Soliman, Elsayed Z.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure (HF) cases and remains diagnostically challenging due to nonspecific symptoms and a lack of accessible noninvasive screening tools, leading to widespread underdiagnosis and delayed treatment. The electrocardiogram (ECG) is a low-cost, widely available tool that reflects myocardial electrical remodeling. We previously developed and externally validated an ECG-based artificial intelligence (ECG-AI) model capable of classifying ECGs into four categories: reduced ejection fraction (rEF), mid-range ejection fraction (mEF), HFpEF, and controls. In this study, we evaluate the ability of this ECG-AI model to predict future HFpEF diagnosis using real-world data from a large integrated health system. Methods: We applied the validated ECG-AI model to an independent cohort of 7713 patients from Wake Forest Baptist Health (WFBH), using one ECG per patient recorded before the clinical diagnosis of HFpEF. Model discrimination was evaluated across multiple prediction windows from six months up to ten years before diagnosis using the area under the receiver operating characteristic curve (AUC), with comparisons performed using DeLong’s test. Performance was also compared head-to-head with the H2FPEF score, a validated clinical score for HFpEF, in the subset of patients with complete data for score calculation. ECG-AI outputs were stratified into quartiles and evaluated using Kaplan–Meier survival analysis and multivariable Cox proportional hazards regression adjusted for demographics and major comorbidities. Results: Of the 7713 patients, 283 (3.7%) were subsequently diagnosed with HFpEF. The ECG-AI model achieved an AUC of 0.79 (95% CI, 0.72–0.86) using ECGs recorded within six months before diagnosis. Discrimination remained stable across prediction windows extending up to ten years before diagnosis (AUC range, 0.78–0.80; all DeLong p > 0.01 vs. the six-month window). Compared with the H2FPEF score, ECG-AI demonstrated superior discrimination, improving the AUC by 0.06–0.07 across the evaluated prediction windows. Patients in the highest ECG-AI risk quartile had an unadjusted hazard ratio (HR) of 11.18 (95% CI, 7.27–17.21; C-index, 0.75) and an adjusted HR of 6.60 (95% CI, 4.24–10.28; C-index, 0.82). Adding clinical covariates to ECG-AI improved the C-index by 0.07 and 0.09 for the five- and ten-year prediction windows, respectively. Conclusions: An independently validated ECG-AI model predicted incident HFpEF up to ten years before clinical diagnosis and outperformed the H2FPEF score using ECG alone, indicating that ECG-derived signatures precede clinical recognition of the syndrome. ECG-AI shows promise as a prognostic, risk-stratification tool to prioritize further evaluation; prospective validation and single-lead assessment are needed before screening or wearable deployment.

Background: The gap between artificial intelligence-derived age (ECG-Age) and chronological age has been validated as a strong predictor of increased cardiovascular morbidity and mortality, independent of age, and is a potential biomarker of biological aging. Acute stress may cause real-time, transient changes in autonomic function via electrophysiological signals that, when repeated over time, may contribute to biological aging and represent mechanisms linking stress and Major Adverse Cardiovascular Events (MACE). We hypothesized that acute mental stress induced in a laboratory is associated with increased ECG and that this increase is associated with a higher risk of MACE among individuals with stable coronary heart disease (CHD). Methods: We pooled two prospective cohorts of participants with stable CHD from a university-based hospital network in Atlanta. Stress was induced using a standardized mental stress test (public speaking task) and measured 12-lead ECGs during rest, mental stress, and recovery periods. To measure ECG-age, we utilized a published algorithm using a neural network on >500,000 independent patients. The study endpoint was MACE including nonfatal myocardial infarction, hospitalization for heart failure, or cardiovascular death. The difference in ECG-Age between resting and acute mental stress was used to define the stress Age-Gap. Cox proportional hazard regression modeled the association of stress Age-Gap operationalized as tertiles adjusting for chronological age, sex, race, cardiovascular risk factors, and baseline Cohen perceived stress scale. Results: 442 participants in the total sample pool (38% women). Over a 5-year median follow-up, 95 participants (21%) experienced MACE. At rest, the mean chronologic age was 55.7±9.9 years, and ECG-Age was 57.1 ±10.7 years, with rest Age-Gap of 0. 9±9.6 (p=0.16). During stress, the stress Age-Gap of 1.95±9.8 (p<0.0001), while recovery Age-Gap was 1.1±10.3 (p=0.13). Those that demonstrated the largest ECG-Age positive change between rest and stress by ECG (top tertile) had a higher risk for MACE when compared to those with the lowest or negative ECG age change (bottom tertile), see Figure. Conclusion: Among patients with stable CHD, acute mental stress caused changes in biological age as measured by AI-ECG consistent with accelerated biological aging. Such changes were associated with MACE. These results uncover accelerated biological aging as a mechanism linking acute stress to CVD outcomes.

