Richard Kazibwe

Background: Sleep disturbance has been associated with atrial fibrillation (AF), but prior studies have largely relied on sleep assessed at a single time point or examined specific sleep disorders. Whether changes in sleep disturbance over time predict AF and, conversely, whether AF predicts subsequent sleep disturbance within the same population is not well established. Methods: We conducted a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), which enrolled adults with hypertension and increased cardiovascular risk without diabetes. Two prospective analytic cohorts were constructed to examine each direction of the association: 7,232 participants without baseline AF for the analysis of sleep disturbance and incident AF, and 6,079 participants without clinically significant sleep disturbance at baseline for the reciprocal analysis. Sleep disturbance was assessed repeatedly using a 0–3 patient-reported symptom score, with clinically significant sleep disturbance defined as a score ≥2. AF was ascertained from protocol 12-lead ECGs. Time-dependent Cox models evaluated time-updated sleep disturbance in relation to incident AF and time-updated AF in relation to incident clinically significant sleep disturbance, with adjustment for demographic, lifestyle, and cardiovascular risk factors. Results: During a median follow-up of 3.3 years, 189 incident AF events occurred. Time-updated clinically significant sleep disturbance was associated with a 78% higher adjusted risk of incident AF (HR, 1.78; 95% CI, 1.27–2.51). Each 1-point increase in the time-updated sleep score was associated with a 26% higher risk of AF (HR, 1.26; 95% CI, 1.09–1.46). Compared with a sleep score of 0, the adjusted HRs were 1.20 (95% CI, 0.85–1.70), 2.05 (95% CI, 1.33–3.15), and 1.72 (95% CI, 1.03–2.88) for scores of 1, 2, and 3, respectively. In the reciprocal analysis, 1,422 incident clinically significant sleep-disturbance events occurred during a median follow-up of 3.2 years. Time-updated AF was associated with a 59% higher adjusted risk of incident clinically significant sleep disturbance (HR, 1.59; 95% CI, 1.16–2.16). Associations in both directions were consistent across prespecified subgroups, with no significant effect modification. Conclusion: In adults with hypertension, sleep disturbance and AF were prospectively and reciprocally associated when evaluated longitudinally. These findings support a bidirectional relationship between sleep disturbance and AF and highlight the potential clinical relevance of assessing sleep health in patients with or at risk for AF.

Background: Electrocardiographic markers of atrial cardiomyopathy (AtCM) are associated with adverse cardiovascular outcomes. Whether AtCM further refines cardiovascular disease (CVD) mortality risk across increasing cardiometabolic risk factor (CMRF) burden is unclear. Methods: We analyzed 7,083 adults free of baseline CVD. AtCM was defined by the presence of ≥1 ECG marker: prolonged P-wave duration ≥120 ms in lead II, abnormal P-wave axis outside 0-75, or deep terminal negativity of the P wave in V1 <-100 μV. CMRF burden was defined as the presence of 0, 1, or ≥2 of hypertension, diabetes, and obesity. CVD mortality was ascertained through December 31, 2006. Results: Among 7,083 participants (mean age 58 years and 48% men), CVD mortality rates increased progressively across the six combined exposure groups. In a multivariable adjusted Cox proportional hazard analysis, AtCM identified higher-risk subgroups within each CMRF burden category, with risk increasing progressively across combined exposure groups and highest among participants with ≥2 risk factors and AtCM (HR 2.25, 95% CI 1.75-2.87). In secondary analyses, a similar pattern was observed for individual CMRFs, with the combination of AtCM and hypertension, diabetes, or obesity conferring the highest risk compared with participants with neither condition (HR (95% CI): 1.58 (1.31-1.89); 2.08 (1.62-2.68); and 1.47 (1.19-1.82), respectively). Conclusions: ECG-defined AtCM refined CVD mortality risk across increasing CMRF burden. Individuals with both AtCM and multiple CMRFs had the highest risk. These findings support the potential role of ECG-based AtCM assessment as a scalable approach to improve cardiovascular risk stratification among individuals with CMRFs.

