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Abstract Background Older heart failure (HF) patients exhibit exercise intolerance during activities of daily living. We hypothesized that reduced lower extremity blood flow (LBF) due to reduced forward cardiac output would contribute to submaximal exercise intolerance in older HF patients. Methods and Results Twelve HF patients both with preserved and reduced left ventricular ejection fraction (LVEF) (aged 68 ± 10 years) without large (aorta) or medium sized (iliac or femoral artery) vessel atherosclerosis, and 13 age and gender matched healthy volunteers underwent a sophisticated battery of assessments including a) peak exercise oxygen consumption (peak VO2), b) physical function, c) cardiovascular magnetic resonance (CMR) submaximal exercise measures of aortic and femoral arterial blood flow, and d) determination of thigh muscle area. Peak VO2 was reduced in HF subjects (14 ± 3 ml/kg/min) compared to healthy elderly subjects (20 ± 6 ml/kg/min) (p = 0.01). Four-meter walk speed was 1.35 ± 0.24 m/sec in healthy elderly verses 0.98 ± 0.15 m/sec in HF subjects (p < 0.001). After submaximal exercise, the change in superficial femoral LBF was reduced in HF participants (79 ± 92 ml/min) compared to healthy elderly (222 ± 108 ml/min; p = 0.002). This occurred even though submaximal stress-induced measures of the flow in the descending aorta (5.0 ± 1.2 vs. 5.1 ± 1.3 L/min; p = 0.87), and the stress-resting baseline difference in aortic flow (1.6 ± 0.8 vs. 1.7 ± 0.8 L/min; p = 0.75) were similar between the 2 groups. Importantly, the difference in submaximal exercise induced superficial femoral LBF between the 2 groups persisted after accounting for age, gender, body surface area, LVEF, and thigh muscle area (p ≤ 0.03). Conclusion During CMR submaximal bike exercise in the elderly with heart failure, mechanisms other than low cardiac output are responsible for reduced lower extremity blood flow.

Abstract Background To determine if patients without dobutamine induced left ventricular wall motion abnormalities (WMA) but an increased LV end-diastolic wall thickness (EDWT) exhibit a favorable cardiac prognosis. Results Between 1999 and 2001, 175 patients underwent a dobutamine stress cardiovascular magnetic resonance (DCMR) procedure utilizing gradient-echo cines. Participants had a LV ejection fraction >55% without evidence of an inducible WMA during peak dobutamine/atropine stress. After an average of 5.5 years, all participants were contacted and medical records were reviewed to determine the post-DCMR occurrence of cardiac death, myocardial infarction (MI), and unstable angina (USA) or congestive heart failure (CHF) warranting hospitalization. In a multivariate analysis, that took into account Framingham and other risk factors associated with cardiac events, a cine gradient-echo derived LV EDWT ≥12 mm was associated independently with an increase in cardiac death and MI (HR 6.0, p = 0.0016), and the combined end point of MI, cardiac death, and USA or CHF warranting hospitalization (HR 3.0, p = 0.0005). Conclusion Similar to echocardiography, CMR measures of increased LV wall thickness should be considered a risk factor for cardiac events in individuals receiving negative reports of inducible ischemia after dobutamine stress. Additional prognostic studies of the importance of LV wall thickness and mass measured with steady-state free precession techniques are warranted.

Abstract Background Left ventricular (LV) mass and wall thickness are closely associated with measures of body size and blood pressure and also correlated with systolic and diastolic function, suggesting a contribution of common physiologic mechanisms, including pleiotropic genes, to their covariation. Methods Doppler echocardiography was performed in 434 African-American (1344 individuals) and 284 white families (1119 individuals). We conducted a genome-wide linkage scan for LV mass, LV structure and function, and composite factors derived from a factor analysis of LV structure and function in the HyperGEN Study population. Results Factor analysis identified (i) a LV wall thickness factor correlated strongly with interventricular septal thickness (IVSTd) and posterior wall thickness (PWTd) and (ii) a LV diastolic filling factor strongly correlated with early and atrial phase peak transmitral filling velocities. The LV phenotypes and composite factor scores were analyzed in multipoint variance components linkage model implemented in SOLAR with 387 microsatellite markers. In whites, the two highest LODs were 3.42 for LV atrial phase peak filling velocity at 144 cM on chromosome 1 and 3.12 for the LV wall thickness factor at 160 cM on chromosome 7. The peak LODs of the component traits (IVSTd and PWTd) clustered at the same region as the composite factor. Adjusting the factor score for body mass index (BMI) substantially reduced the peak LOD at this region (LOD = 1.92). Bivariate linkage analysis of the composite factor with BMI improved LOD to 3.42 at 158 cM. Also in whites, suggestive linkage was observed on chromosomes 2 and 4 for LV mass, chromosomes 3, 5, 10, and 17 for LV atrial phase peak filling velocity, and chromosome 10 for LV diastolic filling factor. In African Americans, suggestive linkage was observed on chromosome 12 for LV mass, chromosome 21 for IVSTd, and chromosome 3 for LV internal diameter at end-diastole. Conclusion Our study suggests that a region on chromosome 7 contains pleiotropic genes contributing to the variations of both LV wall thickness and BMI in whites.

