Galectin-3, Metabolic Risk, and Incident Heart Failure: The ARIC Study.

BACKGROUND: It is unclear how metabolic syndrome (MetS) and diabetes affect Gal-3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal-3, and their joint associations with incident HF. METHODS AND RESULTS: We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996-1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross-sectional associations of metabolic risk categories with high Gal-3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal-3 quartiles with HF. In cross-sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10-1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32-1.92]) were associated with elevated Gal-3. Over a median follow-up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal-3 in the lowest quartile, the combination of MetS with diabetes and Gal-3 ≥75th percentile was associated with a 4-fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30-5.73]). Gal-3 provided HF prognostic information above and beyond MetS, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and CRP (C-reactive protein) (ΔC statistic for models with versus without Gal-3: 0.003; P=0.004). CONCLUSIONS: MetS and diabetes are associated with elevated Gal-3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal-3.

Systemic and organ-specific anti-inflammatory effects of sodium-glucose cotransporter-2 inhibitors.

Inflammation plays an essential role and is a common feature in the pathogenesis of many chronic diseases. The exact mechanisms through which sodium-glucose cotransporter-2 (SGLT2) inhibitors achieve their much-acclaimed clinical benefits largely remain unknown. In this review, we detail the systemic and tissue- or organ-specific anti-inflammatory effects of SGLT2 inhibitors using evidence from animal and human studies. We discuss the potential pathways through which SGLT2 inhibitors exert their anti-inflammatory effects, including oxidative stress, mitochondrial, and inflammasome pathways. Finally, we highlight the need for further investigation of the extent of the contribution of the anti-inflammatory effects of SGLT2 inhibition to improvements in cardiometabolic and renal outcomes in clinical studies.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Association Between Age at Diagnosis of Type 2 Diabetes and Hospitalization for Heart Failure: A Population-Based Study.

BACKGROUND: The relation between age at diagnosis of type 2 diabetes (T2D) and hospitalization for heart failure (HHF) is unclear. We assessed the association between age at diagnosis of T2D and HHF. METHODS AND RESULTS: We conducted a population-based cohort study using administrative health databases from the Canadian province of Ontario, including participants without prior heart failure. We identified people with new-onset T2D between April 1, 2005 and March 31, 2015, and matched each person with 3 diabetes-free adults, according to birth year and sex. We estimated adjusted hazard ratios (HRs) and rate ratios (RRs) for the association between age at T2D diagnosis and incident HHF, which was assessed until March 31, 2020. Among 743 053 individuals with T2D and 2 199 539 matched individuals without T2D, 126 241 incident HHF events occurred over 8.9 years. T2D was associated with a greater adjusted hazard of HHF at younger ages (eg, HR at age 30 years: 6.94 [95% CI, 6.54-7.36]) than at older ages (eg, HR at age 60 years: 2.50 [95% CI, 2.45-2.56]) relative to matched individuals. Additional adjustment for mediators (hypertension, coronary artery disease, and chronic kidney disease) marginally attenuated this relationship. Age at T2D diagnosis was associated with a greater number of HHF events relative to matched individuals at younger ages (eg, RR at age 30 years: 6.39 [95% CI, 5.76-7.08]) than at older ages (eg, RR at age 60 years: 2.65 [95% CI, 2.54-2.76]). CONCLUSIONS: Younger age at T2D diagnosis is associated with a disproportionately elevated HHF risk relative to age-matched individuals without T2D.

Persistence of significant secondary mitral regurgitation post-cardiac resynchronization therapy and survival: a systematic review and meta-analysis : Mitral regurgitation and mortality post-CRT.

Cardiac resynchronization therapy (CRT) significantly reduces secondary mitral regurgitation (MR) in patients with severe left ventricular systolic dysfunction. However, uncertainty remains as to whether improvement in secondary MR correlates with improvement with mortality seen in CRT. We conducted a meta-analysis to determine the association of persistent unimproved significant secondary MR (defined as moderate or moderate-to-severe or severe MR) compared to improved MR (no MR or mild MR) post-CRT with all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A systematic search of PubMed, EMBASE, and Cochrane Library databases till July 31, 2022 identified studies reporting clinical outcomes by post-CRT secondary MR status. In 12 prospective studies of 4954 patients (weighted mean age 66.8 years, men 77.8%), the median duration of follow-up post-CRT at which patients were re-evaluated for significant secondary MR was 6 months and showed significant relative risk reduction of 30% compared to pre-CRT. The median duration of follow-up post-CRT for ascertainment of main clinical outcomes was 38 months. The random effects pooled hazard ratio (95% confidence interval) of all-cause mortality in patients with unimproved secondary MR compared to improved secondary MR was 2.00 (1.57-2.55); p < 0.001). There was insufficient data to evaluate secondary outcomes in a meta-analysis, but limited data that examined the relationship showed significant association of unimproved secondary MR with increased cardiovascular mortality and heart failure hospitalization. The findings of this meta-analysis suggest that lack of improvement in secondary MR post-CRT is associated with significantly elevated risk of all-cause mortality and possibly cardiovascular mortality and heart failure hospitalization. Future studies may investigate approaches to address persistent secondary MR post-CRT to help improved outcome in this population.