Moritz F Sinner, 2012 Finalist and Presenting Author

Abstract Background—Smoking is associated with arrhythmia and sudden cardiac death, but the biological mechanisms remain unclear. Abnormal electrocardiogram (ECG) durations of ventricular repolarization (QT interval), atrial depolarization (P wave), and atrioventricular depolarization (PR interval and segment), predict cardiac arrhythmia and mortality. Objectives—To elucidate how smoking affects cardiac excitation, we assessed in a nationally representative sample (NHANES III) associations between cotinine, abnormalities in P duration, PR interval, PR segment, rate-corrected QT (QTc), QRS duration, and JT interval, and long-term mortality. Methods—We analyzed data from 5,633 adults using survey-weighted multinomial logistic regression to estimate associations between tobacco use (>15 ng/ml serum cotinine) and short (<5th percentile) or long (>95th percentile) ECG intervals, relative to reference (5 – 95th percentile). Results—After adjustment for demographics, risk factors, and conduction-altering medications, smoking was associated with a higher odds of short PR interval, PR segment, and QRS, and long JT. Broader ECG effects of smoking were also assessed by survey-weighted linear regression of continuous cotinine and ECG intervals, which revealed cotinine inversely associated with PR segment and QTc. Over a 22-year follow-up, many ECG abnormalities predicted cardiovascular mortality in smokers, including long JT, QRS, and QTc, and short QRS. Conclusions—Smoking increases likelihood for rapid atrioventricular conduction, rapid ventricular depolarization, and slow ventricular repolarization. The ventricular electrophysiologic abnormalities associated with smoking also predict cardiovascular mortality in smokers; however, traditional ECG measures of cardiac risk like QTc can overlook these ventricular defects and their independent predictive value in smokers.

AbstractBackgroundRecent 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).MethodsARIC‐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.ResultsAmong 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.ConclusionIn 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.

Importance Only modest attention has been paid to the contributions of social determinants of health to atrial fibrillation (AF) risk factors, diagnosis, symptoms, management, and outcomes. The diagnosis of AF provides unique challenges exacerbated by the arrhythmia’s often paroxysmal nature and individuals’ disparate access to health care and technologies that facilitate detection. Social determinants of health affect access to care and management decisions for AF, increasing the likelihood of adverse outcomes among individuals who experience systemic disadvantages. Developing effective approaches to address modifiable social determinants of health requires research to eliminate the substantive inequities in health care delivery and outcomes in AF. Observations The National Heart, Lung, and Blood Institute convened an expert panel to identify major knowledge gaps and research opportunities in the field of social determinants of AF. The workshop addressed the following social determinants: (1) socioeconomic status and access to care; (2) health literacy; (3) race, ethnicity, and racism; (4) sex and gender; (5) shared decision-making in systemically disadvantaged populations; and (6) place, including rurality, neighborhood, and community. Many individuals with AF have multiple adverse social determinants, which may cluster in the individual and in systemically disadvantaged places (eg, rural locations, urban neighborhoods). Cumulative disadvantages may accumulate over the life course and contribute to inequities in the diagnosis, management, and outcomes in AF. Conclusions and Relevance Workshop participants identified multiple critical research questions and approaches to catalyze social determinants of health research that address the distinctive aspects of AF. The long-term aspiration of this work is to eradicate the substantive inequities in AF diagnosis, management, and outcomes across populations.

Background: Stroke symptoms in the general population are common (≈18% of adults 45+) and are associated with future stroke. These symptoms may also identify a broad spectrum of clinically-undetected vascular conditions. Methods: Stroke symptoms (sudden weakness, numbness, unilateral or general loss of vision, and loss of ability to communicate or understand) and time to self-reported hospitalization for any cardiovascular (CVD) reason (heart, stroke, or TIA) or stroke were assessed in the REGARDS Study (a national, population-based, longitudinal study of 30,239 African-American and white adults > 45 years enrolled 2003-2007). The symptom-hospitalization association was assessed by proportional hazards analysis in persons stroke/TIA-free at baseline, with adjustment for demographics (age, race and sex), further adjustment for SES (income and education), CVD risk factors (smoking, hypertension, diabetes, dyslipidemia, atrial fibrillation and heart disease), and “perceived health status.” Results: Over an average follow-up of 5.6 years, presence of any stroke symptom was associated with greater risk of hospitalization for stroke (11% versus 6%; HR = 1.68; 95% CI: 1.52 - 1.85), a risk only modestly attenuated by adjustment for SES (HR = 1.59; 95% CI: 1.44 - 1.76), risk factors (HR = 1.44; 95% CI: 1.29 - 1.60), and perceived health (HR = 1.37; 95% CI: 1.23 - 1.53). However, presence of any stroke symptom was more strongly related to hospitalization for CVD (42% vs. 24%; HR = 1.92; 95 CI: 1.82 - 2.03), only modestly mediated by adjustment for SES (HR = 1.82; 95% CI: 1.73 - 1.93), risk factors (HR = 1.66; 95% CI: 1.57 - 1.76), and perceived health (HR = 1.57; 95% CI: 1.48 - 1.66). Conclusions: Stroke symptoms appear to be a marker not only for stroke risk, but also for general CVD. Simple questions can identify 18% of the general population that have over a 40% chance of hospitalization for CVD over a 5-year horizon. Implications for potential intervention to reduce risk are profound.