Background: Although the prognostic implications of higher pulmonary artery systolic pressure (PASP) are well established, few data exist regarding longitudinal change in pulmonary pressure in late life., Objectives: The aim of this study was to quantify changes in PASP over 6 years and determine the relative contributions of cardiac and pulmonary dysfunction., Methods: Among 1,420 participants in the ARIC (Atherosclerosis Risk in Communities) study with echocardiographic measures of PASP at both the fifth (2011-2013) and seventh (2018-2019) visits, longitudinal changes in PASP over about 6.5 years were quantified. Multivariable regression was used to determine the extent to which cardiac and pulmonary dysfunction were associated with changes in PASP and to define the relationship of changes in PASP with dyspnea development., Results: The mean age was 75 ± 5 years at visit 5 and 81 ± 5 years at visit 7, 24% of subjects were Black adults, and 68% were women. Over the 6.5 years, PASP increased by 5 ± 8 mm Hg, from 28 ± 5 to 33 ± 8 mm Hg. PASP increased more in older participants. Predictors of greater increases in PASP included worse left ventricular (LV) systolic and diastolic function, pulmonary function, and renal function. Increases in PASP were associated with concomitant increases in measures of LV filling pressure, including E/e' ratio and left atrial volume index. Each 5 mm Hg increase was associated with 16% higher odds of developing dyspnea (OR: 1.16; 95% CI: 1.07-1.27; P < 0.001)., Conclusions: Pulmonary pressure increased over 6.5 years in late life, was associated with concomitant increases in LV filling pressure, and predicted the development of dyspnea. Interventions targeting LV diastolic function may be effective at mitigating age-related increases in PASP., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, under contracts HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. Dr Shah is also supported by National Institutes of Health/National Heart, Lung, and Blood Institute grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, R01HL160025, and K24HL152008. The funder had no role design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Shah has received consulting fees from Philips Ultrasound and Janssen; and has received research funds from Novartis through Brigham and Women’s Hospital. Dr Skali has received consulting fees from Astellas; and has research support from ABT Associates. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Lepidopterans affect crop production worldwide. The use of transgenes encoding insecticidal proteins from Bacillus thuringiensis ( Bt ) in crop plants is a well-established technology that enhances protection against lepidopteran larvae. Concern about widespread field-evolved resistance to Bt proteins has highlighted an urgent need for new insecticidal proteins with different modes or sites of action. We discovered a new family of insecticidal proteins from ferns. The prototype protein from Pteris species (Order Polypodiales) and variants from two other orders of ferns, Schizaeales and Ophioglossales, were effective against important lepidopteran pests of maize and soybean in diet-based assays. Transgenic maize and soybean plants producing these proteins were more resistant to insect damage than controls. We report here the crystal structure of a variant of the prototype protein to 1.98 Å resolution. Remarkably, despite being derived from plants, the structure resembles the 3-domain Cry proteins from Bt but has only two out of three of their characteristic domains, lacking the C-terminal domain which is typically required for their activities. Two of the fern proteins were effective against strains of fall armyworm that were resistant to Bt 3-domain Cry proteins Cry1Fa or Cry2A.127. This therefore represents a novel family of insecticidal proteins that have the potential to provide future tools for pest control.