Cardiac Autonomic Dysfunction and Risk of Silent Myocardial Infarction Among Adults With Type 2 Diabetes.

Background There is a paucity of large-scale epidemiological studies on the link between cardiac autonomic neuropathy (CAN) and the risk of silent myocardial infarction (SMI) in type 2 diabetes. We evaluated the association between CAN and the risk of SMI in a large sample of adults with type 2 diabetes. Methods and Results Participants with type 2 diabetes from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study without atherosclerotic cardiovascular disease at baseline were included. CAN was ascertained using heart rate variability indices calculated from 10-s resting electrocardiograms. The heart rate variability indices included standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals. CAN was defined as both the standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals less than the fifth percentile of the general population. We used Cox proportional hazards regression to generate hazard ratios (HRs) for incident SMI in relation to CAN measures. Among 4842 participants (mean age, 62.5 years; 46.6% women; 60.2% White), there were 73 incident SMI cases over a median follow-up of 4.9 years (incidence rate 3.1 out of 1000 person-years [95% CI, 2.5-3.9]). After adjusting for confounders, low heart rate variability was associated with a higher risk of SMI (HR, 1.67 [95% CI, 1.02-2.72] and HR, 1.56 [95% CI, 0.94-2.58] for low standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals, respectively). Participants with CAN had a 1.9-fold greater risk of SMI (HR, 1.91 [95% CI, 1.14-3.20]). Conclusions In a large cohort of adults with type 2 diabetes, CAN was significantly associated with an increased risk of incident SMI.

Insulin Resistance and N-Terminal Pro-B-Type Natriuretic Peptide Among Healthy Adults.

Importance: It is unclear to what extent insulin resistance is associated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the general population after accounting for body composition. Objective: To characterize the association of insulin resistance with NT-proBNP independently of measures of body composition in US adults. Design, Setting, and Participants: In a cross-sectional design, data on participants aged 20 years or older were obtained from the 1999-2004 National Health and Nutrition Examination Survey with measures of NT-pro-BNP, body mass index (BMI), and dual energy x-ray absorptiometry (DEXA)-derived measures of body composition (fat and lean masses). Linear and logistic regression was used to characterize the associations of measures of body mass and composition (BMI, waist circumference, fat mass, and lean mass) with NT-proBNP, adjusting for cardiovascular risk factors. Linear regression was used to characterize the associations of homeostasis model assessment of insulin resistance [HOMA-IR] and NT-proBNP after adjusting for cardiovascular risk factors and body composition measures. The quantitative insulin sensitivity check index [QUICKI], triglyceride-glucose index [TyG index], insulin to glucose ratio [IGR], fasting insulin, and homeostasis model assessment of ß-cell function (HOMA-ß) were also examined. Data for this study were analyzed from August 10, 2022, to June 30, 2023. Main Outcomes and Measures: Adjusted changes in NT-proBNP by insulin resistance levels. Results: A total of 4038 adults without diabetes or cardiovascular disease were included (mean [SD] age, 44 years; 51.2% female; and 74.3% White). In sex-specific analyses, insulin resistance measures were inversely associated with NT-pro-BNP. After adjustment including cardiovascular risk factors, BMI, waist circumference, and DEXA-derived fat mass and lean mass, the percent change in NT-proBNP associated with an SD increase in HOMA-IR was -16.84% (95% CI, -21.23% to -12.21%) in women and -19.04% (95% CI, -24.14 to -13.59) in men. Similar associations were observed for other indices of insulin resistance, including QUICKI (women: 17.27; 95% CI, 10.92-23.99 vs men: 22.17; 95% CI, 15.27 to 29.48), TyG index women: -11.47; 95% CI, -16.12 to -6.57 vs men: -15.81; 95% CI, -20.40 to -10.95), IGR women: -15.15; 95% CI, -19.35 to -10.74 vs men: -16.61; 95% CI, -21.63 to -11.26), and fasting insulin (women: -16.32; 95% CI, -20.63 to -11.78 vs men: -18.22; 95% CI, -23.30 to -12.79), as well as HOMA-ß (women: -10.71; 95% CI, -14.71 to -6.52 vs men: -11.72; 95% CI, -16.35 to -6.85). Conclusions and Relevance: In a national sample of US adults, insulin resistance was inversely associated with NT-proBNP, even after rigorously accounting for multiple measures of fat mass and lean mass. These results suggest that the mechanisms linking NT-proBNP to insulin resistance are partially independent of excess adiposity and may be associated with hyperinsulinemia.

