PASP, PVR, and PAC were each predictive of incident HF or death (hazard ratio per SD 1.3 [95% CI 1.1-1.4], p < 0.001; 1.1 [1.0-1.2], p = 0.04; 1.2 [1.1-1.4], p = 0.001, respectively) independent of LV measures. Elevated pulmonary pressure was predictive of incident HFpEF (HFpEF: 2.4 [1.4-4.0, p = 0.001]) but not HFrEF (1.4 [0.8-2.5, p = 0.31]). Abnormal PAC predicted HFrEF (HFpEF: 2.0 [1.0-4.0, p = 0.05], HFrEF: 2.8 [1.4-5.5, p = 0.003]), whereas abnormal PVR was not predictive of either (HFpEF: 0.9 [0.4-2.0, p = 0.85], HFrEF: 0.7 [0.3-1.4, p = 0.30],). A greater number of abnormal pulmonary vascular measures was associated with greater risk of incident HF. Major limitations include the use of echo Doppler to estimate pulmonary hemodynamic measures, which may lead to misclassification; inclusions bias related to detectable tricuspid regurgitation, which may limit generalizability of our findings; and survivor bias related to the cohort age, which may result in underestimation of the described associations., Conclusions: In this study, we observed abnormalities of PASP, PVR, and PAC in 12%-18% of elders in the community. Higher PASP and lower PAC were independently predictive of incident HF. Abnormally high PASP predicted incident HFpEF but not HFrEF. These findings suggest that impairments in pulmonary vascular function may precede clinical HF and that a comprehensive pulmonary hemodynamic evaluation may identify pulmonary vascular phenotypes that differentially predict HF phenotypes., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: AMS reports receiving research support from Novartis through the Brigham and Women’s Hospital and consulting fees from Bellerophon and Philips Ultrasound. SDS reports receiving research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, and Tremeau. The remaining authors report no competing interests.

Aging-related illnesses are increasing and effective strategies to prevent and/or treat them are lacking. This is because of a poor understanding of therapeutic targets. Low-grade inflammation is often higher in older adults and remains a key risk factor of aging-related morbidities and mortalities. Emerging evidence indicates that abnormal (dysbiotic) gut microbiome and dysfunctional gut permeability (leaky gut) are linked with increased inflammation in older adults. However, currently available drugs do not treat aging-related microbiome dysbiosis and leaky gut, and little is known about the cellular and molecular processes that can be targeted to reduce leaky gut in older adults. Here, we demonstrated that metformin, a safe Food and Drug Administration-approved antidiabetic drug, decreased leaky gut and inflammation in high-fat diet-fed older obese mice, by beneficially modulating the gut microbiota. In addition, metformin increased goblet cell mass and mucin production in the obese older gut, thereby decreasing leaky gut and inflammation. Mechanistically, metformin increased the goblet cell differentiation markers by suppressing Wnt signaling. Our results suggest that metformin can be used as a regimen to prevent and treat aging-related leaky gut and inflammation, especially in obese individuals and people with western-style high-fat dietary lifestyle, by beneficially modulating gut microbiome/goblet cell/mucin biology., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Type 2 diabetes mellitus (T2DM) is associated with a higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF) and body mass index on risk for HF is not well established., Methods: Participants from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. Time-to-event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention and diabetes support and education groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, body mass index, and longitudinal changes in these parameters with risk of HF were evaluated with multivariable adjusted Cox models., Results: Among the 5109 trial participants, there was no significant difference in the risk of incident HF (n=257) between the intensive lifestyle intervention and the diabetes support and education groups (hazard ratio, 0.96 [95% CI, 0.75-1.23]) over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit (tertile 2: hazard ratio, 0.61 [95% CI, 0.44-0.83]) and high fit (tertile 3: hazard ratio, 0.38 [95% CI, 0.24-0.59]) groups, respectively (referent group: low fit, tertile 1). Among HF subtypes, after adjustment for traditional cardiovascular risk factors and interval incidence of myocardial infarction, baseline CRF was not significantly associated with risk of incident HF with reduced ejection fraction. In contrast, the risk of incident HF with preserved ejection fraction was 40% lower in the moderate fit group and 77% lower in the high fit group. Baseline body mass index also was not associated with risk of incident HF, HF with preserved ejection fraction, or HF with reduced ejection fraction after adjustment for CRF and traditional cardiovascular risk factors. Among participants with repeat CRF assessments (n=3902), improvements in CRF and weight loss over a 4-year follow-up were significantly associated with lower risk of HF (hazard ratio per 10% increase in CRF, 0.90 [95% CI, 0.82-0.99]; per 10% decrease in body mass index, 0.80 [95% CI, 0.69-0.94])., Conclusions: Among participants with type 2 diabetes mellitus in the Look AHEAD trial, the intensive lifestyle intervention did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.

Objective: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02])., Methods: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes., Results: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group., Conclusions: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design., (© 2020 The Obesity Society.)

