NT-proBNP and Cardiac Troponin I, but Not Cardiac Troponin T, Are Associated With 7-Year Changes in Cardiac Structure and Function in Older Adults: The ARIC Study.

BACKGROUND: Higher circulating concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) are associated with left ventricular remodeling and with incident heart failure. The associations of these cardiac biomarkers with changes in cardiac structure and function over time are uncharacterized. METHODS: Among 2006 participants in the ARIC prospective cohort study (Atherosclerosis Risk in Communities) who were free of overt cardiovascular disease and underwent echocardiography at study visits 5 (2011- 2013) and 7 (2018-2019), we assessed the associations of NT-proBNP, hs-cTnT, and hs-cTnI concentrations at visit 5 with changes in left ventricular structure and function between visits 5 and 7 (≈7-year change) using multivariable linear regression with the biomarkers modeled as restricted cubic splines. Models were adjusted for age, sex, race, body mass index, smoking, diabetes, hypertension, and renal function at visit 5; blood pressure and heart rate at both visits; and the baseline value of the echocardiographic parameter of interest. RESULTS: Mean±SD age was 74±4 years at visit 5; 61% were women; and 23% were Black adults. Median (25th-75th percentile) concentrations at visit 5 of NT-proBNP, hs-cTnT, and hs-cTnI were 87 ng/L (50-157 ng/L), 9 ng/L (6-12 ng/L), and 2.6 ng/L (1.9-3.9 ng/L). In adjusted models, elevated baseline concentrations of NT-proBNP and hs-cTnI were significantly associated with 7-year decline in left ventricular systolic function (ejection fraction, longitudinal and circumferential strain) and worsening diastolic indices. In contrast, elevated baseline concentrations of hs-cTnT were not significantly associated with 7-year changes in cardiac structure, systolic function, or diastolic function (all P>0.05). CONCLUSIONS: Higher concentrations of NT-proBNP and hs-cTnI, but not hs-cTnT, were associated with greater declines in left ventricular function over ≈7 years in late life independently of traditional cardiovascular risk factors.AQ.

Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. METHODS: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. RESULTS: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. CONCLUSIONS: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.

Association of diabetes and glycemic control with left atrial function: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: Although glycemic status is associated with impaired cardiac structure and function, less is known on left atrial (LA) function across the glycemic spectrum. We evaluated the association of diabetes and glycemic control with LA function in a community-based cohort of older adults. METHODS AND RESULTS: This cross-sectional analysis included 5075 participants from the Atherosclerosis Risk in Communities Study (mean age 75.5 years, 58 % women, and 20 % Black adults) with echocardiographic strain data for LA reservoir, conduit, and contractile function. Multivariable linear regression was used to assess associations of diabetes status and glycemic control with LA function. In participants without diabetes, we used ordinal linear regression to evaluate associations of fasting glucose and HbA1c with LA function. Compared to individuals with a normal fasting glucose, prevalent diabetes was associated with 0.68 % lower LA conduit function (95 % confidence interval (CI): 1.11 to -0.25) and prediabetes a 0.47 % reduction (95 % CI: 0.85 to -0.09) in fully adjusted analyses. Persons with diabetes and high HbA1c (HgbA1c ≥ 7 % vs <7 %) had 1.05 % lower LA conduit function (95 % CI: 1.63, -0.48). Among individuals without diagnosed diabetes, higher fasting glucose, but not HbA1c, was significantly associated with worse LA conduit function. No significant associations were observed for LA reservoir and contractile function. CONCLUSIONS: A history of diabetes, prediabetes, and higher fasting glucose levels in persons without diabetes were associated with worse LA conduit function. Corroborative research is needed in prospective cohorts as well as studies that explore underlying mechanisms.

Left Atrial Mechanical Dysfunction and the Risk for Ischemic Stroke in People Without Prevalent Atrial Fibrillation or Stroke : A Prospective Cohort Study.

