Association of Cumulative Systolic Blood Pressure with Left Atrial Function in the Setting of Normal Left Atrial Size: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Lower left atrial (LA) function is associated with increased risk for cardiovascular disease (CVD) events; data on risk factors for impaired LA function are limited. We evaluated the effect of cumulative systolic blood pressure (cSBP) from midlife to older age on LA strain in adults with normal LA size. METHODS: We included participants in the Atherosclerosis Risk in Communities study with LA strain measured on the Visit 5 echocardiogram (2011-2013), excluding those with atrial fibrillation and LA volume index >34ml/m2. cSBP was calculated from Visit 1 (1987-1989) through Visit 5. Linear regression models were used to evaluate associations between cSBP and LA strain measures. RESULTS: 3,859 participants with mean (SD) age of 75.2 (5.0) years were included in the analysis; 725 (18.8%) Black and 2342 (60.7%) women. After adjusting for demographics, CVD risk factors, heart failure, and coronary heart disease, each 10mmHg higher cSBP was associated with 0.32% (95% CI -0.52%, -0.13%) and 0.37% (95% CI -0.51%, -0.22%) absolute reduction in LA reservoir and conduit strain, respectively. Associations were attenuated after adjustment for left ventricular (LV) systolic and diastolic function and mass (-0.12%; 95% CI, -0.31, 0.06 for reservoir strain and -0.24%; 95% CI -0.38%, -0.10% for conduit strain). In subgroup analyses, the association of cSBP with conduit strain was statistically significant among those with normal LV systolic and diastolic function. CONCLUSIONS: Cumulative exposure to elevated blood pressure from midlife to late life was modestly associated with lower LA reservoir and conduit strain in older adults with normal LA size, mostly related to the effect of blood pressure on LV function and mass. However, the association of cSBP and LA conduit strain in subgroups with normal LV function suggests that LA remodeling in response to hypertension occurs before LV dysfunction is detected on echocardiography.

Deep terminal negative of the P wave in V1 and incidence of ischemic stroke: The atherosclerosis risk in communities (ARIC) study.

BACKGROUND: Deep terminal negative of the P wave in V1 (DTNPV1) is a marker of left atrial remodeling. We aimed to evaluate the association of DTNPV1 with incident ischemic stroke. METHODS: The Atherosclerosis Risk in Communities study is a prospective community-based cohort study. All participants at visit 4 (1996-1998) except those with prevalent stroke, missing covariates, and missing or uninterpretable ECG were included. DTNPV1 was defined as the absolute value of the depth of the terminal negative phase >100 µV in the presence of biphasic P wave in V1. Association between DTNPV1 as a time-dependent exposure variable and incident ischemic stroke was evaluated. The accuracy of the prediction model consisting of DTNPV1 and CHA2DS2-VASc variables in predicting ischemic stroke was analyzed. RESULTS: Among 10,605 participants (63 ± 6 years, 56% women, 20% Black), 803 cases of ischemic stroke occurred over a median follow-up of 20.19 years. After adjusting for demographics, DTNPV1 was associated with an increased risk of stroke (HR 1.96, [95% CI 1.39-2.77]). After further adjusting for stroke risk factors, use of aspirin and anticoagulants, and time-dependent atrial fibrillation, DTNPV1 was associated with a 1.50-fold (95% CI 1.06-2.13) increased risk of stroke. When added to the CHA2DS2-VASc variables, DTNPV1 did not significantly improve stroke prediction as assessed by C-statistic. However, there was improvement in risk classification for participants who did not develop stroke. CONCLUSION: DTNPV1 is significantly associated with higher risk of ischemic stroke. Since DTNPV1 is a simplified electrocardiographic parameter, it may help stroke prediction, a subject for further research.

Percutaneous left atrial appendage occlusion and risk of stroke, hospitalized bleeding and death in Medicare beneficiaries.

PURPOSE: Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA2DS2-VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death. METHODS: Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA2DS2-VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used. RESULTS: Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years. CONCLUSION: In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications.

Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. Objective: To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. Design, Setting, and Participants: This 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. Exposures: CHIP (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 Measure: Incident AF. Results: A 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 Relevance: Large 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.

Use of Sodium-Glucose Cotransporter-2 Inhibitors and Angiotensin Receptor-Neprilysin Inhibitors in Patients With Atrial Fibrillation and Heart Failure From 2021 to 2022: An Analysis of Real-World Data.

BACKGROUND: Contemporary use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF) has not been described. METHODS AND RESULTS: We analyzed the MarketScan databases for the period January 1, 2021 to July 30, 2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower use, including demographics and comorbidities. The study population included 60 927 patients (mean age, 75 years; 43% women) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), whereas the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (22%-29% in HFrEF, 6%-8% in HFpEF), and SGLT2i from 3% to 9% (6%-16% in HFrEF, 2%-7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type. CONCLUSIONS: Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among women and older individuals, though use is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.

Associations of Physical Activity and Heart Rate Variability from a Two-Week ECG Monitor with Cognitive Function and Dementia: the ARIC Neurocognitive Study.

BACKGROUND: Low physical activity (PA) measured from accelerometers and low heart rate variability (HRV) measured from short-term ECG recordings are associated with worse cognitive function. Wearable long-term ECG monitors are now widely used. These monitors can provide long-term HRV data and, if embedded with an accelerometer, they can also provide PA data. Whether PA or HRV measured from long-term ECG monitors is associated with cognitive function among older adults is unknown. METHODS: Free-living PA and HRV were measured simultaneously over 14-days using the Zio ® XT Patch among 1590 participants in the Atherosclerosis Risk in Communities Study [aged 72-94 years, 58% female, 32% Black]. Total amount of PA was estimated by total mean amplitude deviation (TMAD) from the 14-day accelerometry raw data. HRV indices (SDNN and rMSSD) were measured from the 14-day ECG raw data. Cognitive factor scores for global cognition, executive function, language, and memory were derived using latent variable methods. Dementia or mild cognitive impairment (MCI) status was adjudicated. Linear or multinomial regression models examined whether higher PA or higher HRV was cross-sectionally associated with higher factor scores or lower odds of MCI/dementia. Models were adjusted for demographic and medical comorbidities. RESULTS: Each 1-unit higher in total amount of PA was significantly associated with 0.30 higher global cognition factor scores (95% CI: 0.16-0.44), 0.38 higher executive function factor scores (95% CI: 0.22-0.53), and 62% lower odds of MCI (OR: 0.38, 95% CI: 0.22-0.67) or 75% lower odds of dementia (OR: 0.25, 95% CI: 0.08-0.74) versus unimpaired cognition. Neither HRV measure was significantly associated with cognitive function or dementia. CONCLUSIONS: PA derived from a 2-week ECG monitor with an embedded accelerometer was significantly associated with higher cognitive test performance and lower odds of MCI/dementia among older adults. By contrast, HRV indices measured over 2 weeks were not significantly associated with cognitive outcomes. More research is needed to define the role of wearable ECG monitors as a tool for digital phenotyping of dementia. CLINICAL PERSPECTIVE: What Is New?: This cross-sectional study evaluated associations between physical activity (PA) and heart rate variability (HRV) measured over 14 days from a wearable ECG monitor with cognitive function.Higher total amount of PA was associated with higher global cognition and executive function, as well as lower odds of mild cognitive impairment or dementia.HRV indices measured over 2 weeks were not significantly associated with cognitive outcomes.What Are the Clinical Implications?: These findings replicate positive associations between PA and cognitive function using accelerometer data from a wearable ECG monitor with an embedded accelerometer.These findings raise the possibility of using wearable ECG monitors (with embedded accelerometers) as a promising tool for digital phenotyping of dementia.

Ion channel dysfunction and fibrosis in atrial fibrillation: Two sides of the same coin.