Frailty, a syndrome characterized by an exaggerated decline in function and reserve of multiple physiological systems, is common in older patients with heart failure (HF) and is associated with worse clinical and patient-reported outcomes. Although several detailed assessment tools have been developed and validated in the geriatric population, they are cumbersome, not validated in patients with HF, and not commonly used in routine management of patients with HF. More recently, there has been an increasing interest in developing simple frailty screening tools that could efficiently and quickly identify frail patients with HF in routine clinical settings. As the burden and recognition of frailty in older patients with HF increase, a more comprehensive approach to management is needed that targets deficits across multiple domains, including physical function and medical, cognitive, and social domains. Such a multidomain approach is critical to address the unique, multidimensional challenges to the care of these high-risk patients and to improve their functional status, quality of life, and long-term clinical outcomes. This review discusses the burden of frailty, the conceptual underpinnings of frailty in older patients with HF, and potential strategies for the assessment, screening, and management of frailty in this vulnerable patient population., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess the prevalence of frailty, its associations with physical function, quality of life (QoL), cognition, and depression and to investigate more efficient methods of detection in older patients hospitalized with acute decompensated heart failure (ADHF)., Background: In contrast to the outpatient population with chronic HF, much less is known regarding frailty in older, hospitalized patients with ADHF., Methods: Older hospitalized patients (N = 202) with ADHF underwent assessment of frailty (using Fried criteria), short physical performance battery (SPPB), 6-min walk test (6-MWT) distance, quality of life (QoL using the Kansas City Cardiomyopathy Questionnaire), cognition (using the Montreal Cognition Assessment), and depression (using the Geriatric Depression Screen [GDS]). The associations of frailty with these patient-centered outcomes were assessed by using adjusted linear regression models. Novel strategies to identify frailty were examined., Results: A total of 50% of older, hospitalized patients with ADHF were frail, 48% were pre-frail, and 2% were non-frail. Female sex, burden of comorbidity, and prior HF hospitalization were significantly associated with higher likelihood of frailty. Frailty (vs. pre-frail status) was associated with a significantly worse SPPB score (5 ± 2.2 vs. 7 ± 2.4, respectively), 6-MWT distance (143 ± 79 m vs. 221 ± 99 m, respectively), QoL (35 ± 19 vs. 46 ± 21, respectively), and more depression (GDS score: 5.5 ± 3.5 vs. 4.2 ± 3.3, respectively) but similar cognition. These associations were unchanged after adjustment for age, sex, race, total comorbidities, and body mass index. Slow gait speed plus low physical activity signaled frailty status as well (C-statistic = 0.85)., Conclusions: Ninety-eight percent of older, hospitalized patients with ADHF are frail or pre-frail. Frailty (vs. pre-frail status) is associated with worse physical function, QoL, comorbidity, and depression. The simple 4-m walk test combined with self-reported physical activity may quickly and efficiently identify frailty in older patients with ADHF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The emerging role of the gut microbiome in several human diseases demands a breakthrough of new tools, techniques and technologies. Such improvements are needed to decipher the utilization of microbiome modulators for human health benefits. However, the large-scale screening and optimization of modulators to validate microbiome modulation and predict related health benefits may be practically difficult due to the need for large number of animals and/or human subjects. To this end, in vitro or ex vivo models can facilitate preliminary screening of microbiome modulators. Herein, it is optimized and demonstrated an ex vivo fecal microbiota culture system that can be used for examining the effects of various interventions of gut microbiome modulators including probiotics, prebiotics and other food ingredients, aside from nutraceuticals and drugs, on the diversity and composition of the human gut microbiota. Inulin, one of the most widely studied prebiotic compounds and microbiome modulators, is used as an example here to examine its effect on the healthy fecal microbiota composition and its metabolic activities, such as fecal pH and the fecal levels of organic acids including lactate and short-chain fatty acids (SCFAs). The protocol may be useful for studies aimed at estimating the effects of different interventions of modulators on fecal microbiota profiles and at predicting their health impacts.

Importance: Limited data exist on the prevalence and prognostic importance of right ventricular (RV) dysfunction for heart failure (HF) in the general population., Objective: To assess the prevalence of RV dysfunction and its association with HF and mortality in a community-based elderly cohort., Design, Setting, and Participants: Cross-sectional and time-to-event analysis of participants in the Atherosclerosis Risks in the Community (ARIC), a multicenter, population-based cohort study at the fifth study visit from 2011 to 2013, with a median follow-up of 4.1 years. This study included 1004 elderly participants in the ARIC study attending the fifth study visit who underwent both 3-dimensional and 2-dimensional RV echocardiography. Three-dimensional echocardiography data were analyzed between September 15, 2015, and July 24, 2016., Exposures: Right ventricular ejection fraction (RVEF), RV-pulmonary artery (PA) coupling defined by the RVEF/PA systolic pressure (PASP) ratio, and RV longitudinal strain by 3-dimensional echocardiography., Main Outcomes and Measures: For cross-sectional analysis, the prevalence of RV dysfunction across ACCF/AHA HF stages (0; A, at elevated risk for HF but without structural heart disease or clinical HF; B, structural heart disease but without clinical HF; and C, prevalent HF). For time-to-event analysis, a composite of incident HF hospitalization or all-cause death among participants free of HF at visit 5., Results: Of the 1004 participants, mean (SD) age was 76 (5) years, 385 were men (38%), and 121 were black (12%). Mean (SD) RVEF was 53% (8%). Right ventricular EF, RVEF/PASP, and RV longitudinal strain were each progressively lower across advancing HF stages. Using reference limits from stage 0 participants, RVEF was abnormal in 103 asymptomatic persons with stage A HF (15%) and 27 with stage B HF (24%). Among participants free of HF at baseline, lower RVEF and worse RV-PA coupling (ie, lower RVEF/PASP ratio) both were associated with incident HF or death independent of LVEF and N-terminal pro b-type natriuretic peptide (hazard ratio, 1.20; 95% CI, 1.02-1.42 per 5% decrease in RVEF; P = .03; hazard ratio, 1.65, 95% CI, 1.15-2.37 per 0.5 unit decrease in RVEF/PASP ratio; P = .007)., Conclusions and Relevance: Right ventricular function and RV-PA coupling declined progressively across American College of Cardiology Foundation/American Heart Association HF stages. Among persons free of HF, lower RVEF was associated with incident HF or death independent of LVEF or N-terminal pro b-type natriuretic peptide.

Arterial stiffness, typically assessed as the aortic pulse wave velocity (PWV), and central blood pressure levels may be indicators of cardiovascular disease (CVD) risk. This ancillary study to the Systolic Blood Pressure Intervention Trial (SPRINT) obtained baseline assessments (at randomization) of PWV and central systolic blood pressure (C-SBP) to: 1) characterize these vascular measurements in the SPRINT cohort, and 2) test the hypotheses that PWV and C-SBP are associated with glucose homeostasis and markers of chronic kidney disease (CKD). The SphygmoCor® CPV device was used to assess carotid-femoral PWV and its pulse wave analysis study protocol was used to obtain C-SBP. Valid results were obtained from 652 participants. Mean (±SD) PWV and C-SBP for the SPRINT cohort were 10.7 ± 2.7 m/s and 132.0 ± 17.9 mm Hg respectively. Linear regression analyses for PWV and C-SBP results adjusted for age, sex, and race/ethnicity in relation to several markers of glucose homeostasis and CKD did not identify any significant associations with the exception of a marginally statistically significant and modest association between PWV and urine albumin-to-creatinine ratio (linear regression estimate ± SE, 0.001 ± 0.0006; P-value 0.046). In a subset of SPRINT participants, PWV was significantly higher than in prior studies of normotensive persons, as expected. For older age groups in the SPRINT cohort (age > 60 years), PWV was compared with a reference population of hypertensive individuals. There were no compelling associations noted between PWV or C-SBP and markers of glucose homeostasis or CKD., Clinical Trial Registration: NCT01206062., Competing Interests: Suzanne Oparil has received research grant support or support/reimbursement for travel to meetings or other, non-financial support from: Actelion Clinical Research/George Clinical; AstraZeneca AB; Bayer; Lundbeck; Novartis; Novo Nordisk; ROX Medical; and has consulted for: Actelion/George Clinical, Lundbeck and Novo Nordisk. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To determine predictors of serious adverse events (SAEs) involving syncope, hypotension, and falls, with particular attention to age, in the Systolic Blood Pressure Intervention Trial., Design: Randomized clinical trial., Setting: Academic and private practices across the United States (N = 102)., Participants: Adults aged 50 and older with a systolic blood pressure (SBP) of 130 to 180 mmHg at high risk of cardiovascular disease events, but without diabetes, history of stroke, symptomatic heart failure or ejection fraction less than 35%, dementia, or standing SBP less than 110 mmHg (N = 9,361)., Intervention: Treatment of SBP to a goal of less than 120 mmHg or 140 mmHg., Measurements: Outcomes were SAEs involving syncope, hypotension, and falls. Predictors were treatment assignment, demographic characteristics, comorbidities, baseline measurements, and baseline use of cardiovascular medications., Results: One hundred seventy-two (1.8%) participants had SAEs involving syncope, 155 (1.6%) hypotension, and 203 (2.2%) falls. Randomization to intensive SBP control was associated with greater risk of an SAE involving hypotension (hazard ratio (HR) = 1.67, 95% confidence interval (CI) = 1.21-2.32, P = .002), and possibly syncope (HR = 1.32, 95% CI = 0.98-1.79, P = .07), but not falls (HR = 0.98, 95% CI = 0.75-1.29, P = .90). Risk of all three outcomes was higher for participants with chronic kidney disease or frailty. Older age was also associated with greater risk of syncope, hypotension, and falls, but there was no age-by-treatment interaction for any of the SAE outcomes., Conclusions: Participants randomized to intensive SBP control had greater risk of hypotension and possibly syncope, but not falls. The greater risk of developing these events associated with intensive treatment did not vary according to age., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Background: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear., Methods: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP., Results: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level ( P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57-1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61-0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events., Conclusions: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062., (© 2017 American Heart Association, Inc.)