BACKGROUND: Atrial myopathy-characterized by changes in left atrial function and size-may precede and promote atrial fibrillation (AF) and cardiac thromboembolism. In people without prior AF or stroke, whether analysis of left atrial function and size can improve ischemic stroke prediction is unknown. OBJECTIVE: To evaluate the association of echocardiographic left atrial function (reservoir, conduit, and contractile strain) and left atrial size (left atrial volume index) with ischemic stroke and determine whether these measures can improve the stroke prediction achieved by CHA2DS2-VASc score variables. DESIGN: Prospective cohort study. SETTING: ARIC (Atherosclerosis Risk in Communities) study. PARTICIPANTS: 4917 ARIC participants without prevalent stroke or AF. MEASUREMENTS: Ischemic stroke events (2011 to 2019) were adjudicated by physicians. Left atrial strain was measured using speckle-tracking echocardiography. RESULTS: Over 5 years, the cumulative incidences of ischemic stroke in the lowest quintiles of left atrial reservoir, conduit, and contractile strain were 2.99% (95% CI, 1.89% to 4.09%), 3.18% (CI, 2.14% to 4.22%), and 2.15% (CI, 1.09% to 3.21%), respectively, and that of severe left atrial enlargement was 1.99% (CI, 0.23% to 3.75%). On the basis of the Akaike information criterion, left atrial reservoir strain plus CHA2DS2-VASc variables was the best predictive model. With the addition of left atrial reservoir strain to CHA2DS2-VASc variables, 11.6% of the 112 participants with stroke after 5 years were reclassified to higher risk categories and 1.8% to lower risk categories. Among the 4805 participants who did not develop stroke, 12.2% were reclassified to lower and 12.7% to higher risk categories. Decision curve analysis showed a predicted net benefit of 1.34 per 1000 people at a 5-year risk threshold of 5%. LIMITATION: Underascertainment of subclinical AF. CONCLUSION: In people without prior AF or stroke, when added to CHA2DS2-VASc variables, left atrial reservoir strain improves stroke prediction and yields a predicted net benefit, as shown by decision curve analysis. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy.

BACKGROUND: Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI. METHODS: In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes. RESULTS: Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e'lat (P=0.005), decrease in E/e'lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure. CONCLUSIONS: Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Vitamin D Levels in Black Americans and the Association With Left Ventricular Remodeling and Incident Heart Failure With Preserved Ejectin Fraction: The Jackson Heart Study.

BACKGROUND: In observational studies, a lower serum vitamin D3 concentration has been associated with an increased risk of cardiovascular disease. However, the associations between serum vitamin D3 levels and left ventricular (LV) structure and heart failure with preserved ejection fraction (HFpEF) have not been well-characterized among Black Americans. The prevalence of vitamin D3 deficiency is higher among Black Americans than in other race/ethnicity groups. We hypothesized that serum vitamin D3 levels are associated with LV concentric remodeling and incident HFpEF in Black Americans. METHODS AND RESULTS: Among 5306 Black Americans in the Jackson Heart Study cohort, we investigated the relationships between serum vitamin D3 levels and LV structure and function, evaluated with echocardiography, and incident HF hospitalization, categorized as either HF with reduced EF (HFrEF; an EF of <50%) or HFpEF (an EF of ≥50%). After adjustment for possible confounding factors, lower vitamin D3 levels were associated with greater relative wall thickness (ß for 1 standard deviation [SD] increase -0.003, 95% confidence interval -0.005 to -0.000). Over a median follow-up period of 11 years (range 10.2-11.0 years), 340 participants developed incident HF (7.88 cases per 1000 person-years), including 146 (43%) HFrEF and 194 (57%) HFpEF cases. After adjustment, higher serum vitamin D3 levels were associated with decreased hazard for HF overall (hazard ratio for 1 SD increase 0.88, 95% confidence interval 0.78-0.99) driven by a significant association with HFpEF (hazard ratio for 1 SD increase 0.84, 95% confidence interval 0.71-0.99). CONCLUSIONS: In this community-based Black American cohort, lower serum vitamin D3 levels were associated with LV concentric remodeling and an increased hazard for HF, mainly HFpEF. Further investigation is required to examine whether supplementation with vitamin D3 can prevent LV concentric remodeling and incident HFpEF in Black Americans.

Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study.

AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993-1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.0 years, 54% women, 27% black adults), elevated GDF-15 (≥75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.0001). During 23 years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (ΔC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001). CONCLUSIONS/INTERPRETATION: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes.

Apolipoprotein E Polymorphism, Cardiac Remodeling, and Heart Failure in the ARIC Study.

BACKGROUND: ß-Amyloid has recently been discovered in the myocardium of patients with Alzheimer's disease (AD). Whether genetic variation in apolipoprotein E (APOE) ɛ4, a common variant associated with Alzheimer's disease, is associated with incident heart failure (HF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac structure and function is unknown. METHODS AND RESULTS: We studied 15,064 White and Black participants in the Atherosclerosis Risk in Communities, relating genotype status at visit 1 (1987-1989) to incident HF hospitalization using Cox regression. At visits 2, 4, and 5, we assessed NT-proBNP levels by genotype. At visits 3 and 5, we related Aß peptides to incident HF. At visit 5 (2011-2013, n = 6251), we assessed the relationship of genotype with prevalent HF and echocardiographic parameters. The mean participant age was 54.7 ± 5.8 years, 45% were men, and 73% were White. At visit 5, there was no difference in prevalent HF by genotype. The APOE ε4 carriers did not have increased risk for HF hospitalization. The APOE ε4 genotype was not associated with cardiac structure and function or NT-proBNP levels. The Aß peptides were not associated with incident HF after multivariable adjustment. CONCLUSIONS: A genetic predisposition to Alzheimer's disease through APOE ε4 is not associated with an increased prevalence of HF, HF hospitalization, myocardial remodeling, or biochemical evidence of HF.