Background: There is limited data regarding longitudinal changes of diastolic function in the very old, who are at the highest risk for heart failure (HF)., Objectives: This study aims to quantify intraindividual longitudinal changes of diastolic function over 6 years in late life., Methods: The authors studied 2,524 older adult participants in the prospective community-based ARIC (Atherosclerosis Risk In Communities) study who underwent protocol-based echocardiography at study visits 5 (2011-2013) and 7 (2018-2019). The primary diastolic measures were tissue Doppler e', E/e' ratio, and left atrial volume index (LAVI)., Results: Mean age was 74 ± 4 years at visit 5 and 80 ± 4 at visit 7, 59% were women, and 24% were Black. At visit 5, mean e' septal was 5.8 ± 1.4 cm/s, E/e' septal 11.7 ± 3.5, and LAVI 24.3 ± 6.7 mL/m 2 . Over a mean of 6.6 ± 0.8 years, e' septal decreased by 0.6 ± 1.4 cm/s, E/e' septal increased by 3.1 ± 4.4, and LAVI increased by 2.3 ± 6.4 mL/m 2 . The proportion with 2 or more abnormal diastolic measures increased from 17% to 42% (P < 0.001). Compared with participants free of cardiovascular (CV) risk factors or diseases at visit 5 (n = 234), those with prevalent CV risk factors or diseases but without prevalent or incident HF (n = 2,150) demonstrated greater increases in E/e' septal and LAVI. Increases of E/e' septal and LAVI were both associated with the development of dyspnea between visits in analyses adjusted for CV risk factors., Conclusions: Diastolic function generally deteriorates over 6.6 years in late life, particularly among persons with CV risk factors, and is associated with development of dyspnea. Further studies are necessary to determine if risk factor prevention or control will mitigate these changes., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), under contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. Dr Shah was supported by NIH/NHLBI grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, R01HL160025, and K24HL152008; and has received research support not related to the present work from Novartis and Philips Ultrasound; and consulting fees from Philips Ultrasound. Dr Claggett has received consulting fees from Myokardia, Gilead, AOBiome, Boehringer Ingelheim, Novartis, Amgen, and Corvia. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pre-heart failure (pre-HF) is an entity known to progress to symptomatic heart failure (HF)., Objectives: This study aimed to characterize pre-HF prevalence and incidence among Hispanics/Latinos., Methods: The Echo-SOL (Echocardiographic Study of Latinos) assessed cardiac parameters on 1,643 Hispanics/Latinos at baseline and 4.3 years later. Prevalent pre-HF was defined as the presence of any abnormal cardiac parameter (left ventricular [LV] ejection fraction <50%; absolute global longitudinal strain <15%; grade 1 or more diastolic dysfunction; LV mass index >115 g/m 2 for men, >95 g/m 2 for women; or relative wall thickness >0.42). Incident pre-HF was defined among those without pre-HF at baseline. Sampling weights and survey statistics were used., Results: Among this study population (mean age: 56.4 years; 56% female), HF risk factors, including prevalence of hypertension and diabetes, worsened during follow-up. Significant worsening of all cardiac parameters (except LV ejection fraction) was evidenced from baseline to follow-up (all P < 0.01). Overall, the prevalence of pre-HF was 66.7% at baseline and the incidence of pre-HF during follow-up was 66.3%. Prevalent and incident pre-HF were seen more with increasing baseline HF risk factor burden as well as with older age. In addition, increasing the number of HF risk factors increased the risk of prevalence of pre-HF and incidence of pre-HF (adjusted OR: 1.36 [95% CI: 1.16-1.58], and adjusted OR: 1.29 [95% CI: 1.00-1.68], respectively). Prevalent pre-HF was associated with incident clinical HF (HR: 10.9 [95% CI: 2.1-56.3])., Conclusions: Hispanics/Latinos exhibited significant worsening of pre-HF characteristics over time. Prevalence and incidence of pre-HF are high and are associated with increasing HF risk factor burden and with incidence of cardiac events., Competing Interests: Funding Support and Author Disclosures The baseline examination of HCHS/SOL was conducted as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC652237). The following institutes/centers/offices contributed to the HCHS/SOL first funding period through a transfer of funds to the National Heart, Lung, and Blood Institute: National Institute of Deafness and Other Communications Disorders; the National Institute of Dental and Craniofacial Research; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Neurological Disorders and Stroke; and the National Institutes of Health Office of Dietary Supplements. Echo-SOL was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL04199, Epidemiological Determinants of Cardiac Structure and Function among Hispanics; 2R01HL104199, Epidemiologic Determinants of Change in Cardiac Structure and Function among Hispanics: Carlos J. Rodriguez, MD, MPH, principal investigator). Dr Kizer owns stocks in Abbott, Bristol Myers Squibb, Johnson and Johnson, Medtronic, Merck, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Frailty and heart failure frequently coexist in late life. Limited data exist regarding the longitudinal associations of frailty and subclinical cardiac dysfunction. We aim to quantify the association of frailty with longitudinal changes in cardiac function and of cardiac function with progression in frailty status in older adults. Methods and Results Participants in the Atherosclerosis Risk in Communities cohort underwent frailty assessments at Visit 5 (V5; 2011-2013), V6 (2016-2017), and V7 (2018-2019), and echocardiographic assessments at V5 and V7. We assessed the association between frailty status at V5 and changes in frailty status from V5 to V7 and changes in cardiac function over 6 years. We then evaluated the association of cardiac function measured at Visit 5 with progression in frailty status over 4 years. Multivariable regression models adjusted for demographics and comorbidities. Among 2574 participants free of heart failure at V5 and V7 (age 74±4 years at V5 and 81±4 years at V7), 3% (n=83) were frail. Frailty at V5 was associated with greater left atrial volume index and E/e' ratio at V5 and 7. Participants who transitioned from robust at V5 to frail at V7 demonstrated greater increases in left ventricular mass index, left atrial volume index, and E/e' over the same period. Among 1648 robust participants at Visit 5, greater left ventricular mass index and mean wall thickness, lower tissue Doppler imaging e', and higher E/e' ratio at Visit 5 were associated with progression in frailty status. Conclusions Among robust, older adults free of heart failure, progression in frailty and subclinical left ventricular remodeling and diastolic dysfunction are interrelated.