Background: The contribution of cardiovascular dysfunction to frailty in older adults is uncertain. This study aimed to define the relationship between frailty and cardiovascular structure and function, and determine whether these associations are independent of coexisting abnormalities in other organ systems., Methods: We studied 3,991 older adults (mean age 75.6±5.0 years; 59% female) from the Atherosclerosis Risk in Communities (ARIC) Study in whom the following six organ systems were uniformly assessed: cardiac (by echocardiography), vascular (by ankle-brachial-index and pulse-wave-velocity), pulmonary (by spirometry), renal (by estimated glomerular filtration rate), hematologic (by hemoglobin), and adipose (by body mass index and bioimpedance). Frailty was defined by the presence of ≥3 of the following: low strength, low energy, slowed motor performance, low physical activity, or unintentional weight loss., Results: Two hundred eleven (5.3%) participants were frail. In multivariable analyses adjusted for demographics, diabetes, hypertension, and measures of other organ system function, frailty was independently and additively associated with left ventricular hypertrophy (odds ratio [OR] = 1.72; 95% confidence interval [CI] = 1.30-2.40), reduced global longitudinal strain (reflecting systolic function; OR = 1.68; 95% CI = 1.16-2.44), and greater left atrial volume index (reflecting diastolic function; OR = 1.60; 95% CI = 1.13-2.27), which together demonstrated the greatest association with frailty (OR = 2.10; 95% CI = 1.57-2.82) of the systems studied. Lower magnitude associations were observed for vascular and pulmonary abnormalities, anemia, and impaired renal function. Cardiovascular abnormalities remained associated with frailty after excluding participants with prevalent cardiovascular disease., Conclusions: Abnormalities of cardiac structure and function are independently associated with frailty, and together show the greatest association with frailty among the organ systems studied., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Several markers detected on the routine 12-lead ECG are associated with future heart failure events. We examined whether these markers are able to separate the risk of heart failure with reduced ejection fraction (HFrEF) from heart failure with preserved ejection fraction (HFpEF)., Methods and Results: We analyzed data of 6664 participants (53% female; mean age 62±10 years) from MESA (Multi-Ethnic Study of Atherosclerosis) who were free of cardiovascular disease at baseline (2000-2002). A competing risks analysis was used to compare the association of several baseline ECG predictors with HFrEF and HFpEF detected during a median follow-up of 12.1 years. A total of 127 HFrEF and 117 HFpEF events were detected during follow-up. In a multivariable adjusted model, prolonged QRS duration, delayed intrinsicoid deflection, left-axis deviation, right-axis deviation, prolonged QT interval, abnormal QRS-T axis, left ventricular hypertrophy, ST/T-wave abnormalities, and left bundle-branch block were associated with HFrEF. In contrast, higher resting heart rate, abnormal P-wave axis, and abnormal QRS-T axis were associated with HFpEF. The risk of HFrEF versus HFpEF was significantly differently for delayed intrinsicoid deflection (hazard ratio: 4.90 [95% confidence interval (CI), 2.77-8.68] versus 0.94 [95% CI, 0.29-2.97]; comparison P =0.013), prolonged QT interval (hazard ratio: 2.39 [95% CI, 1.55-3.68] versus 0.52 [95% CI, 0.23-1.19]; comparison P <0.001), and ST/T-wave abnormalities (hazard ratio: 2.47 [95% CI, 1.69-3.62] versus 1.13 [95% CI, 0.72-1.77]; comparison P =0.0093)., Conclusions: Markers of ventricular repolarization and delayed ventricular activation are able to distinguish between the future risk of HFrEF and HFpEF. These findings suggest a role for ECG markers in the personalized risk assessment of heart failure subtypes., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Although age-associated changes in left ventricular diastolic function are well recognized, limited data exist characterizing measures of diastolic function in older adults, including both reference ranges reflecting the older adult population and prognostically relevant values for incident heart failure (HF), as well as their associations with circulating biomarkers of HF risk., Methods: Among 5801 elderly participants in the ARIC study (Atherosclerosis Risk in Communities; age range, 67-90 years; mean age, 76±5 years; 42% male; 21% black), we determined the continuous association of diastolic measures (tissue Doppler imaging [TDI] e', E/e', and left atrial size) with concomitant N-terminal pro-brain natriuretic peptide and subsequent HF hospitalization or death. We also determined sex-specific 10th and 90th percentile limits for these measures using quantile regression in 401 participants free of prevalent cardiovascular disease and risk factors., Results: Each measure of diastolic function was robustly associated with N-terminal pro-brain natriuretic peptide and incident HF or death. ARIC-based reference limits for TDI e' (4.6 and 5.2 cm/s for septal and lateral TDI e', respectively) were substantially lower than guideline cut points (7 and 10 cm/s, respectively), whereas E/e' and left atrial size demonstrated good agreement with guideline cut points. TDI e' was nonlinearly associated with incident HF or death, with inflection points for risk supportive of ARIC-based limits. ARIC-based limits for diastolic function improved risk discrimination over guideline-based cut points based on the integrated discrimination improvement (P<0.001) and continuous net reclassification improvement (P<0.001), reclassifying 42% of the study population as having normal diastolic function. We replicate these findings in the Copenhagen City Heart Study. With these limits, 46% had normal diastolic function and were at low risk of HF hospitalization or death (1%/y over a mean 1.7-year follow-up), 49% had 1 or 2 abnormal measures and were at intermediate risk (2.4%/y), and all 3 diastolic measures were abnormal in 5% who were at high risk (7.5%/y)., Conclusions: Our findings suggest that left ventricular longitudinal relaxation velocity declines as a part of healthy aging and is largely prognostically benign. The use of age-based normative values when considering an elderly population improves the risk discrimination of diastolic measures for incident HF or death., Competing Interests: The other authors report no disclosures., (© 2016 American Heart Association, Inc.)