BACKGROUND: Atrial fibrillation (AF) is a common heart rhythm disorder that is associated with an increased risk of stroke and heart failure (HF). Initially, an association between AF and ion channel dysfunction was identified, classifying the pathology as a predominantly electrical disease. More recently it has been recognized that fibrosis and structural atrial remodeling play a driving role in the development of this arrhythmia also in these cases. PURPOSE: Understanding the role of fibrosis in genetic determined AF could be important to better comprise the pathophysiology of this arrhythmia and to refine its management also in nongenetic forms. In this review we analyze genetic and epigenetic mechanisms responsible for AF and their link with atrial fibrosis, then we will consider analogies with the pathophysiological mechanism in nongenetic AF, and discuss consequent therapeutic options.

Validation of a Zio XT Patch Accelerometer for the Objective Assessment of Physical Activity in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Combination devices to monitor heart rate/rhythms and physical activity are becoming increasingly popular in research and clinical settings. The Zio XT Patch (iRhythm Technologies, San Francisco, CA, USA) is US Food and Drug Administration (FDA)-approved for monitoring heart rhythms, but the validity of its accelerometer for assessing physical activity is unknown. OBJECTIVE: To validate the accelerometer in the Zio XT Patch for measuring physical activity against the widely-used ActiGraph GT3X. METHODS: The Zio XT and ActiGraph wGT3X-BT (Actigraph, Pensacola, FL, USA) were worn simultaneously in two separately-funded ancillary studies to Visit 6 of the Atherosclerosis Risk in Communities (ARIC) Study (2016-2017). Zio XT was worn on the chest and ActiGraph was worn on the hip. Raw accelerometer data were summarized using mean absolute deviation (MAD) for six different epoch lengths (1-min, 5-min, 10-min, 30-min, 1-h, and 2-h). Participants who had ≥3 days of at least 10 h of valid data between 7 a.m-11 p.m were included. Agreement of epoch-level MAD between the two devices was evaluated using correlation and mean squared error (MSE). RESULTS: Among 257 participants (average age: 78.5 ± 4.7 years; 59.1% female), there were strong correlations between MAD values from Zio XT and ActiGraph (average r: 1-min: 0.66, 5-min: 0.90, 10-min: 0.93, 30-min: 0.93, 1-h: 0.89, 2-h: 0.82), with relatively low error values (Average MSE × 106: 1-min: 349.37 g, 5-min: 86.25 g, 10-min: 56.80 g, 30-min: 45.46 g, 1-h: 52.56 g, 2-h: 54.58 g). CONCLUSIONS: These findings suggest that Zio XT accelerometry is valid for measuring duration, frequency, and intensity of physical activity within time epochs of 5-min to 2-h.

Factors Associated With Fatigue in Persons With Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia affecting over 6 million people in the U.S. Fatigue is a frequent symptom of AF, yet no underlying biological mechanisms have been identified in AF-related fatigue as in other chronic conditions such as cancer or HIV fatigue (inflammation, tissue injury). We aimed to identify biomarkers and correlates of AF-fatigue in ARIC participants. METHODS: Participants with AF from ARIC visit 5 (2011-2013) were included in the study. Multiple linear regression was used to estimate the association of high sensitivity troponin (hs-TnT), N-terminal fragment B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) levels with self-reported fatigue (SF-12 and PROMIS Fatigue Scale), depressive symptoms (Center for Epidemiological Studies Depression survey), and physical functioning (Short Physical Performance Battery) scores. All biomarkers underwent natural-log transformation. RESULTS: There were 446 participants (mean age: 78 y ± 5; 44% women). In adjusted analyses, NT-proBNP was associated with AF-fatigue (ß: 0.11, 95% CI: 0.03, 0.19), increased depressive symptoms (ß: 0.44, 95% CI: 0.19, 0.70), and decreased physical function (ß: -0.48, 95% CI: -0.72, -0.23). Hs-TnT was also associated with elevated AF-fatigue (ß: 0.24, 95% CI: 0.09, 0.39) along with decreased physical function (ß: -1.19, 95% CI: -1.64, -0.75). No significant associations were found with hsCRP and fatigue. CONCLUSION: Increased levels of cardiac injury biomarkers, depressive symptoms, and decreased physical function were associated with AF-fatigue. Inflammation was not associated with AF-fatigue; other physiological pathways, such as cardiac overload or myocardial injury may be more relevant in AF-fatigue.