Background: Clinical trials are needed to study topics relevant to older adults with serious illness. Investigators conducting clinical trials with this population are challenged by how to appropriately define, classify, report, and monitor serious and non-serious adverse events (SAEs/AEs), given that some traditionally reported AEs (pressure ulcers, delirium) and SAEs (death, hospitalization) are common in persons with serious illness, and may be consistent with their goals of care., Objectives: A multi-stakeholder group convened to establish greater clarity on and new approaches to address this critical issue., Participants: Thirty-two study investigators, members of regulatory and sponsor agencies, and patient stakeholders took part., Approach: The group met virtually four times and, using a collaborative approach, conducted a survey, select interviews, and reviewed regulatory guidance to collectively define the problem and identify a new approach., Results: SAE/AE challenges fell into two areas: (1) definitions and classifications, including (a) implausible relationships, (b) misalignment with patient-centered care goals, and (c) well-known associations, and (2) reporting and monitoring, including (a) limited guidance, (b) inconsistent standards across regulators, and (c) Data Safety Monitoring Board (DSMB) member knowledge gaps. Problems largely reflected practice norms rather than regulatory requirements that already support context-specific and aggregate reporting. Approaches can be improved by adopting principles that better align strategies for addressing adverse events with the type of intervention being tested, favoring routine and aggregate over expedited reporting, and prioritizing how SAE/AEs relate to patient-centered care goals. Reporting plans and decisions should follow an algorithm underpinned by these principles., Conclusions: Adoption of the proposed approach-and supporting it with education and better alignment with regulatory guidance and procedures-could improve the quality and efficiency of clinical trials' safety involving older adults with serious illness and other vulnerable populations., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Limited data exist to characterize novel measures of left atrial (LA) structure and function in older adults without prevalent heart failure (HF)., Objectives: The aim was to assess reference range of LA measures, their associations with N-terminal pro-B-type natriuretic-peptide (NT-proBNP) and the related risk for incident HF or death., Methods: We analyzed LA structure (LA maximal [LAViMax] and minimal volume indexed by body surface area) and function (LA emptying fraction, LA reservoir, conduit, and contraction strain) in 4,901 participants from the ARIC (Atherosclerosis Risk In Communities) study (mean age 75 ± 5 years, 40% male, and 19% Black) without prevalent HF. We assessed sex-specific 10th and 90th percentile ARIC-based reference limits in 301 participants free of prevalent cardiovascular disease, and related LA measures to NT-proBNP and incident HF or death (median follow-up of 5.5 years) in the whole ARIC cohort., Results: Approximately 20% of the overall population had LA abnormalities according to the ARIC-based reference limit. Each LA measure was associated with NT-proBNP and, except for LAViMax, with incident HF or death after multivariable adjustment (including left ventricular function and NT-proBNP). Results were consistent in participants with normal LAViMax (P for interaction > 0.05). LA measures were prognostic for both incident HF with preserved ejection fraction or death and incident HF with reduced ejection fraction or death. When added to HF risk factors and NT-proBNP (baseline C-statistics = 0.74) all LA measures, except for LAViMax, significantly enhanced the prognostic accuracy., Conclusions: Novel measures of LA structure and function, but not standard assessment by LAViMax, are associated with increased risk of incident HF or death regardless of measures of left ventricular function and NT-proBNP., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I. This study was funded by grants R01 HL141288 (Dr Chen). Additionally, Dr Chen is funded by R01 HL126637 and K24 HL155813. Dr Skali has received stock options in OptimizeRx for consulting/advisory roles. Dr Shah has received other fees from Novartis; and has received personal fees from Philips Ultrasound and Bellerophon Therapeutics, outside the submitted work. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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: 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.

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.)

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.)

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.)

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.

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.)