Objective: Although an elevated resting heart rate is linked to higher mortality, the pathways underlying this relationship are not fully defined. One candidate mechanism is subclinical myocardial injury (SCMI), an asymptomatic form of cardiac damage indexed by a Cardiac Infarction/Injury Score (CIIS) of at least 10, which has prognostic value for adverse cardiovascular (CV) outcomes. Methods: We analyzed 7152 participants from NHANES III who underwent electrocardiogram (ECG) recording and were free of CV disease. Heart rate was categorized as bradycardia (≤50 bpm), normal (>50–<100 bpm), or tachycardia (≥100 bpm). Mortality was assessed through National Death Index linkage. Logistic and Cox regression models evaluated associations with SCMI and mortality, respectively, and attenuation was assessed by change in hazard ratios after adjusting for SCMI. Results: SCMI was present in 1744 (24.3%) participants. Tachycardia was associated with increased odds of SCMI (adjusted OR 2.34, 95% CI 1.42–3.88). Over 13.9 years median follow-up, 2311 (32.3%) died from all causes and 933 (13.1%) from CV causes. Tachycardia was associated with increased all-cause mortality (HR 3.58, 95% CI 2.63–4.88) and CV mortality (HR 2.05, 95% CI 1.06–3.79). Adjustment for SCMI attenuated the tachycardia–CV mortality association by 8.6% and all-cause mortality by 5%. Bradycardia was not associated with SCMI or mortality. Conclusions: These findings suggest that SCMI modestly attenuates the heart rate–mortality association, suggesting that silent myocardial damage may represent one potential intermediary pathway.

Aims: The prognostic value of jointly assessing lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) in primary prevention among individuals without standard modifiable risk factors (SMuRFs) remains unclear. Methods and results: We analysed 50 450 UK Biobank participants free of cardiovascular disease at baseline who were SMuRF-less, defined as absence of current smoking, obesity, hypertension, dyslipidemia, and diabetes. Elevated Lp(a) and hsCRP were defined using cohort-specific 75th percentile cutoffs and established clinical thresholds. Incident atherosclerotic cardiovascular disease (ASCVD), defined as nonfatal myocardial infarction, nonfatal ischaemic stroke, or cardiovascular death, was ascertained. Associations were evaluated using Fine–Gray competing-risk regression models to estimate subdistribution hazard ratios (sHRs) with 95% confidence intervals (CI), accounting for competing non-cardiovascular death. Over 15 years of follow-up, 1104 (2.2%) incident ASCVD events occurred. Using cohort-specific cutoffs, elevated hsCRP was associated with higher ASCVD risk (sHR 1.35, 95% CI 1.16–1.57), while elevated Lp(a) showed a more modest association (sHR 1.24, 95% CI 1.06–1.45). In joint analyses, isolated elevations of hsCRP or Lp(a) were each associated with increased risk, with the highest risk observed among individuals with concurrent elevations (sHR 1.64, 95% CI 1.28–2.09), without evidence of interaction. Similar patterns were observed using clinical cutoffs [Lp(a) ≥ 125 nmol/L; hsCRP ≥2.0 mg/L], with concurrent elevation conferring the greatest risk (sHR 1.74, 95% CI 1.17–2.59). Conclusion: In SMuRF-less individuals, Lp(a) and hsCRP independently predict ASCVD risk. These findings suggest that combined assessment of Lp(a) and hsCRP may provide complementary information for risk characterization among SMuRF-less adults in primary prevention.