Associations between diet quality and NT-proBNP in U.S. adults, NHANES 1999-2004.

Objective: N-terminal pro-brain-type natriuretic peptide (NT-proBNP) is a marker of cardiac wall stress and is a predictor of cardiovascular disease. Higher diet quality is associated with lower risk of cardiovascular disease. The association between diet quality and subclinical cardiovascular disease assessed by NT-proBNP is uncharacterized. We investigated the associations between diet quality, using Healthy Eating Index-2015 (HEI-2015), and NT-proBNP from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Methods: We included 9,782 adults from NHANES 1999-2004 without self-reported cardiovascular disease. The HEI-2015 ranges from 0 to 100, with higher scores indicating better diet quality. The HEI-2015 was categorized into sex-specific quintiles. Regression models were used to quantify associations between the overall HEI-2015 score and its 13 components with log-transformed NT-proBNP. The beta coefficients were converted to percent differences. Results: Among 9,782 participants, mean age was 45 years, 48% were men, and 72% were non-Hispanic White adults. After adjusting for sociodemographic characteristics, lifestyle factors, and medical history, those in the highest vs. lowest HEI-2015 quintile had an 8.5% (95% CI: -14.6% to -2.0%) lower NT-proBNP level. There was a dose-response association between HEI-2015 and NT-proBNP (P value for trend = 0.01). Each 1-unit higher in sodium and added sugars score indicating lower intake was associated with lower NT-proBNP by 7.7% (95% CI: -12.8% to -2.2%) and 6.5% (95% CI: -12.0% to -0.7%), respectively. Conclusion: Higher diet quality, especially lower intakes of sodium and added sugars, was associated with lower serum levels of NT-proBNP.

Racial and ethnic differences in circulating N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in US adults.

Background: The presence and interpretation of racial and ethnic differences in circulating N-terminal pro-brain-type natriuretic peptide (NT-proBNP), a diagnostic biomarker for heart failure, are controversial. Objective: To examine racial and ethnic differences in NT-proBNP levels among the general US adult population. Methods: We performed a cross-sectional analysis of data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). We included 4717 non-Hispanic White, 1675 non-Hispanic Black, and 2148 Mexican American adults aged 20 years or older without a history of cardiovascular disease. We examined the associations of race and ethnicity with NT-proBNP using linear and logistic regression models in the overall population and in a younger, 'healthy' subsample. Results: The mean age was 45 years. Median NT-proBNP levels were significantly lower among Black (29.3 pg/mL) and Mexican American adults (28.3.4 pg/mL) compared to White adults (49.1pg/mL, P-values<0.001). After adjusting for sociodemographic factors and cardiovascular risk factors, NT-proBNP was 34.4% lower (95%CI -39.2 to -29.3%) in Black adults and 22.8% lower (95%CI -29.4 to -15.5) in Mexican American adults compared to White adults. Our findings were consistent in a young, healthy subsample, suggesting non-cardiometabolic determinants of these differences. Conclusions: NT-proBNP levels are significantly lower among Black and Mexican American adults compared with White adults, independent of cardiometabolic risk. Although race/ethnicity is a poor proxy for genetic differences, our findings may have clinical implications for the management of HF. However, studies in diverse populations are needed to characterize the biological basis of NT-proBNP variation.

Association of cumulative social risk and gestational diabetes mellitus in the US, 2007-2018.