Background: Multiple studies have shown that atrial fibrillation (AF), a common cardiac arrhythmia, is associated with increased mortality and higher incidence of stroke and heart failure. However, evidence for this association in African Americans is lacking. Methods: We studied 4,063 African Americans and 11,280 whites in the Atherosclerosis Risk in Communities (ARIC) Study, a US community-based cohort study, aged 45-64 (55% women) and free of AF at baseline in 1987-89. Three additional follow-up exams were conducted in 1990-92, 1993-95, and 1996-98. AF was ascertained during follow-up with study visit ECGs and hospital surveillance. Mortality and incidence of stroke and heart failure were ascertained according to study protocols. Using multivariable Cox proportional hazards models with time-dependent covariates, we calculated hazard ratios (HR) and 95% confidence intervals (CI) of mortality, stroke and heart failure in those with new-onset AF compared to those without AF by race. Results: During an average follow-up of 18 years, 332 AF cases were ascertained in African Americans and 1407 in whites. Overall, African Americans showed higher all-cause mortality and cardiovascular disease rates than whites ( Table ). AF was associated with increased mortality and risk of incident stroke and heart failure in whites and African Americans, even after adjustment for baseline and time-dependent potential confounders ( Table ). Associations of AF with all-cause mortality and stroke were of similar magnitude in both racial groups. However, the association between AF and heart failure was stronger in whites than in African Americans (HR 3.6, 95% CI 3.1-4.2 in whites, vs. HR 2.2, 95% CI 1.6-3.0 in African Americans). Conclusion: New-onset AF was associated with an increased risk of all-cause mortality, stroke, and heart failure in whites and African Americans independently of other cardiovascular risk factors. Table. Hazard ratios (95% confidence interval) of all-cause mortality, stroke, and heart failure in those with new-onset atrial fibrillation (AF) versus those without AF by race, ARIC, 1987-2008 Blacks Whites P for interaction No AF (n=3731) AF (n=332) No AF (n=9873) AF (n=1407) Mortality Deaths (n) 1144 188 2042 630 Person-years 69,483 1268 200,878 7493 Mortality rate 1 18.6 126.3 10.1 62.3 Model 1 1 (ref.) 5.80 (4.93-6.82) 1 (ref.) 4.58 (4.17-5.04) 0.27 Model 2 1 (ref.) 3.20 (2.71-3.76) 1 (ref.) 2.87 (2.61-3.17) 0.68 Stroke Events (n) 281 23 347 64 Person-years 51,082 867 147,608 5040 Incidence rate 1 6.0 25.0 2.4 11.5 Model 1 1 (ref.) 2.91 (1.81-4.68) 1 (ref.) 2.52 (1.86-3.43) 0.94 Model 2 1 (ref.) 1.83 (1.13-2.96) 1 (ref.) 1.91 (1.39-2.62) 0.82 Heart failure Events 613 71 992 364 Person-years 62,570 721 187,847 4578 Incidence rate 1 10.7 108.1 5.3 76.1 Model 1 1 (ref.) 3.35 (2.41-4.65) 1 (ref.) 4.75 (4.09-5.51) 0.02 Model 2 1 (ref.) 2.18 (1.56-3.04) 1 (ref.) 3.63 (3.12-4.21) 0.0006 1 Age- and sex-standardized, per 1000 person-years; Model 1 : Cox proportional hazards model adjusted for age, sex, and study center, with AF incidence as a time-dependent covariate; Model 2 : As model 1, but additionally adjusting for baseline education, and time-dependent body mass index, smoking, diabetes, hypertension, stroke, heart failure, and myocardial infarction Funding(This research has received full or partial funding support from the American Heart Association, National Center)