Background: Although heart failure (HF) disproportionately affects older adults, little data exist regarding the prevalence of American College of Cardiology/American Heart Association HF stages among older individuals in the community. Additionally, the role of contemporary measures of longitudinal strain and diastolic dysfunction in defining HF stages is unclear., Methods: HF stages were classified in 6118 participants in the Atherosclerosis Risk in Communities study (67-91 years of age) at the fifth study visit as follows: A (asymptomatic with HF risk factors but no cardiac structural or functional abnormalities), B (asymptomatic with structural abnormalities, defined as left ventricular hypertrophy, dilation or dysfunction, or significant valvular disease), C1 (clinical HF without prior hospitalization), and C2 (clinical HF with earlier hospitalization)., Results: Using the traditional definitions of HF stages, only 5% of examined participants were free of HF risk factors or structural heart disease (Stage 0), 52% were categorized as Stage A, 30% Stage B, 7% Stage C1, and 6% Stage C2. Worse HF stage was associated with a greater risk of incident HF hospitalization or death at a median follow-up of 608 days. Left ventricular (LV) ejection fraction was preserved in 77% and 65% in Stages C1 and C2, respectively. Incorporation of longitudinal strain and diastolic dysfunction into the Stage B definition reclassified 14% of the sample from Stage A to B and improved the net reclassification index (P=0.028) and integrated discrimination index (P=0.016). Abnormal LV structure, systolic function (based on LV ejection fraction and longitudinal strain), and diastolic function (based on e', E/e', and left atrial volume index) were each independently and additively associated with risk of incident HF hospitalization or death in Stage A and B participants., Conclusions: The majority of older adults in the community are at risk for HF (Stages A or B), appreciably more compared with previous reports in younger community-based samples. LV ejection fraction is robustly preserved in at least two-thirds of older adults with prevalent HF (Stage C), highlighting the burden of HF with preserved LV ejection fraction in the elderly. LV diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and LV ejection fraction in identifying persons at risk for HF hospitalization or death., (© 2016 American Heart Association, Inc.)

Background: Advanced age is related to left ventricular (LV) remodeling. We sought to investigate the relationships between aging, elevated hemodynamic load, cardiac mechanics, and LV remodeling in an elderly community-based population., Methods and Results: We studied 1105 subjects (76±5 years, 61% women) without prevalent heart failure, who attended the visit 5 of the ARIC study (Atherosclerosis Risk in Communities). LV global longitudinal strain, global circumferential strain, and torsion indices were analyzed using 3-dimensional echocardiography. Advanced age was associated with greater LV concentricity, lower myocardial diastolic relaxation, reduced global longitudinal strain (adjusted estimate, 0.39±0.19% (SE)/decade; P=0.038), borderline greater global circumferential strain (adjusted estimate, -0.59±0.36% (SE)/decade; P=0.08), and higher torsion indices (adjusted estimate for torsion, 0.33±0.04° (SE)/decade; P<0.001). In addition, greater concentricity was associated with decreased global longitudinal strain and greater torsion in multivariable models (all P<0.001). Women showed smaller LV cavity size, greater concentricity, lower myocardial relaxation velocity E', though demonstrated greater global longitudinal strain, global circumferential strain, and torsion than men (all P<0.05). Overall, subjects with hypertension and increasing age were more likely to have higher torsion, though the association between advanced age and greater torsion was more pronounced in women than in men (both interaction P<0.05)., Conclusions: In an asymptomatic, senescent community-dwelling population, we observed a distinct, sex-specific pattern of cardiac remodeling. Although we observed worse diastolic and longitudinal function with advanced age or elevated load in both sexes, a significant increase of torsion was more pronounced in women., (© 2017 American Heart Association, Inc.)

Unlabelled: Heart failure with preserved ejection fraction (HFpEF), a major public health problem with high morbidity and mortality rates, remains difficult to manage because of a lack of effective treatment options. Although HFpEF is a heterogeneous clinical syndrome, elevated left atrial pressure-either at rest or with exertion-is a common factor among all forms of HFpEF and one of the primary reasons for dyspnea and exercise intolerance in these patients. On the basis of clinical experience with congenital interatrial shunts in mitral stenosis, it has been hypothesized that the creation of a left-to-right interatrial shunt to decompress the left atrium (without compromising left ventricular filling or forward cardiac output) is a rational, nonpharmacological strategy for alleviating symptoms in patients with HFpEF. A novel transcatheter interatrial shunt device has been developed and evaluated in patients with HFpEF in single-arm, nonblinded clinical trials. These studies have demonstrated the safety and potential efficacy of the device. However, a randomized, placebo-controlled evaluation of the device is required to further evaluate its safety and efficacy in patients with HFpEF. In this article, we give the rationale for a therapeutic transcatheter interatrial shunt device in HFpEF, and we describe the design of REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I), the first randomized controlled trial of a device-based therapy to reduce left atrial pressure in HFpEF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02600234., (© 2016 American Heart Association, Inc.)

Background: Race and sex differences in silent myocardial infarction (SMI) are not well established., Methods and Results: The analysis included 9498 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of cardiovascular disease at baseline (visit 1, 1987-1989). Incident SMI was defined as ECG evidence of MI without clinically documented MI (CMI) after the baseline until ARIC visit 4 (1996-1998). Coronary heart disease and all-cause deaths were ascertained starting from ARIC visit 4 until 2010. During a median follow-up of 8.9 years, 317 participants (3.3%) developed SMI and 386 (4.1%) developed CMI. The incidence rates of both SMI and CMI were higher in men (5.08 and 7.96 per 1000-person years, respectively) than in women (2.93 and 2.25 per 1000-person years, respectively; P<0.0001 for both). Blacks had a nonsignificantly higher rate of SMI than whites (4.45 versus 3.69 per 1000-person years; P=0.217), but whites had higher rate of CMI than blacks (5.04 versus 3.24 per 1000-person years; P=0.002). SMI and CMI (compared with no MI) were associated with increased risk of coronary heart disease death (hazard ratio, 3.06 [95% confidence interval, 1.88-4.99] and 4.74 [95% confidence interval, 3.26-6.90], respectively) and all-cause mortality (hazard ratio, 1.34 [95% confidence interval, 1.09-1.65] and 1.55 [95% confidence interval, 1.30-1.85], respectively). However, SMI and CMI were associated with increased mortality among both men and women, with potentially greater increased risk among women (interaction P=0.089 and 0.051, respectively). No significant interactions by race were detected., Conclusions: SMI represents >45% of incident MIs and is associated with poor prognosis. Race and sex differences in the incidence and prognostic significance of SMI exist that may warrant considering SMI in personalized assessments of coronary heart disease risk., (© 2016 American Heart Association, Inc.)

Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate <30 mL/min per 1.73 m2) were half as likely to be prescribed a thiazide as participants with preserved kidney function. In conclusion, among persons with hypertension and heightened cardiovascular risk, we found that thiazide prescription varied significantly by demographics and kidney disease status, despite limited evidence about relative differences in effectiveness., (© 2016 American Heart Association, Inc.)

Background: Information regarding the prevalence and determinants of cardiac structure and function (systolic and diastolic) among the various Hispanic background groups in the United States is limited., Methods and Results: The Echocardiographic Study of Latinos (ECHO-SOL) ancillary study recruited 1,824 participants through a stratified-sampling process representative of the population-based Hispanic Communities Health Study - Study of Latinos (HCHS-SOL) across four sites (Bronx, NY; Chicago, Ill; San Diego, Calif; Miami, Fla). The HCHS-SOL baseline cohort did not include an echo exam. ECHO-SOL added the echocardiographic assessment of cardiac structure and function to an array of existing HCHS-SOL baseline clinical, psychosocial, and socioeconomic data and provides sufficient statistical power for comparisons among the Hispanic subgroups. Standard two-dimensional (2D) echocardiography protocol, including M-mode, spectral, color and tissue Doppler study was performed. The main objectives were to: 1) characterize cardiac structure and function and its determinants among Hispanics and Hispanic subgroups; and 2) determine the contributions of specific psychosocial factors (acculturation and familismo) to cardiac structure and function among Hispanics., Conclusion: We describe the design, methods and rationale of currently the largest and most comprehensive study of cardiac structure and function exclusively among US Hispanics. ECHO-SOL aims to enhance our understanding of Hispanic cardiovascular health as well as help untangle the relative importance of Hispanic subgroup heterogeneity and sociocultural factors on cardiac structure and function.

Background: Heart failure with preserved ejection fraction (HFPEF) is common and characterized by exercise intolerance and lack of proven effective therapies. Exercise training has been shown to be effective in improving cardiorespiratory fitness (CRF) in patients with systolic heart failure. In this meta-analysis, we aim to evaluate the effects of exercise training on CRF, quality of life, and diastolic function in patients with HFPEF., Methods and Results: Randomized controlled clinical trials that evaluated the efficacy of exercise training in patients with HFPEF were included in this meta-analysis. Primary outcome of the study was change in CRF (measured as change in peak oxygen uptake). Effect of exercise training on quality of life (estimated using Minnesota living with heart failure score), and left ventricular systolic and diastolic function was also assessed. The study included 276 patients who were enrolled in 6 randomized controlled trials. In the pooled data analysis, patients with HFPEF undergoing exercise training had significantly improved CRF (mL/kg per min; weighted mean difference, 2.72; 95% confidence interval, 1.79-3.65) and quality of life (weighted mean difference, -3.97; 95% confidence interval, -7.21 to -0.72) when compared with the control group. However, no significant change was observed in the systolic function (EF-weighted mean difference, 1.26; 95% confidence interval, -0.13% to 2.66%) or diastolic function (E/A-weighted mean difference, 0.08; 95% confidence interval, -0.01 to 0.16) with exercise training in patients with HFPEF., Conclusions: Exercise training in patients with HFPEF is associated with an improvement in CRF and quality of life without significant changes in left ventricular systolic or diastolic function., (© 2014 American Heart Association, Inc.)

Objective: The objective of this study was to assess the frequency and prognostic utility of small, short-duration left ventricular myocardial perfusion defects during dobutamine cardiovascular magnetic resonance (DCMR) stress imaging., Methods: We performed first-pass contrast-enhanced DCMR at peak stress in 331 consecutively recruited individuals (aged 68 ± 8 years, 50% men) at intermediate risk for a future cardiac event. Size, location, and persistence of low-signal intensity perfusion defects were recorded. Cardiac events were assessed by personnel blinded to imaging results for a median of 24 months after the DCMR., Results: Among the 55 individuals (16.6%) who exhibited small (<25% myocardial thickness) and short-duration (<5 frames in persistence) perfusion defects, diabetes was more prevalent (P = 0.019) and no cardiac events were observed. Large, persistent perfusion defects were associated with coronary artery disease, prior myocardial infarction, and decreased left ventricular function (P < 0.001 for all) and increased 2-year risk for a cardiac event (hazard ratio, 10.3; P < 0.001; confidence interval, 3.3-33.0)., Conclusions: In individuals with diabetes, hypertension, or coronary artery disease at intermediate risk for a future cardiac event, small, short-duration DCMR perfusion defects are not associated with increased 2-year risk for a subsequent cardiac event.

Background: Heart failure is an important public health concern, particularly among persons>65 years of age. Women and blacks are critically understudied populations that carry a sizeable portion of the heart failure burden. Limited normative and prognostic data exist on measures of cardiac structure, diastolic function, and novel measures of systolic deformation in older adults living in the community., Methods and Results: The Atherosclerosis Risk in Communities (ARIC) study is a large, predominantly biracial, National Heart, Lung, and Blood Institute-sponsored epidemiological cohort study. Between 2011 and 2013, ≈6000 surviving participants, now in their seventh to ninth decade of life, are expected to return for a fifth study visit during which comprehensive 2-dimensional, Doppler, tissue Doppler, and speckle-tracking echocardiography will be performed uniformly in all cohort clinic visit participants. The following objectives will be addressed: (1) to characterize cardiac structural and functional abnormalities among the elderly and to determine how they differ by sex and race/ethnicity, (2) to determine the relationship between ventricular and vascular abnormalities, and (3) to prospectively examine the extent to which these noninvasive measures associate with incident heart failure., Conclusions: We describe the design, imaging acquisition and analysis methods, and quality assurance metrics for echocardiography in visit 5 of the ARIC cohort. A better understanding of the differences in cardiac structure and function through the spectrum of heart failure stages in elderly persons generally, and between sexes and racial/ethnic groups specifically, will deepen our understanding of the pathophysiology driving heart failure progression in these at-risk populations and may inform novel prevention or therapeutic strategies.