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.

Association of Atrial Fibrillation With Stroke and Dementia Accounting for Left Atrial Function and Size.

BACKGROUND: Atrial fibrillation (AF) is associated with higher risks of ischemic stroke (IS) and dementia. Whether alterations in left atrial (LA) function or size-atrial myopathy-confound these associations remains unknown. OBJECTIVES: The purpose of this study was to examine the association of prevalent and incident AF with ischemic stroke and dementia in the ARIC (Atherosclerosis Risk In Communities) study, adjusting for LA function and size. METHODS: Participants at visit 5 (2011-2013) with echocardiographic LA function (reservoir, conduit, contractile strain, and emptying fraction) and size (maximal, minimal volume index) data, and without prevalent stroke or dementia were followed through 2019. For analysis, we used time-varying Cox regression. RESULTS: Among 5,458 participants (1,193 with AF, mean age of 76 years) in the stroke analysis and 5,461 participants (1,205 with AF, mean age of 75 years) in the dementia analysis, 209 participants developed ischemic stroke, and 773 developed dementia over 7.1 years (median). In a demographic and risk factor-adjusted model, AF was significantly associated with ischemic stroke (HR, 1.63; 95% CI: 1.11-2.37) and dementia (HR: 1.38, 95% CI: 1.13-1.70). After additionally adjusting for LA reservoir strain, these associations were attenuated and no longer statistically significant (stroke [HR: 1.33, 95% CI: 0.88-2.00], dementia [HR: 1.15, 95% CI: 0.92-1.43]). Associations with ischemic stroke and dementia were also attenuated and not statistically significant after adjustment for LA contractile strain, emptying fraction, and minimal volume index. CONCLUSIONS: AF-ischemic stroke and AF-dementia associations were not statistically significant after adjusting for measures of atrial myopathy. This proof-of-concept analysis does not support AF as an independent risk factor for ischemic stroke and dementia.

Use of SGLT2i and ARNi in patients with atrial fibrillation and heart failure in 2021-2022: an analysis of real-world data.

Objective: To evaluate utilization of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF). Methods: We analyzed the MarketScan databases for the period 1/1/2021 to 6/30/2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower utilization, including demographics and comorbidities. Results: The study population included 60,927 patients (mean age 75, 43% female) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), while the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (from 22% to 29% in HFrEF, from 6% to 8% in HFpEF), and SGLT2i from 3% to 9% (from 6% to 16% in HFrEF, from 2% to 7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower utilization of these two medication types overall and by HF type. Conclusion: Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among females and older individuals, though utilization is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.

MMP-2 Associates With Incident Heart Failure and Atrial Fibrillation: The ARIC Study.

BACKGROUND: MMP (matrix metalloproteinase)-2 participates in extracellular matrix regulation and may be involved in heart failure (HF), atrial fibrillation (AF), and coronary heart disease. METHODS: Among the 4693 ARIC study (Atherosclerosis Risk in Communities) participants (mean age, 75±5 years; 42% women) without prevalent HF, multivariable Cox proportional hazard models were used to estimate associations of plasma MMP-2 levels with incident HF, HF with preserved ejection fraction (≥50%), HF with reduced ejection fraction (<50%), AF, and coronary heart disease. Mediation of the association between MMP-2 and HF was assessed by censoring participants who developed AF or coronary heart disease before HF. Multivariable linear regression models were used to assess associations of MMP-2 with measures of left ventricular and left atrial structure and function. RESULTS: Compared with the 3 lower quartiles, the highest MMP-2 quartile associated with greater risk of incident HF overall (adjusted hazard ratio, 1.48 [95% CI, 1.21-1.81]), incident HF with preserved ejection fraction (1.44 [95% CI, 1.07-1.94]), incident heart failure with reduced ejection fraction (1.48 [95% CI, 1.08-2.02]), and incident AF (1.44 [95% CI, 1.18-1.77]) but not incident coronary heart disease (0.97 [95% CI, 0.71-1.34]). Censoring AF attenuated the MMP-2 association with HF with preserved ejection fraction. Higher plasma MMP-2 levels were associated with larger left ventricular end-diastolic volume index, greater left ventricular mass index, higher E/e' ratio, larger left atrial volume index, and worse left atrial reservoir and contractile strains (all P<0.001). CONCLUSIONS: Higher plasma MMP-2 levels associate with diastolic dysfunction, left atrial dysfunction, and a higher risk of incident HF and AF. AF is a mediator of MMP-2-associated HF with preserved ejection fraction risk.