PR interval (PR) prolongation is a predictor of atrial fibrillation, a common cardiac arrhythmia, and is an established risk factor for pacemaker implantation, heart failure, stroke, and all-cause mortality. Previous genome-wide association studies in European (EU) and African (AA) descent populations have identified multiple loci associated with PR. However, it is unclear whether these loci are relevant in other racial groups, including Hispanic/Latinos (HL). Extending studies to include admixed populations such as HL also provides the potential to narrow regions associated with PR and identify population specific variants. Therefore, we evaluated 1,135 SNPs from four previously identified PR loci ( SCN5A, SCN10A, CAV1-CAV2, and TBX5-TBX3 ), fine-mapped on the Illumina Metabochip for association with PR. Associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry and clinical covariates (age, sex, RR interval, body mass index, height, systolic blood pressure) in 11,800 HL participants from participating studies of the Population Architecture using Genomics and Epidemiology (PAGE) consortia. Three of the four loci ( SCN5A, SCN10A, and CAV1-CAV2 ) generalized to HL populations ( P <7.1E-4 based on the number of SNPs correlated at r 2 >0.2 with EU-identified index SNPs). At each of these loci, we identified SNPs with stronger evidence of association with PR than the EU-identified index SNP when examined in the HL population ( SCN5A : rs7374540; SCN10A : rs6801957; CAV-CAV2 : rs717957). Conditional analyses also identified two additional independent SNPs at each of the three generalized loci ( SCN5A : rs3796387, rs9861242; SCN10A : rs10428132, rs7433723; CAV1-CAV2 : rs3801995, rs3807994), representing potential secondary signals. Furthermore, linkage disequilibrium (LD) patterns in Hispanics enabled the narrowing of the regions flanking the EU-identified index SNPs. For example, at the CAV1-CAV2 locus, HL LD patterns indicated that seven SNPs were in LD with rs3807989, the EU-identified index SNP, compared to 17 SNPs that were in LD with rs3807989 when applying EU LD patterns, reducing the size of the region by 71 kilobases. Finally, we examined evidence for population specific signals outside of the specific regions identified in EU populations which were associated with PR in Hispanics by focusing on SNPs uncorrelated with the EU index signals. At all four loci, multiple SNPs had evidence of association independent of the signals examined based on EU results. In conclusion, the same genetic loci that influence PR in European descent populations are also important in Hispanic populations, although we detected evidence for population specific SNPs. These results emphasize the importance of examining genetic associations in diverse populations in order to narrow the genomic interval for future functional interrogation.

Objective: To investigate the association between low forced expiratory volume in 1 second (FEV 1 ) and incident atrial fibrillation (AF) in a population-based cohort. Background: Impaired FEV 1 , a complex measure indicating genetic, developmental, obstructive and restrictive airway disease, musculoskeletal function, and motivation, has been inconsistently associated with an increased risk of cardiovascular disease mortality. Also, extant reports do not provide separate estimates for African Americans, who surprisingly have lower AF incidence than Caucasians. Methods: We examined 15,282 middle-aged African Americans (26%) and Caucasians, men (45%) and women from four U.S. communities enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Lung volumes by standardized spirometry and information on covariates were collected on these participants at the baseline visit (1987-1989). Prevalent AF cases were excluded by 12-lead ECG at baseline. Incident AF was defined as the first event identified from the following: ICD codes for AF from hospital discharge records or death certificates, or ECGs performed during three triennial follow-up visits. Results: Over an average follow-up of 17.5 years, a total of 1,733 (11%) participants developed new-onset AF. The rate of incident AF increased monotonically and inversely by tertiles of FEV 1 in each of the 4 gender-race strata. The unadjusted average incidence rates of AF per 100 person years of follow up by tertiles of FEV 1 (from lowest to highest tertile) were 13.6, 8.3, and 5.7 for white men; 8.7, 4.5, and 3.4 for white women; 8.2, 5.5, and 3.8 for black men; 6.9, 4.1, and 2.4 for black women. After multivariable adjustment for traditional cardiovascular disease risk factors and height, hazard ratios (95% CI) of AF comparing the lowest with the highest tertile of FEV 1 were 1.44 (1.16,1.78) among white men, 1.45 (1.12, 1.87) among white women, 1.81 (1.09, 3.02) among black men, and 1.84(1.20, 2.82) among black women. The trend estimate for per 1 Standard-Deviation lower FEV 1 for the corresponding race and gender groups were 1.21 (1.12, 1.32), 1.38 (1.25, 1.54), 1.45 (1.18, 1.76), and 1.35 (1.12, 1.63), respectively. The above associations were observed across all smoking status categories (current, former, and never). The association between low lung function and incidence of AF was similarly unchanged after exclusion of participants with heart failure (n = 689) or CHD (n = 558) at baseline. The hazard of AF was about 50% higher among those with FEV1/FVC ratio below 0.7. Conclusions: In this large population-based cohort study with a long term follow-up, reduced FEV 1 is strongly associated with a higher AF risk, independent of race, gender, smoking, and several other CVD risk factors. These findings suggest the need for research on mechanisms underlying the observed association to seek broader opportunities for prevention of AF.