Objectives: This study sought to examine the association between baseline beta-blocker (BB) dose and outcomes in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial., Background: Beta-blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction, but it is unclear whether titrating to higher BB doses improves outcomes in this setting., Methods: The HF-ACTION trial was a randomized, multicenter trial enrolling 2,331 ambulatory HF patients with systolic dysfunction (New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35) randomized to exercise training versus usual care, with median follow-up of 2.5 years. The BB dose at baseline was standardized with carvedilol equivalents and analyzed as a continuous variable and by discrete dose groups. The relationship between BB dose and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints was determined before and after adjustment for variables significantly associated with outcomes in the HF-ACTION cohort., Results: Ninety-five percent of patients were receiving a BB. There was a significant inverse relationship between BB dose and all-cause death or hospitalization but not other cardiovascular endpoints after adjustment for other predictors of outcome, with a linear benefit up to the 50-mg daily dose. There was a significant association between BB dose and change in peak VO(2) at 3 months. There was no increase in bradycardia with higher doses of BB., Conclusions: There was a significant inverse relationship between BB dose and the endpoint of all-cause death or all-cause hospitalization in this well-treated HF cohort with systolic dysfunction, supporting recommendations that titrating doses up to 50 mg/day might confer a benefit in such patients. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

About 50% or more of heart failure (HF) patients living in the community have preserved left ventricular ejection fraction (HFpEF), and the proportion is higher among women and the very elderly. A cardinal feature of HFpEF is reduced aerobic capacity, measured objectively as peak exercise pulmonary oxygen uptake (peak VO(2)), that results in decreased quality of life. Specifically, peak VO(2) of HFpEF patients is 30-70% lower than age-, sex-, and comorbidity-matched control patients without HF. The mechanisms for the reduced peak VO(2) are due to cardiovascular and skeletal muscle dysfunction that results in reduced oxygen delivery to and/or utilization by the active muscles. Currently, four randomized controlled exercise intervention trials have been performed in HFpEF patients. These studies have consistently demonstrated that 3-6 months of aerobic training performed alone or in combination with strength training is a safe and effective therapy to increase aerobic capacity and endurance and quality of life in HFpEF patients. Despite these benefits, the physiologic mechanisms underpinning the improvement in peak exercise performance have not been studied; therefore, future studies are required to determine the role of physical training to reverse the impaired cardiovascular and skeletal muscle function in HFpEF patients.

Purpose: Standards for estimating maximal HR are important when interpreting the adequacy of physiologic stress during exercise testing, assessing chronotropic response, and prescribing an exercise training regimen. The equation 220 - age is used to estimate maximum HR; however, it overestimates measured maximal HR in patients taking β-adrenergic blockade (βB) therapy. This study developed and validated a practical equation to predict maximal HR in patients with heart failure (HF) taking βB therapy., Methods: Data from symptom-limited exercise tests completed on patients with systolic HF participating in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial and taking a βB agent were used to develop a simplified equation, which was validated using bootstrapping., Results: The simplified derived equation was 119 + 0.5 (resting HR) - 0.5 (age) - (0, if test was completed using a treadmill; 5, if using a stationary bike). The R2 and SEE were 0.28 and 18 beats·min(-1), respectively. Validation of this equation yielded a mean R and SEE of 0.28 and 18 beats·min(-1), respectively. For the equation 220 - age, the R2 was -2.93, and the SEE was 43 beats·min(-1)., Conclusions: We report a valid and simple population-specific equation for estimating peak HR in patients with HF taking βB therapy. This equation should be helpful when evaluating chronotropic response or assessing if a maximum effort was provided during exercise testing. We caution, however, that the magnitude of the variation (SEE = 18 beats·min(-1)) associated with this prediction equation may make it impractical when prescribing exercise intensity.

Background: Many African Americans carry an amyloidogenic transthyretin mutation (TTR V122I), with a high risk for cardiac TTR amyloid deposition after the age of 65 years. We wished to determine the allele frequency and its clinical penetrance in community-dwelling African Americans., Methods: Five thousand consenting African Americans, aged 41 to 93 years, in 2 community studies of cardiovascular risk (CHS and ARIC) were included in the study. The following were performed: genotyping of banked DNA for TTR V122I allele status and review of cardiovascular and demographic parameters in CHS and ARIC databases, with statistical comparisons of the frequency of congestive heart failure, survival, and occurrence of features of cardiac amyloidosis in carriers of the amyloidogenic allele and controls., Results: One hundred nineteen (3.23%) of 3,712 ARIC and 17 (2.12%) of 805 CHS African Americans carried TTR V122I. After the age of 65 years (CHS), the frequencies of congestive heart failure (38% vs 15%, relative risk 2.62, P = .04) and mortality (76% vs 53%, relative risk 1.46, P = .08) were higher in V122I allele carriers than in age-, gender- and ethnically matched controls. In ARIC (all subjects <65 years old), there were no differences between carriers and noncarriers in mortality, frequency of congestive heart failure, or findings consistent with cardiac amyloidosis., Conclusions: Heterozygosity for the amyloidogenic TTR V122I mutation is relatively common in community-dwelling African Americans. Before the age of 65 years, the allele has no discernible impact on cardiac function or mortality. After the age of 70 years, carriers show a higher frequency of congestive failure and greater mortality with more echocardiographic evidence suggestive of cardiac amyloidosis, findings consistent with age-dependent clinical penetrance of this autosomal dominant gene., (2010 Mosby, Inc. All rights reserved.)

Background: Ventilatory efficiency (VE/VCO(2) slope) and peak oxygen consumption (VO) provide robust prognostic information in patients with heart failure undergoing cardiopulmonary exercise testing (CPX). The purpose of this study is to assess the change in prognostic characteristics of CPX at different time intervals., Methods and Results: Seven hundred ninety-one subjects (74% male, mean age: 60.7+/-12.9 years, ejection fraction: 34.6+/-15.0%, ischemic etiology: 51%) underwent CPX and were tracked for major cardiac events over a 4-year period. All event-free subjects were tracked for at least 3 years. Mean VE/VCO(2) slope and peak VO(2) were 35.0+/-10.0 and 16.0+/-6.4 mL O(2) . kg(-1) . min(-1), respectively. There were a total of 263 major cardiac events (199 deaths, 45 transplants, and 19 left ventricular assist device implantations). Both continuous and dichotomous expressions of the VE/VCO(2) slope and peak VO(2) were prognostically significant up to 18 months post-CPX. Continuous and dichotomous expressions of the VE/VCO(2) slope remained prognostically significant up to 36 months post-CPX, whereas peak VO(2) was not predictive during the third and fourth year of follow-up. In a multivariate analysis, the VE/VCO(2) slope was consistently the superior prognostic marker, whereas peak VO(2) added predictive value and was retained in the regression up to 18 months post-CPX., Conclusions: These results indicate that commonly assessed CPX variables retain prognostic value for at least 2 years. The VE/VCO(2) slope is the superior predictor of adverse events throughout follow-up, although peak VO(2) provides additive prognostic information during the first 2 years of follow-up.