Background: Ketone bodies (KB) are endogenous energy sources synthesized by the liver in response to metabolic stress. Their associations with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and mortality and their potential beneficial or harmful effects have yet to be determined. This study aimed to examine the association between KB and incident cardiovascular outcomes and mortality in a large general population cohort free from ASCVD and HF at baseline. Methods: This analysis included 90 987 participants (mean age 56.4 ± 8.1 years; 54.7% women) from the UK Biobank without prevalent ASCVD or HF. KB were measured by nuclear magnetic resonance spectroscopy. The primary outcomes were ASCVD, HF, and all‐cause death. Secondary outcomes were myocardial infarction, ischemic stroke, peripheral artery disease, and CVD death. All outcomes were defined based on International Classification of Diseases, Ninth Revision ( ICD‐9 ) and Tenth Revision ( ICD‐10 ) codes. Multivariable‐adjusted Cox proportional hazards models examined the association of total KB with incident cardiovascular outcomes and mortality. Results: At a median follow‐up of 13.4 years, higher levels of total KB (per 10‐fold increase) were associated with a greater risk of incident ASCVD, HF, and all‐cause mortality (hazard ratio [HR], 1.31 [95% CI, 1.18–1.46], 1.44 [95% CI, 1.24–1.6]7, and 1.51 [95% CI, 1.38–1.66]), respectively. Participants also demonstrated a 37% (95% CI, 11%–69%) increased risk of stroke and 69% (95% CI, 43%–100%) increased risk of CVDdeath. There was no significant association between KB and incident myocardial infarction. Conclusions: Elevation in endogenous KB in a population free from CVD at baseline is associated with an increased risk of ASCVD, HF, stroke, and mortality.

Background: Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. Methods: This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride‐glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log‐transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as P ‐value for the multiplicative interaction between TyG and Lp(a) was 0.07. Relative to reference, aHRs (95% CI) were 1.15 (1.10–1.20) for ≥125/low IR, 1.09 (1.06–1.12) for <125/high IR, and 1.32 (1.24–1.41) for ≥125/high IR. Conclusions: Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)‐associated risk in the context of primary CVD prevention setting.

Objective: To examine whether the association between smoking status and cardiovascular (CV) mortality differs by arterial stiffness, assessed by pulse pressure index (PPI), among U.S. adults without baseline cardiovascular disease (CVD). Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2016, we analyzed 16,605 adults aged 40–79 years without baseline CVD, with mortality follow-up through December 31, 2019. PPI was calculated as (systolic blood pressure [SBP] − diastolic blood pressure [DBP])/SBP and split at the cohort median (0.415) as low versus high. Smoking status was classified as never, former, or current, yielding six joint PPI–smoking groups. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CV mortality, adjusting for demographics and cardiometabolic risk factors. Results: Over a median follow-up of 8.4 years, 518 CV deaths (3.1%) occurred. Among individuals with low PPI, former smokers had CV mortality comparable to never smokers (HR 0.86, 95% CI 0.56–1.33), whereas current smokers remained at elevated risk (HR 2.51, 95% CI 1.65–3.81). This pattern was not observed in the high PPI stratum, where both former and current smokers had significantly higher CV mortality than never smokers. Conclusion: Former smokers with low PPI had CV mortality similar to never smokers, whereas former smokers with high PPI remained at elevated risk. These findings suggest that the CV benefit of smoking cessation may be greatest when arterial stiffness is minimal, supporting early cessation before substantial vascular aging occurs.

Background/Objectives: The Metabolic Score for Insulin Resistance (METS-IR), a non-insulin-based index of insulin resistance (IR), and subclinical myocardial injury (SCMI), identified by electrocardiogram (ECG), are each associated with cardiovascular disease (CVD). However, their joint impact on mortality remains unclear. We examined the association of the METS-IR with SCMI and evaluated the individual and combined associations of SCMI and IR with cardiovascular mortality. Methods: We analyzed adults without baseline CVD from the Third National Health and Nutrition Examination Survey (1988–1994) with mortality follow-up through 31 December 2019. The METS-IR was calculated from fasting glucose, triglycerides, high-density lipoprotein cholesterol, and body mass index and categorized as low (<75th percentile) or high (≥75th percentile). SCMI was defined as a cardiac infarction injury score ≥ 10 on ECG. Multivariable logistic regression assessed associations between the METS-IR and SCMI, and Cox regression estimated cardiovascular mortality risk across SCMI-IR combinations. Results: Among 6079 participants, 14.1% had SCMI. Higher METS-IR values were associated with greater SCMI odds (OR (95% CI): 1.58 (1.31–1.90)). Over a median of 18.8 years, 563 (9.1%) cardiovascular deaths occurred. Both SCMI and high IR were individually associated with increased cardiovascular mortality ((HR (95% CI): 1.41 (1.19–1.69) and 1.32 (1.09–1.59), respectively). Participants with both SCMI and high IR had the highest risk (HR 1.92; 95% CI 1.49–2.50) compared with those with neither condition. Conclusions: In adults without prior CVD, the METS-IR was positively associated with SCMI. The coexistence of SCMI and high IR identified a subgroup at nearly twofold higher risk of cardiovascular mortality, supporting the combined use of ECG-based injury markers and metabolic indices for cardiovascular risk stratification.