SGLT2 Inhibitors Are Associated With Reduced Cardiovascular Disease in Patients With Type 2 Diabetes: An Analysis of Real-World Data.

OBJECTIVE: To assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and other second-line diabetes therapies with risk of cardiovascular disease (CVD), as well as conduct head-to-head comparisons between SGLT2 inhibitors. PATIENTS AND METHODS: Using data from the MarketScan databases (January 1, 2013, through December 31, 2019), SGLT2 inhibitor users were matched with up to five other second-line therapy users by age, sex, date of enrollment, and date of second-line therapy initiation. The primary composite outcome included stroke, atrial fibrillation, myocardial infarction, and heart failure. Hazard ratios were estimated, adjusting for demographics and a propensity score reflecting comorbidities and medications. RESULTS: In this study population of 313,396 patients (mean age 53±10 years; 47% female), 9787 incident CVD events occurred over a median follow-up of 1.36 years. After multivariable adjustments, SGLT2 inhibitor users had a lower risk of CVD than other second-line therapy users (HR, 0.66; 95% CI, 0.62 to 0.71). Significant associations were also observed when each CVD outcome was assessed separately. No differences were noted when comparing individual SGLT2 inhibitors. CONCLUSION: SGLT2 inhibitors were associated with a clinically meaningfully lower CVD risk in the real-world setting. In head-to-head comparisons, the different SGLT2 inhibitors were consistent in their protective associations with CVD. This suggests that as a class, SGLT2 inhibitors may have widespread benefit in preventing CVD among patients with type 2 diabetes.

Cardiovascular Autonomic Function and Incident Chronic Obstructive Pulmonary Disease Hospitalizations in Atherosclerosis Risk in Communities.

Rationale: The autonomic nervous system extensively innervates the lungs, but its role in chronic obstructive pulmonary disease (COPD) outcomes has not been well studied. Objective: We assessed relationships between cardiovascular autonomic nervous system measures (heart rate variability [HRV] and orthostatic hypotension [OH]) and incident COPD hospitalization in the multicenter ARIC (Atherosclerosis Risk In Communities) study. Methods: We used Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals between baseline (1987-1989) autonomic function measures (HRV measures from 2-minute electrocardiograms and OH variables) and incident COPD hospitalizations through 2019. Adjusted analyses included demographic data, smoking status, lung function, comorbidities, and physical activity. We also performed analyses stratified by baseline airflow obstruction. Results: Of the 11,625 participants, (mean age, 53.8 yr), 56.5% were female and 26.3% identified as Black. Baseline mean percentage predicted forced expiratory volume in 1 second was 94 ± 17% (standard deviation), and 2,599 participants (22.4%) had airflow obstruction. During a median follow-up time of 26.9 years, there were 2,406 incident COPD hospitalizations. Higher HRV (i.e., better autonomic function) was associated with a lower risk of incident COPD hospitalization. Markers of worse autonomic function (OH and greater orthostatic changes in systolic and diastolic blood pressure) were associated with a higher risk of incident COPD hospitalization (hazard ratio for the presence of OH, 1.5; 95% confidence interval, 1.25-1.92). In stratified analyses, results were more robust in participants without airflow obstruction at baseline. Conclusions: In this large multicenter prospective community cohort, better cardiovascular autonomic function at baseline was associated with a lower risk of subsequent hospitalization for COPD, particularly among participants without evidence of lung disease at baseline.