Factors Associated With Cognitive Impairment in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Cognitive impairment is prevalent in heart failure and is associated with higher mortality rates. The mechanism behind cognitive impairment in heart failure with preserved ejection fraction (HFpEF) has not been established. OBJECTIVE: The aim of this study was to evaluate associations between abnormal cardiac hemodynamics and cognitive impairment in individuals with HFpEF. METHODS: A secondary analysis of Atherosclerosis Risk in Communities (Atherosclerosis Risk in Communities) study data was performed. Participants free of stroke or dementia who completed in-person assessments at visit 5 were included. Neurocognitive test scores among participants with HFpEF, heart failure with reduced ejection fraction (HFrEF), and no heart failure were compared. Sociodemographics, comorbid illnesses, medications, and echocardiographic measures of cardiac function that demonstrated significant (P < .10) bivariate associations with neurocognitive test scores were included in multivariate models to identify predictors of neurocognitive test scores among those with HFpEF. Multiple imputation by chained equations was used to account for missing values. RESULTS: Scores on tests of attention, language, executive function, and global cognitive function were worse among individuals with HFpEF than those with no heart failure. Neurocognitive test scores were not significantly different among participants with HFpEF and HFrEF. Worse diastolic function was weakly associated with worse performance in memory, attention, and language. Higher cardiac index was associated with worse performance on 1 test of attention. CONCLUSIONS: Cognitive impairment is prevalent in HFpEF and affects several cognitive domains. The current study supports the importance of cognitive screening in patients with heart failure. An association between abnormal cardiac hemodynamics and cognitive impairment was observed, but other factors are likely involved.

Association of Echocardiographic Measures of Left Atrial Function and Size With Incident Dementia.

Importance: Atrial myopathy-characterized by alterations in left atrial (LA) function and size-is associated with ischemic stroke, independent of atrial fibrillation (AF). Electrocardiographic markers of atrial myopathy are associated with dementia, but it is unclear whether 2-dimensional echocardiographic (2DE)-defined LA function and size are associated with dementia. Objective: To examine the association of LA function and size with incident dementia. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is a community-based prospective cohort. An exploratory, retrospective analysis was conducted. ARIC centers are located in Forsyth County, North Carolina; Jackson, Mississippi; Washington County, Maryland; and suburban Minneapolis, Minnesota. For this analysis, visit 5 (2011-2013) served as the baseline. Participants without prevalent AF and stroke and who had 2DEs in 2011-2013 were included and surveilled through December 31, 2019. Exposures: LA function (reservoir strain, conduit strain, contractile strain, emptying fraction, passive emptying fraction, and active emptying fraction), and LA size (maximal and minimal volume index) as evaluated by 2DE. Main Outcomes and Measures: Dementia cases were identified using in-person and phone cognitive assessments, hospitalization codes, and death certificates. Cox proportional hazards models were used. Results: Among 4096 participants (mean [SD] age, 75 [5] years; 60% women; 22% Black individuals), 531 dementia cases were ascertained over a median follow-up of 6 years. Dementia incidence for the lowest LA quintile was 4.80 for reservoir strain, 3.94 for conduit strain, 3.29 for contractile strain, 4.20 for emptying fraction, 3.67 for passive emptying fraction, and 3.27 for active emptying fraction per 100 person-years. After full-model adjustments, there were statistically significant associations between measures of LA function and dementia; the hazard ratios (HRs) from the lowest vs highest quintile for reservoir strain were 1.98 (95% CI, 1.42-2.75); for conduit strain, 1.50 (95% CI, 1.09-2.06); for contractile strain, 1.57 (95% CI, 1.16-2.14); for emptying fraction, 1.87 (95% CI, 1.31-2.65); and for active emptying fraction, 1.43 (95% CI, 1.04-1.96). LA passive emptying fraction was not significantly associated with dementia (HR, 1.26 [95% CI, 0.93-1.71]). Dementia incidence for the highest LA maximal volume index quintile was 3.18 per 100 person-years (HR for highest vs lowest quintile, 0.77 [95% CI, 0.58-1.02]) and for the highest minimal volume index quintile was 3.50 per 100 person-years (HR for the highest vs lowest quintile, 0.95 [95% CI, 0.71-1.28]). Both measures were not significantly associated with dementia. These findings were robust to sensitivity analyses that excluded participants with incident AF or stroke. Conclusions and Relevance: In this exploratory analysis of a US community-based cohort, several echocardiographic measures of lower LA function were significantly associated with an increased risk of subsequent dementia. Measures of LA size were not significantly associated with dementia risk. These findings suggest that impaired LA function may be a risk factor associated with dementia.