AIMS: Little is known regarding the association of multiple social risk factors and gestational diabetes mellitus (GDM). METHODS: We analyzed the 2007-2018 National Health and Nutrition Examination Surveys including 10,439 women aged ≥20 years (8 % with history of GDM). We created a cumulative social risk score (CSR) by adding scores assigned to each of the following: race/ethnicity, citizenship status and country of birth, education, and family income (score of 0 used as reference group). Using logistic regression, we assessed the associations of individual social risk factors (education, income, race/ethnicity and citizenship status) and CSR score with GDM, adjusting for age, parity, insurance status, care access, smoking, diet, physical activity, and body mass index. RESULTS: Among individual social risk factors, being a non-U.S. citizen (OR:1.51, 95% CI: 1.06-2.15) or belonging to a minority racial/ethnic group (OR:1.30, 95% CI: 1.04-1.59) was significantly associated with a greater odds of GDM. When examining the combined effects of social risk factors, a CSR score ≥3 was associated with an increased odds of GDM (OR:1.64, 95% CI: 1.22-2.1). CONCLUSIONS: Women with a greater burden of social risk factors are more likely to have GDM, thus should be the focus of interventions to prevent and treat GDM.

Body Composition Measures and N-terminal pro-B-type Natriuretic Peptide (NT-pro-BNP) in US Adults.

BACKGROUND: The associations of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with dual energy x-ray absorptiometry (DEXA)-derived measures of body mass and composition are largely unknown. METHODS: We included participants aged ≥20 years from the 1999-2004 National Health and Nutrition Examination Survey with NT-pro-BNP and DEXA-derived body composition (fat and lean mass) measures. We used linear and logistic regression to characterize the associations of measures of body mass and composition (body mass index [BMI], waist circumference [WC], fat mass, and lean mass) with NT-pro-BNP, adjusting for cardiovascular risk factors. RESULTS: We conducted sex-specific analyses among 9134 adults without cardiovascular disease (mean age 44.4 years, 50.8% women, and 72% White adults). The adjusted mean NT-proBNP values were lowest in the highest quartiles of BMI, WC, fat mass, and lean mass. There were large adjusted absolute differences in NT-pro-BNP between the highest and lowest quartiles of DEXA-derived lean mass, -6.26 pg/mL (95% confidence interval [CI], -8.99 to -3.52) among men and -22.96 pg/mL (95% CI, -26.83 to -19.09) among women. Lean mass exhibited a strong inverse association with elevated NT-pro-BNP ≥ 81.4 pg/mL (highest quartile) - odds ratio (OR) 0.58 (95% CI, 0.39-0.86) in men and OR 0.59 (95% CI, 0.47-0.73) in women for highest lean mass quartile vs. lowest quartile. Further adjustment for fat mass, BMI, or WC did not appreciably alter the inverse association of lean mass with NT-pro-BNP. CONCLUSIONS: In a national sample of US adults, lean mass was inversely associated with NT-pro-BNP.

Prevalence of Elevated NT-proBNP and its Prognostic Value by Blood Pressure Treatment and Control.

BACKGROUND: The prognostic utility of NT-proBNP in the setting of hypertension has not been well-characterized in the general US adult population. METHODS: We measured NT-proBNP in stored blood samples collected from participants 1 year or older who participated in the 1999-2004 National Health and Nutrition Examination Survey. In adults 20 years or older without a history of cardiovascular disease, we assessed the prevalence of elevated NT-pro-BNP by blood pressure (BP) treatment and control categories. We examined the extent to which NT-proBNP identifies participants at higher risk for mortality across BP treatment and control categories. RESULTS: Among US adults without CVD, the prevalence of elevated NT-proBNP (≥125 pg/ml) was 27.2% among those with untreated hypertension, 24.9% among those with treated controlled hypertension, and 43.3% among those with treated uncontrolled hypertension. Over a median follow-up of 17.3 years and after adjusting for demographic and clinical risk factors, US adults with treated controlled hypertension and elevated NT-proBNP had increased risk of all-cause mortality (HR 2.29, 95% CI 1.79, 2.95) and cardiovascular mortality (HR 3.83, 95% CI 2.34, 6.29), compared to adults without hypertension and with low levels of NT-proBNP (<125 pg/ml). Across all levels of SBP and irrespective of antihypertensive medication use, elevated NT-proBNP was associated with an increased risk of mortality, compared to low levels of NT-proBNP. CONCLUSIONS: Among a general population of adults free of CVD, NT-proBNP can provide additional prognostic information within and across categories of BP. Measurement of NT-proBNP may have potential for clinical use to optimize hypertension treatment.

Blood Pressure Variability and Risk of Atrial Fibrillation in Adults With Type 2 Diabetes.

