| 1. |
- Yu, Bing, et al.
(författare)
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Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure
- 2021
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 78:1, s. 42-52
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Tidskriftsartikel (refereegranskat)abstract
- Background: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). Objectives: This study sought to evaluate whether CHIP is associated with incident HF. Methods: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. Results: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. Conclusions: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
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| 2. |
- Brown, Jenifer M., et al.
(författare)
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Cardiac Structure and Function Across the Spectrum of Aldosteronism: the Atherosclerosis Risk in Communities Study
- 2022
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Ingår i: Hypertension. - : LIPPINCOTT WILLIAMS & WILKINS. - 0194-911X .- 1524-4563. ; 79:9, s. 1984-1993
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aldosterone production and mineralocorticoid receptor activation are implicated in myocardial fibrosis and cardiovascular events. Methods: Cardiac structure and function were assessed in 4547 participants without prevalent heart failure (HF) in the ARIC study (Atherosclerosis Risk in Communities), with echocardiography, aldosterone, and plasma renin activity measurement (2011-2013). Subjects were characterized by plasma renin activity as suppressed (<= 0.5 ng/mL per hour) or unsuppressed (>0.5 ng/mL per hour). Cross-sectional relationships with cardiac structure and function, and longitudinal relationships with outcomes (HF hospitalization; HF and all-cause death; HF, death, myocardial infarction, and stroke; and incident atrial fibrillation) were assessed. Models were adjusted for demographic and anthropometric characteristics and additively, for blood pressure and antihypertensives. Results: Evidence of primary aldosteronism physiology was prevalent (11.6% with positive screen) and associated with echocardiographic parameters. Renin suppression was associated with greater left ventricular mass, left ventricular volumes, and left atrial volume index, and a lower E/A ratio (adjusted P<0.001 for all). Higher aldosterone was associated with greater left ventricular mass and lower global longitudinal strain and lateral E . The highest tertile of aldosterone was associated with a hazard ratio of 1.37 (95% CI, 1.06-1.77; 5.5-year follow-up) for incident atrial fibrillation relative to the lowest. Renin suppression was associated with HF (hazard ratio, 1.34 [95% CI, 1.05-1.72]; 7.3-year follow-up), although these relationships did not remain statistically significant after additional adjustment for hypertension. Conclusions: Renin suppression and aldosterone excess, consistent with primary aldosteronism pathophysiology, were associated with cardiac structural and functional alterations and may represent an early target for mitigation of fibrosis with mineralocorticoid receptor antagonists.
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| 3. |
- Saadatagah, Seyedmohammad, et al.
(författare)
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Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1
- 2024
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Ingår i: JAMA CARDIOLOGY. - 2380-6583 .- 2380-6591. ; 9:6, s. 497-506
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Tidskriftsartikel (refereegranskat)abstract
- ImportanceClonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. ObjectiveTo determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. Design, Setting, and ParticipantsThis was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023. ExposuresCHIP (variant allele frequency [VAF] >= 2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF >= 10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices. Main Outcome MeasureIncident AF. ResultsA total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index. Conclusions and RelevanceLarge TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.
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| 4. |
- Solomon, Scott D., et al.
(författare)
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Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis : Analysis of the APOLLO Study
- 2019
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 139:4, s. 431-443
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Tidskriftsartikel (refereegranskat)abstract
- 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: -0.90.4 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.
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| 5. |
- Wijkman, Magnus, et al.
(författare)
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Resistance to antihypertensive treatment and long-term risk: The Atherosclerosis Risk in Communities study
- 2021
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Ingår i: The Journal of Clinical Hypertension. - : Wiley. - 1524-6175 .- 1751-7176. ; 23:10, s. 1887-1896
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Tidskriftsartikel (refereegranskat)abstract
- More stringent blood pressure (BP) goals have led to greater prevalence of apparent resistant hypertension (ARH), yet the long-term prognostic impact of ARH diagnosed according to these goals in the general population remains unknown. We assessed the prognostic impact of ARH according to contemporary BP goals in 9612 participants of the Atherosclerosis Risk in Communities (ARIC) study without previous cardiovascular disease. ARH, defined as BP above goal (traditional goal <140/90 mmHg, more stringent goal <130/80 mmHg) despite the use of >= 3 antihypertensive drug classes or any BP with >= 4 antihypertensive drug classes (one of which was required to be a diuretic) was compared with controlled hypertension (BP at goal with 1-3 antihypertensive drug classes). Cox regression models were adjusted for age, sex, race, study center, BMI, heart rate, smoking, eGFR, LDL, HDL, triglycerides, and diabetes. Using the traditional BP goal, 133 participants (3.8% of the treated) had ARH. If the more stringent BP goal was instead applied, 785 participants (22.6% of the treated) were reclassified from controlled hypertension to uncontrolled hypertension (n = 725) or to ARH (n = 60). Over a median follow-up time of 19 years, ARH was associated with increased risk for a composite end point (all-cause mortality, hospitalization for myocardial infarction, stroke, or heart failure) regardless of whether traditional (adjusted HR 1.50, 95% CI: 1.23-1.82) or more stringent (adjusted HR 1.43, 95% CI: 1.20-1.70) blood pressure goals were applied. We conclude that in patients free from cardiovascular disease, ARH predicted long-term risk regardless of whether traditional or more stringent BP criteria were applied.
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