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

BACKGROUND: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. METHODS: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. RESULTS: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. CONCLUSIONS: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).

High-Sensitivity Cardiac Troponin, Natriuretic Peptide, and Long-Term Risk of Acute Kidney Injury: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized. METHODS: We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996-1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs). RESULTS: During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59-2.21] for ≥14 ng/L, 1.36 [1.18-1.57] for 9-13 ng/L, and 1.16 [1.03-1.30] for 5-8 ng/L compared to <5 ng/L). The graded association was also observed for NTproBNP (HR, 2.27 [1.93-2.68] for ≥272.7 pg/mL, 1.67 [1.45-1.93] for 142.4-272.6 pg/mL, and 1.31 [1.17-1.47] for 64.0-142.3 pg/mL compared to <64.0 pg/mL). The addition of hs-cTnT and NTproBNP to a model with established predictors significantly improved 10-year risk prediction for hospitalization with AKI (Δc-statistic, 0.015 [95%CI, 0.006-0.024]). CONCLUSIONS: In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population.

Mid- to Late-Life Inflammation and Risk of Cardiac Dysfunction, HFpEF and HFrEF in Late Life.

BACKGROUND: Epidemiologic data supporting the association of accumulated inflammation from mid- to late life with late-life risk of cardiac dysfunction and heart failure (HF) is limited. METHODS AND RESULTS: Among 4011 participants in the Atherosclerosis Risk in Communities study who were free of prevalent cardiovascular disease at study Visit 5, accumulated inflammation was defined as time-averaged high-sensitivity c-reactive protein (hsCRP) over 3 visits spanning 1990 to 2013. Associations with left ventricular (LV) function at Visit 5 and with incident adjudicated HF post Visit 5 were assessed using linear and Cox regression, adjusting for demographics and comorbidities. Higher accumulated hsCRP was associated with greater LV mass index, lower e', higher E/e', and higher adjusting for demographics (all P ≤0.01), but only with higher pulmonary artery systolic pressure after adjustment for comorbidities (P = 0.024). At 5.3 ± 1.2 year follow-up, higher accumulated hsCRP was associated with greater risk of incident HF (HR 1.31 [95% CI 1.18-1.47], P < 0.001), HFrEF (1.26 [1.05-1.52], P = 0.01), and HFpEF (1.30 [1.11-1.53], P = 0.001) in demographic-adjusted models, but not after adjustment for comorbidities (all P > 0.10). Only Visit 5 hsCRP remained associated with incident HF (1.12 [1.02-1.24], P = 0.02) after full adjustment. CONCLUSIONS: Greater accumulated inflammation is associated with worse LV function and heightened HF risk in late-life. These relationships are attenuated after adjusting for HF risk factors.

Heart Failure With Preserved Ejection Fraction In Perspective.

Approximately half of the patients with signs and symptoms of heart failure have a left ventricular ejection fraction that is not markedly abnormal. Despite the historically initial surprise, heightened risks for heart failure specific major adverse events occur across the broad range of ejection fraction, including normal. The recognition of the magnitude of the problem of heart failure with preserved ejection fraction in the past 20 years has spurred an explosion of clinical investigation and growing intensity of informative outcome trials. This article addresses the historic development of this component of the heart failure syndrome, including the epidemiology, pathophysiology, and existing and planned therapeutic studies. Looking forward, more specific phenotyping and even genotyping of subpopulations should lead to improvements in outcomes from future trials.

Associations of the Dietary Approaches to Stop Hypertension dietary pattern with cardiac structure and function.