Objective: To examine the association between Atherogenic Index of Plasma (AIP) and subclinical myocardial injury (SCMI), and their combined impact on cardiovascular disease (CVD) mortality in the general population. Methods: This analysis included 7,093 participants without CVD from the Third National Health and Nutrition Examination Survey. AIP was calculated as the logarithmic ratio of triglycerides to HDL cholesterol. Participants were stratified into low or high AIP groups based on the median AIP value (0.958). Electrocardiographic SCMI was defined as Cardiac Infarction/Injury Score >=10 points. CVD mortality data were obtained from the National Death Index. Multivariable logistic regression models assessed the baseline cross-sectional association between AIP and SCMI, while Cox proportional hazards models examined the relationship between different baseline AIP/SCMI groups and CVD mortality. Results: High AIP was associated with increased odds of SCMI [OR(95% CI): 1.20(1.07-1.35)] in multivariable logistic regression analysis. In multivariable Cox proportional hazard models, compared to participants with low AIP and absent SCMI, those with SCMI had a higher risk of CVD mortality regardless of AIP level [(HR(95% CI) 1.28(1.05-1.57) and 1.33(1.10-1.60)]. However, high AIP without SCMI was not associated with CVD mortality [HR (95% CI) 0.94(0.79-1.11)]. Conclusions: High AIP was associated with an increased risk of SCMI. SCMI was linked to a higher risk of CVD mortality regardless of AIP levels, while high AIP was only associated with CVD mortality when SCMI was present, suggesting that the reported adverse outcomes linked to high AIP may be driven by the development of SCMI. Keywords: Atherogenic Index of Plasma; Subclinical Myocardial Injury; Cardiovascular Mortality; NHANES; Lipid Metabolism

Background/Objectives: The Metabolic Score for Insulin Resistance (METS-IR), a non-insulin-based index of insulin resistance (IR), and subclinical myocardial injury (SCMI), identified by electrocardiogram (ECG), are each associated with cardiovascular disease (CVD). However, their joint impact on mortality remains unclear. We examined the association of METS-IR with SCMI and evaluated the individual and combined associations of SCMI and IR with cardiovascular mortality. Methods: We analyzed adults without baseline CVD from the Third National Health and Nutrition Examination Survey. METS-IR was calculated from fasting glucose, triglycerides, high-density lipoprotein cholesterol, and body mass index and categorized as low (Results: Among 6,079 participants, 14.1% had SCMI. Higher METS-IR was associated with greater SCMI odds (OR(95%CI): 1.58(1.31-1.90)). Over a median of 18.8 years, 563 (9.1%) cardiovascular deaths occurred. Both SCMI and high IR were individually associated with increased cardiovascular mortality ((HR(95% CI): 1.41(1.19–1.69) and 1.32(1.09–1.59), respectively). Participants with both SCMI and high IR had the highest risk (HR 1.92; 95% CI 1.49–2.50) compared with those with neither condition. Conclusions: In adults without prior CVD, METS-IR was positively associated with SCMI. The coexistence of SCMI and high IR identified a subgroup at nearly twofold higher risk of cardiovascular mortality, supporting combined use of ECG-based injury markers and metabolic indices for cardiovascular risk stratification.