Several investigations have demonstrated that higher body weight, as assessed by the body mass index, is associated with improved prognosis in patients with heart failure (HF). The purpose of the present investigation was to assess the influence of HF etiology on the prognostic ability of the body mass index in a cohort undergoing cardiopulmonary exercise testing. A total of 1,160 subjects were included in the analysis. All subjects underwent cardiopulmonary exercise testing, at which the minute ventilation/carbon dioxide production slope and peak oxygen consumption were determined. In the overall group, 193 cardiac deaths occurred during a mean follow-up of 30.7 +/- 25.6 months (annual event rate 6.0%). The subjects classified as obese consistently had improved survival compared to those classified as normal weight (overall survival rate 88.0% vs or=43.4, p <0.001) for both etiologies, and the body mass index added prognostic value (residual chi-square >or=4.7, p <0.05). In conclusion, these results further support the notion that obesity confers improved prognosis in patients with HF, irrespective of the HF etiology. Moreover, the body mass index appears to add predictive value during the cardiopulmonary exercise testing assessment. However, survival appears to differ according to HF etiology in subjects classified as overweight.

There is scarce information regarding the prognostic utility of peak exercise oxygen pulse (peak O(2) pulse), a surrogate for stroke volume, in patients with heart failure (HF). From May 1994 to November 2007, 998 patients with HF underwent cardiopulmonary exercise testing. The ability of peak oxygen uptake (VO(2)) and peak O(2) pulse to predict cardiac events was examined. Peak O(2) pulse was calculated by dividing peak VO(2) by heart rate at the time peak VO(2) was achieved and was expressed in both milliliters per beat and as a percentage achieved of the age-predicted value. There were 212 cardiac events (176 deaths, 26 transplantations, and 10 left ventricular assist device implantations) over a mean of 28 +/- 26 months of follow-up. Peak VO(2) and age-predicted peak O(2) pulse were demonstrated by univariate and multivariate Cox regression analyses to be independent predictors of mortality (p <0.001). The optimal cut points for peak VO(2) and age-predicted peak O(2) pulse (<14.3 and > or =14.3 [mL/kg(-1)/min(-1)] and <85% and > or =85%, respectively) were established by areas under the receiver-operating characteristic curves. Patients exhibiting abnormalities for both responses had 4.8-fold (95% confidence interval 2.7 to 8.5) and 6.7-fold (95% confidence interval 4.1 to 11.1) higher risks for mortality and cardiac events, respectively, than those whose responses were normal. Age-predicted peak O(2) pulse also predicted mortality in patients in the intermediate range of peak VO(2) (10 to 14 (mL/kg(-1)/min(-1))). The 3-year mortality rate for patients in this range who had age-predicted peak O(2) pulse values <85% was even slightly higher than those with peak VO(2) <10.1 (mL/kg(-1)/min(-1)). In conclusion, age-predicted peak O(2) pulse was a strong and independent predictor of cardiac mortality and complemented peak VO(2) in predicting risk in patients with HF.

Background: The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement., Methods and Results: We evaluated left atrial size in 230 healthy participants (mean age, 76+/-5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build., Conclusions: These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification.

Background: Peak oxygen consumption (Vo(2)) is routinely assessed in patients with heart failure undergoing cardiopulmonary exercise testing. The purpose of the present investigation was to determine the prognostic ability of several established peak Vo(2) prediction equations in a large heart failure cohort., Methods and Results: One thousand one hundred sixty-five subjects (70% males; age, 57.0+/-13.8 years; ischemic etiology, 43%) diagnosed with heart failure underwent cardiopulmonary exercise testing. Percent-predicted peak Vo(2) was calculated according to normative values proposed by Wasserman and Hansen (equation), Jones et al (equation), the Cooper Clinic (below low fitness threshold), a Veteran's Administration male referral data set (4 equations), and the St James Take Heart Project for women (equation). The prognostic significance of percent-predicted Vo(2) values derived from the 2 latter, sex-specific equations were assessed collectively. There were 179 major cardiac events (117 deaths, 44 heart transplantations, and 18 left ventricular assist device implantations) during the 2-year tracking period (annual event rate, 10%). Measured peak Vo(2) and all percent-predicted peak Vo(2) calculations were significant univariate predictors of adverse events (chi(2)> or =31.9, P<0.001) and added prognostic value to ventilatory efficiency (VE/Vco(2) slope), the strongest cardiopulmonary exercise testing predictor of adverse events (chi(2)=150.7, P<0.001), in a multivariate regression. The Wasserman/Hansen prediction equation provided optimal prognostic information., Conclusions: Actual peak Vo(2) and the percent-predicted models included in this analysis all were significant predictors of adverse events. It seems that the percent-predicted peak Vo(2) value derived from the Wasserman/Hansen equations may outperform other expressions of this cardiopulmonary exercise testing variable.

Background and Objectives: Although physical function is a major determinant of health outcomes and quality of life in older adults, standard tools for its assessment have not been routinely applied to the fastest growing segment of the kidney transplant candidate population, which is at high risk of comorbidity and disability--people over age 60. The objective of this study was to describe the baseline physical function in older adults with renal failure referred for transplantation and compare them with older adults with other significant comorbidity., Design, Setting, Participants, & Measurements: An observational sample comparing physical performance in renal transplant candidates over age 60 (Renal Failure) to older people with diastolic heart failure (Heart Failure), chronic obstructive pulmonary disease (COPD), or at high risk for cardiovascular disease (High CV Risk) was studied., Results: Older people with Renal Failure were significantly impaired by objective measures of physical function, including lower Short Physical Performance Battery, slower gait speed, and lower grip strength., Conclusions: Older people referred for renal transplantation had poorer physical performance than older adults with other common chronic diseases and may be at high risk for disability while awaiting transplantation.

Background: The resting partial pressure of end-tidal carbon dioxide (Petco2) has been shown to reflect cardiac performance in acute care settings in patients with heart failure (HF). The purpose of the present study was to compare the prognostic ability of the partial pressure of Petco2 at rest to other commonly collected resting variables in patients with systolic HF., Methods: A total of 353 patients (mean age 58.6+/-13.7, 72% male) with systolic HF were included in this study. All patients underwent cardiopulmonary exercise testing where New York Heart Association (NYHA) class, resting Petco2, peak oxygen consumption, and the minute ventilation/carbon dioxide production slope were determined. Subjects were then followed for major cardiac events (mortality, left ventricular assist device implantation implantation, urgent heart transplantation)., Results: There were 104 major cardiac events during the 23.6+/-17.0-month tracking period. Multivariate Cox regression analysis revealed NYHA class (chi2 28.7, P<.001), left ventricular ejection fraction (residual chi2 21.7, P<.001), and resting Petco2 (residual chi2 14.1, P<.001) were all prognostically significant and retained in the regression. In a separate Cox regression analysis, left ventricular ejection fraction (residual chi2 8.8, P=.003), NYHA class (residual chi2 7.7, P=.005), and resting Petco2 (residual chi2 5.7, P=.02) added prognostic value to the minute ventilation/carbon dioxide production slope (chi2 26.0, P<.001)., Conclusion: Resting Petco2 can be noninvasively collected from subjects in a short period, at a low cost, and with no risk or discomfort to the patient. Given the prognostic value demonstrated in the present study, the clinical assessment of resting Petco2 in the HF population may be warranted.