BACKGROUND AND AIMS: Various food groups have been associated with measures of left ventricular geometry and function. Whether the Dietary Approaches to Stop Hypertension (DASH) dietary pattern in mid-life is associated with a favorable cardiac structure and function later in life is unknown. METHODS AND RESULTS: The study population consisted of the Atherosclerosis Risk in Communities study participants free of cardiovascular disease at study visit 3 in 1993-1995. Dietary intake was assessed by food frequency questionnaire at study visits 1 (1987-1989) and 3 (1993-1995). Participants who underwent transthoracic echocardiograms at the Jackson field center at visit 3 (n = 1974) and at all field centers at study visit 5 (2011-2013; n = 4651) were included in this study. General linear regression was used to evaluate associations between dietary intake and markers of cardiac structure and function adjusting for potential confounders. Higher DASH score was associated with lower left ventricle mean wall thickness and higher absolute value of longitudinal strain at visit 5 (ptrend = 0.004 and < 0.001, respectively). CONCLUSION: The DASH dietary pattern in midlife was favorably associated with left ventricle structure and systolic function later in life. These results emphasize the importance of adhering to a healthy eating plan as one lifestyle measure to preserve cardiac structure and function.

Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis.

BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

Refining Prediction of Atrial Fibrillation-Related Stroke Using the P2-CHA2DS2-VASc Score.

BACKGROUND: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)-prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA2DS2-VASc score would improve its ability to predict AF-related ischemic stroke. METHODS: We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement. RESULTS: Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33-2.55) independent of CHA2DS2-VASc variables, and that resulted in meaningful improvement in stroke prediction. The ß estimate was approximately twice that of the CHA2DS2-VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P2-CHA2DS2-VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51-0.69) to 0.67 (0.60-0.75) in ARIC and 0.68 (0.52-0.84) to 0.75 (0.60-0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13-0.39) and 0.51 (0.18-0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96-1.44) and 0.82 (0.36-1.39), respectively. CONCLUSIONS: Abnormal P-wave axis-an ECG correlate of left atrial abnormality- improves ischemic stroke prediction in AF. Compared with CHA2DS2-VASc, the P2-CHA2DS2-VASc is a better prediction tool for AF-related ischemic stroke.

Pulmonary vascular dysfunction among people aged over 65 years in the community in the Atherosclerosis Risk In Communities (ARIC) Study: A cross-sectional analysis.

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.

Smaller Left Ventricle Size at Noncontrast CT Is Associated with Lower Mortality in COPDGene Participants.

Background Smokers with chronic obstructive pulmonary disease (COPD) have smaller left ventricles (LVs) due to reduced preload. Skeletal muscle wasting is also common in COPD, but less is known about its contribution to LV size. Purpose To explore the relationships between CT metrics of emphysema, venous vascular volume, and sarcopenia with the LV epicardial volume (LVEV) (myocardium and chamber) estimated from chest CT images in participants with COPD and then to determine the clinical relevance of the LVEV in multivariable models, including sex and anthropomorphic metrics. Materials and Methods The COPDGene study (ClinicalTrials.gov identifier: NCT00608764) is an ongoing prospective longitudinal observational investigation that began in 2006. LVEV, distal pulmonary venous blood volume for vessels smaller than 5 mm2 in cross section (BV5), CT emphysema, and pectoralis muscle area were retrospectively extracted from 3318 nongated, unenhanced COPDGene CT scans. Multivariable linear and Cox regression models were used to explore the association between emphysema, venous BV5, pectoralis muscle area, and LVEV as well as the association of LVEV with health status using the St George's Respiratory Questionnaire, 6-minute walk distance, and all-cause mortality. Results The median age of the cohort was 64 years (interquartile range, 57-70 years). Of the 2423 participants, 1806 were men and 617 were African American. The median LVEV between Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and GOLD 4 COPD was reduced by 13.9% in women and 17.7% in men (P < .001 for both). In fully adjusted models, higher emphysema percentage (ß = -4.2; 95% confidence interval [CI]: -5.0, -3.4; P < .001), venous BV5 (ß = 7.0; 95% CI: 5.7, 8.2; P < .001), and pectoralis muscle area (ß = 2.7; 95% CI: 1.2, 4.1; P < .001) were independently associated with reduced LVEV. Reductions in LVEV were associated with improved health status (ß = 0.3; 95% CI: 0.1, 0.4) and 6-minute walk distance (ß = -12.2; 95% CI: -15.2, -9.3). These effects were greater in women than in men. The effect of reduced LVEV on mortality (hazard ratio: 1.07; 95% CI: 1.05, 1.09) did not vary by sex. Conclusion In women more than men with chronic obstructive pulmonary disease, a reduction in the estimated left ventricle epicardial volume correlated with a loss of pulmonary venous vasculature, greater pectoralis muscle sarcopenia, and lower all-cause mortality. © RSNA, 2020 Online supplemental material is available for this article.