BACKGROUND: There is a paucity of epidemiological data on the association between long-term variability of blood pressure (BP) and incident atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to evaluate the association of BP variability with incident AF in a large sample of adults with type 2 diabetes. METHODS: We included participants who had ≥5 BP measurements in the first 24 months of action to control cardiovascular risk in diabetes. The visit-to-visit variability of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using the coefficient of variation, SD, and variability independent of the mean. Incident AF was recorded using follow-up electrocardiograms. Modified Poisson regression was used to generate risk ratios (RRs) and 95% CI for AF. RESULTS: A total of 8,399 participants were included (average age 62.6 ± 6.5 years, 38.8% women, 63.2% White). Over a median follow-up of 5 years, 155 developed AF. Compared to the lowest quartile, the highest quartile of BP variability was associated with an increased risk of AF (RR: 1.85 [95% CI: 1.13-3.03] and 1.63 [95% CI: 1.01-2.65] for coefficient of variation of SBP and DBP, respectively). Participants in the highest quartile of both SBP and DBP had a 2-fold higher risk of AF compared to those in the lowest 3 quartiles of both SBP and DBP (RR: 1.94; 95% CI: 1.29-2.93). CONCLUSIONS: In a large cohort of adults with type 2 diabetes, higher variability in SBP and DBP was independently associated with an increased risk of AF.

Incidence of Heart Failure Related to Co-Occurrence of Gestational Hypertensive Disorders and Gestational Diabetes.

BACKGROUND: The extent to which their co-occurrence of gestational hypertensive disorders (GHTD) and gestational diabetes mellitus (GDM) influences heart failure (HF) risk is unclear. OBJECTIVES: The purpose of this study was to characterize the risk of HF related to concomitant GHTD and GDM. METHODS: We conducted a population-based cohort study using the Ministry of Health and Long-Term Care of Ontario (Canada) health care administrative databases. We included women with a livebirth singleton delivery between July 1, 2007, and March 31, 2018, and excluded those with prepregnancy diabetes, hypertension, HF, or coronary artery disease. GDM, GHTD, peripartum cardiomyopathy (at index pregnancy) were identified using diagnosis coding. Incident HF was assessed from index pregnancy until March 31, 2020. We estimated associations of GDM and/or GHTD with peripartum cardiomyopathy and incident HF. RESULTS: Among 885,873 women (mean age: 30 years, 54,015 with isolated GDM, 43,750 with isolated GHTD, 4,960 with GDM and GHTD), there were 489 HF events over 8 years. Compared to no-GDM and no-GHTD, isolated GDM (adjusted hazard ratio [aHR]: 1.44; 95% CI: 1.02-2.04) and isolated GHTD (aHR: 1.65; 95% CI: 1.17-2.31) were associated with a higher risk of incident HF. The co-occurrence of GDM and GHTD was associated with a higher HF risk (aHR: 2.64; 95% CI: 1.24-5.61). GDM and GHTD increased the risk of peripartum cardiomyopathy (adjusted risk ratio [aRR]: 7.30; 95% CI: 6.92-7.58), similarly to isolated GHTD (aRR: 7.40; 95% CI: 7.23-7.58). CONCLUSIONS: The co-occurrence of GDM and GHTD was associated with a significantly high risk of incident HF.

NT-proBNP Reference Intervals in Healthy U.S. Children, Adolescents, and Adults.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a cardiac biomarker used in the clinical management of heart failure. We sought to create updated reference intervals for NT-proBNP for healthy US children, adolescents, and adults. METHODS: We identified a population of healthy individuals using the 1999 to 2004 cycles of the National Health and Nutrition Examination Survey (NHANES). We measured serum NT-proBNP in 12 346 adults and 15 752 children and adolescents with the Elecsys NT-proBNP assay on the Roche e601 autoanalyzer. We compared 4 methods for reference interval calculation, and presented the final reference intervals using the robust method partitioned by age and sex categories. RESULTS: NT-proBNP values were available for 1949 healthy adults and 5250 healthy children and adolescents. NT-proBNP concentrations in males and females varied according to age, being higher in early childhood, relatively lower in late adolescence, and highest through middle age and older age. Females tended to have higher NT-proBNP concentrations compared to men from late adolescence until middle age. The upper reference limit, or 97.5th percentile, for 50 to 59 year-old men was 225 ng/L (90% CI: 158 to 236), and for 50 to 59 year-old women, 292 ng/L (90% CI: 242 to 348). CONCLUSIONS: Among healthy individuals, NT-proBNP concentrations varied greatly according age and sex. The reference intervals presented here should inform future clinical decision limits and suggest that age- and sex-specific intervals may be necessary to more precisely characterize risk.