Mortality associated with antiarrhythmic medication for atrial fibrillation among patients with left ventricular hypertrophy.

BACKGROUND: Atrial fibrillation (AF) guidelines recommend amiodarone as the preferred antiarrhythmic medication (AAM) in patients with left ventricular hypertrophy (LVH), due to potential pro-arrhythmic risk with other AAM. However, there are limited data to support this assertion. METHODS: We retrospectively analyzed the records of 8204 patients who were prescribed AAM for AF and had transthoracic echocardiogram (TTE) at the multicenter, VA Midwest Health Care Network from 2000 to 2021. We excluded patients without LVH (septal or posterior wall dimension ≤1.4 cm). The primary outcome variable was all-cause mortality during antiarrhythmic therapy or within 6 months after stopping it. Propensity-stratified analyses were performed between amiodarone versus non-amiodarone (Vaughan-Williams Class I and III) AAM. RESULTS: A total of 1277 patients with LVH (mean age 70.2 ± 9.5 years) were included in the analysis. Of these, 774 (60.6%) were prescribed amiodarone. Baseline characteristics of the two comparison groups were similar after propensity adjustment. After a median 1.40 years of follow-up, 203 (15.9%) patients died. Incidence rates per 100 patient-year follow-up was 9.02 (7.58-10.66) for amiodarone and 4.98 (3.91-62.56) for non-amiodarone. In propensity-stratified analysis, amiodarone use was associated with 1.58 times higher risk of mortality (95% CI 1.03-2.44; p = .038). Sub-group analysis in 336 (26.3%) patients with severe LVH showed no difference in mortality (HR 1.41, 95% CI 0.82-2.43, p = .21). CONCLUSION: Among patients with AF and LVH, amiodarone was associated with a significantly higher mortality risk than other AAM.

Circulating Magnesium and Risk of Major Adverse Cardiac Events among Patients with Atrial Fibrillation in the ARIC Cohort.

Background: Serum magnesium (Mg) has been reported to be inversely associated with the risk of atrial fibrillation (AF), coronary artery disease (CAD), and major adverse cardiovascular events (MACE). The association between serum Mg and the risk of MACE, heart failure (HF), stroke, and all-cause mortality among patients with AF has not been evaluated. Objective: We aim to examine whether higher serum Mg is associated with a lower risk of MACE, heart failure (HF), stroke, and all-cause mortality among patients with AF. Methods: We evaluated prospectively 413 participants of the Atherosclerosis Risk in Communities (ARIC) Study with a diagnosis of AF at the time of Mg measurement participating in visit 5 (2011-2013). Serum Mg was modeled in tertiles and as a continuous variable in standard deviation units. Endpoints (HF, MI, stroke, cardiovascular (CV) death, all-cause mortality, and MACE) were identified and modeled separately using Cox proportional hazard regression adjusting for potential confounders. Results: During a mean follow-up of 5.8 years, there were 79 HFs, 34 MIs, 24 strokes, 80 CV deaths, 110 MACEs, and 198 total deaths. After adjustment for demographic and clinical variables, participants in the second and third tertiles of serum Mg had lower rates of most endpoints, with the strongest inverse association for the incidence of MI (HR 0.20, 95% CI 0.07, 0.61) comparing top to bottom tertile. Serum Mg modeled linearly as a continuous variable did not show clear associations with endpoints except MI (HR 0.50, 95% CI 0.31, 0.80). Due to the limited number of events, the precision of most estimates of association was relatively low. Conclusions: Among patients with AF, higher serum Mg was associated with a lower risk of developing incident MI and, to a lesser extent, other CV endpoints. Further studies in larger patients with AF cohorts are needed to evaluate the role of serum Mg in preventing adverse CV outcomes in these patients.

Association of abnormal p-wave parameters with brain MRI morphology: The atherosclerosis risk in communities neurocognitive study (ARIC-NCS).

BACKGROUND: Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). METHODS: ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes. RESULTS: Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume. CONCLUSION: In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia.

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.