There is a need for an accurate, sensitive and selective high-performance liquid chromatography (HPLC) method for the quantitation of ivermectin in human plasma that separates the parent drug from metabolites. Ivermectin and the internal standard, moxidectin, were extracted from 0.2 ml of human plasma using Oasis HLB solid phase extraction cartridges. After extraction, fluorescent derivatives of ivermectin and moxidectin were made by reaction with trifluoroacetic anhydride and N-methylimidazole. Separation was achieved on a Alltech Ultrasphere C18 5mu column with a mobile phase composed of tetrahydrofuran-acetonitrile-water (40:38:22 v/v/v). Detection is by fluorescence, with an excitation of 365 nm and emission of 475 nm. The retention times of ivermectin and internal standard, moxidectin are approximately 24.5 and 12.5 min, respectively. The assay is linear over the concentration range of 0.2-200 ng/ml of ivermectin in human plasma (r = 0.9992, weighted by 1/concentration). Recoveries of ivermectin are greater than 80% at all concentrations. The analysis of quality control samples for ivermectin 0.2, 25, and 200 ng/ml demonstrated excellent precision with coefficient of variation of 6.1, 3.6 and 2.3%, respectively (n = 6). The method is accurate with all intra-day (n = 6) and interday (n = 12) mean concentration within 10% of nominal values at all quality control sample concentrations. Storage stability for 30 days at -80 degrees C and after three freeze-thaw cycles are within acceptable limits. The method separates ivermectin from multiple less and more polar unidentified metabolites. This method is robust and suitable for clinical pharmacokinetic studies. The analytical procedure has been applied to a pharmacokinetic study of ivermectin in healthy volunteers and to the analysis of plasma specimens from patients with disseminated strongyloidiasis.

Exaggerated blood pressure (BP) reactivity to stress may contribute to left ventricular (LV) hypertrophy, a major risk factor for cardiovascular morbidity. This study examined the extent to which BP responses to acute stress are associated with LV mass and relative wall thickness in a community sample of African-American and white men and women. BP was measured at rest and in response to 2 acute challenges (mental arithmetic and handgrip). Systolic BP at rest was positively associated with LV mass and relative wall thickness (p < 0.001). The associations between the responses to the stressors and LV mass were not significant. African-American and white men who exhibited high BP responses to the arithmetic stressor had greater relative wall thickness than those with low reactivity (p < 0.05). In conclusion, BP reactivity is not related to LV mass, but may be related to concentric remodeling.

Congestive heart failure in the elderly is recognized as a national public health priority; however, clinical diagnosis can be problematic in elderly persons, many of whom have a history of heart failure in the presence of normal or only minimally decreased ejection fraction. Findings of the Cardiovascular Health Study have underscored the common substrate and predictors underlying heart failure both with decreased ejection fraction and with normal ejection fraction (i.e., diastolic heart failure). Coronary heart disease, systolic blood pressure, and C-reactive protein (a measure of inflammation) are predictive of heart failure independent of ejection fraction. Left atrial size, arguably a marker of the effects of impaired diastolic filling over time, is increased in both systolic and diastolic heart failure of the elderly, as is atrial natriuretic peptide. The outcome of heart failure in elderly persons is poor both for systolic and diastolic heart failure. Moreover, many community-dwelling elderly persons have decreased ejection fraction without heart failure. In these persons the chance of death is similar to that of participants with diastolic heart failure. Since most clinical trials have studied younger patients with predominantly systolic heart failure, the appropriate therapy for heart failure in elderly persons remains to be determined.

A sensitive and selective HPLC chromatography method using UV detection (295 nm) was developed for the determination of albendazole, albendazole sulfoxide (ABZSO), and albendazole sulfone (ABZSO2) in human plasma. Albendazole, ABZSO, ABZSO2, and the internal standard, oxibendazole, were extracted from human plasma by loading onto a conditioned C(18) SPE cartridge, rinsing with 15% methanol, and eluting with 90% methanol. Samples were evaporated under a stream of nitrogen, reconstituted with mobile phase, 1.25% triethylamine in water-methanol-acetonitrile (72:15:13, v/v/v) (pH* 3.1), and injected onto a Waters muBondapak Phenyl 3.9 x 300 mm HPLC column. Mobile phase flow rate was 1.0 ml/min. The retention times of albendazole, ABZSO, ABZSO2, and the internal standard were approximately 24.4, 7.9, 13.4, and 11.3 min, respectively. Total run time was 30 min. The assay was linear for concentration ranges in human plasma of 20-600 ng/ml for albendazole, 20-1000 ng/ml for ABZSO, and 20-300 ng/ml for ABZSO2. The analysis of quality control samples demonstrated excellent precision. Coefficients of variation for albendazole (20, 400, 600 ng/ml) were 6.7, 8.1 and 7.0%; ABZSO (20, 400, 800 ng/ml) were 6.0, 8.5 and 5.9%; ABZSO2 (20, 150, 300 ng/ml) were 3.1, 3.9 and 2.3%, respectively. The method appears to be robust and has been applied to a pharmacokinetic study of albendazole in healthy volunteers., (Copyright 2002 Elsevier Science B.V.)

Background: Evidence suggests that left ventricular (LV) mass is under genetic control, independently of risk factors known to influence LV size and geometry., Methods: As part of the HyperGEN study, four field centers recruited African American and white hypertensive siblings (n = 1,664), aged 23 to 87 years. Two-dimensionally guided M-mode echocardiography was performed, and LV mass and relative wall thickness (RWT) were measured at a central reading center. Familial correlations were calculated separately for each ethnic group using maximum likelihood methods, adjusted for the potential confounding influences of age, gender, systolic blood pressure, and obesity., Results: In African Americans, brother-sister, brother-brother, and sister-sister correlation coefficients and standard errors for LV mass were 0.29 (0.08), 0.44 (0.10), and 0.33 (0.05). In whites, the corresponding correlations were lower than in African Americans at 0.05 (0.08), 0.12 (0.11), and 0.22 (0.09), respectively. Sibling correlation of LV geometry, assessed by RWT, was less in African Americans than in whites: brother-sister, 0.04 (0.10) v 0.21 (0.10), brother-brother, 0.12 (0.22) v 0.28 (0.09), and sister-sister, 0.11 (0.07) v 0.19 (0.11)., Conclusions: LV mass is strongly correlated in hypertensive African American siblings, and modestly correlated in their white counterparts, whereas RWT has stronger sibling correlation in whites. The patterns of familial correlation of echocardiographic LV mass and RWT suggest that the genetic underpinnings of LV hypertrophy and geometric remodeling may differ among ethnic groups.