Citations

Introduction: The MI-GENES randomized clinical trial (NCT01936675) assessed the effect of disclosing a polygenic risk score (PRS) for coronary heart disease (CHD), in addition to a clinical risk based on Framingham risk score (FRS), on LDL-C levels. The trial enrolled participants from Olmsted County, Minnesota, without cardiovascular disease, at intermediate CHD risk (10-y risk: 5-20%), and not on statins. There was a significant LDL-C reduction in the integrated risk score group (IRS g ; received PRS information in addition to the FRS) compared to the FRS group (FRS g ; received their risk based on FRS), due to more frequent statin initiation. Research Question: Does disclosure of an IRS for CHD lead to a lower rate of major adverse cardiovascular events (MACE)? Methods: Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain cardiovascular events, testing for CHD, and risk factor changes, by blinded review of electronic health records. The primary outcome was time from randomization to the first MACE— defined as cardiovascular death, nonfatal MI, coronary revascularization, and nonfatal stroke. Analyses were done using Cox and linear mixed-effects models. Results: We followed all 203 participants, who completed the MI-GENES trial, 100 in FRS g and 103 in IRS g (mean age at the end of follow-up 68.2±5.2 years, 48% male). During a median follow-up of 9.5 years, 9 MACE occurred in FRS g and 2 in IRS g (HR, 0.20; 95% CI, 0.04 to 0.94; P =0.042, Figure 1A). In FRS g , 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRS g (HR, 0.51; 95% CI, 0.32 to 0.81; P =0.004, Figure 1B). IRS g participants had a longer duration of statin therapy during the first four years post-randomization (Figure 1C) and a greater reduction in LDL-C for up to 3 years post-randomization (Figure 1D). No significant differences between the two groups were observed for hemoglobin A1C, blood pressure, weight, and smoking cessation rate during follow-up. Conclusion: The disclosure of 10-year CHD risk that included a PRS to those at intermediate risk was associated with lower incidence of MACE after a decade, likely due to more frequent and prolonged statin use, leading to lower LDL-C levels.

Background: Coronary heart disease (CHD) results from environmental and genetic factors. Lifestyle-psychosocial factors that capture environmental risk and polygenic risk scores (PRS) that capture genetic risk have been associated with CHD in prior studies. Aim: To assess whether higher CHD risk traditionally attributed to non-White race/ethnicty is mediated by PSS CHD or PRS CHD . Methods: In UK Biobank, we ascertained incident CHD (MI/coronary revascularization) and calculated an ancestry-specific PRS for CHD (PGS000018). Based on self-reported race/ethnicity, participants were classified as White and non-White. An age, sex, and ethnicity-adjusted polysocial score for CHD (PSS CHD ) was derived from 100 self-reported lifestyle-psychosocial factors across nine domains: Adulthood Relationship, Education, Entertainment, Housing, Income, Occupation, Physical Activity, Psychological Health, and Sleep. Those with CHD or statin use at recruitment or missing age, sex, race/ethnicity or genotype were excluded. Machine learning (elastic net model) was used to develop PSS CHD . Cox and mediation analyses were performed. Results: In 398,403 participants (56±8 y, 43% male, 96.3% White, 1.8% Asian, 1.6% Black, and 0.3% Chinese), 10,033 had an incident CHD event during a 10-year follow-up. The HRs (95% CIs) for a 1 SD increase in PSS CHD and PRS CHD for CHD risk were 1.5 (1.4–1.5, P <10 -16 ), and 1.6 (1.5 - 1.6, P <10 -16 ), respectively (Figure 1A-B). Asians and Blacks had the highest PSS CHD (mean±SD: 0.5±1, and 0.5±1, respectively), followed by Chinese (0.1±0.9), and Whites (0.0±1) (Figure 1C). After adjustment for age, sex, diabetes, hypertension, LDL-C, and smoking, non-Whites had higher CHD risk: HR (95% CI): 1.2 (1.0–1.4, P <10 -16 ), and the higher risk was mediated more substantially by PSS CHD than PRS CHD (63% (38%-100%) vs. 16% (8%-41%), both P <10 -16 ). Conclusions: The higher CHD risk observed in non-Whites in UK Biobank was mainly due to unfavorable lifestyle-psychosocial factors, rather than PRS, consistent with the paradigm that race/ethnicity is not a biological but rather a social construct. Our findings support substituting race/ethnicity with lifestyle-psychosocial factors and social determinants of health in CHD risk equations.

Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy. Among women with LQT2, the post-partum period has been considered high risk for cardiac events. However, whether this risk persists after establishing their diagnosis and implementing their LQT2-directed treatment program remains to be determined. Objective: To describe the management and outcomes of LQT2 women during the 9 months post-partum period. Methods: A retrospective analysis of 1869 patients with LQTS treated and evaluated at a tertiary center specializing in Genetic Heart Disease from January 2000 to November 2023 was performed to identify women with diagnosed and treated LQT2 who had a pregnancy during follow-up. Data were abstracted for patient demographics, clinical characteristics, symptomatic status, and treatment plans before and after pregnancy. Results: Overall, 30 pregnancies occurred in 22 women with LQT2. Their average QTc was 489 ± 34 ms with 7 patients (32%) having a resting QTc > 500 ms. Prior to their first post-partum period, 5/22 (23%) were symptomatic with 2 (9%) experiencing a LQT2-triggered sudden cardiac arrest (SCA). Before their post-partum period, their LQT2-directed therapy comprised preventative measures only in 7 (23%), drug therapy in 16 (53%), combination therapy in 7 (23%), and 10 women (43%) had an implantable cardioverter defibrillator (ICD). Pre-emptive treatment intensification was done for 24/30 post-partum periods. Only a single VF-terminating ICD therapy occurred in 1 (3%) of the 30 post-partum periods involving a 21-year-old with p.Lys610Asn-KCNH2 variant, QTc = 490 ms, and a pre-diagnosis presentation of seizures. Conclusion: Although the post-partum period is regarded as a ‘high risk’ window of time for women with LQT2, the risk of a LQT2-triggered cardiac event after diagnosis and implementation of contemporary therapies is very low. This designation of “high risk” among correctly diagnosed and treated women is misleading and generates inappropriate and unnecessary anxiety.

Introduction: Preload insufficiency can mimic HFpEF or complicate its treatment, and SGLT2 inhibitors may worsen preload insufficiency by reducing stressed blood volume. A drop in pulse pressure (PP) when going from supine to standing (i.e., orthostatic PP) may indicate an inability to vasoconstrict the splanchnic circulation, leading to preload insufficiency. We, therefore, sought to determine baseline characteristics associated with orthostatic PP and whether the effects of dapagliflozin vary by baseline orthostatic PP in patients with HFpEF. Hypothesis: In patients with HFpEF, the magnitude of treatment response to dapagliflozin – in terms of efficacy and safety - may be associated with orthostatic PP at baseline. Methods: We measured orthostatic PP (standing PP – supine PP) at baseline in 321 of the 324 patients with HFpEF randomized in the PRESERVED-HF trial. We categorized patients into tertiles of orthostatic PP and compared baseline characteristics. We examined the interaction between baseline orthostatic PP, treatment, and the following outcomes during 12 weeks of follow-up: (1) Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); (2) 6-minute walk distance (6MWD); (3) volume depletion events. Results: At baseline, the median orthostatic PP was 0 mmHg (25 th -75 th percentile, -8.0, +5.3 mmHg). Patients with lower orthostatic PP had higher supine SBP and lower standing SBP. There were no differences in age, comorbidities, laboratory studies, KCCQ, and 6MWD among tertiles of orthostatic PP. Dapagliflozin improved KCCQ-CSS and 6MWD across the range of orthostatic PP; participants with the highest (vs lowest) orthostatic PP appeared to have numerically greater improvements with dapagliflozin, but these differences were not statistically significant (Table). Overall, 18 (5.6%) experienced volume depletion events (dapagliflozin 11 [6.8%], placebo 7 [4.3%]). In tertile 1 (lowest orthostatic PP), there were numerically more volume depletion events with dapagliflozin than placebo (8 [14.3%] vs 3 [5.0%] events); whereas the numbers of such events were similar in tertiles 2 and 3 (Table). Conclusions: In patients with HFpEF, dapagliflozin improved KCCQ and 6MWD across the range of orthostatic PP, although those with the highest (vs lowest) orthostatic PP appeared to have numerically greater improvements. Very low orthostatic PP may identify patients who could be at increased risk of volume depletion events with SGLT2 inhibitors.

Introduction: Postural orthostatic tachycardia syndrome (POTS) is a chronic syndrome with symptoms of orthostatic intolerance, tachycardia, and exercise intolerance. POTS predominately affects young females, with notable variations in incidence and manifestations between females and males. Limited data exist on sex differences in the response to cardiopulmonary exercise test (CPET) in patients diagnosed with POTS. Methods: Retrospective analysis of 307 POTS patients who underwent CPET between 2000 and 2023 at Mayo Clinic. Diagnosis of POTS was confirmed by tilt-table testing with a sustained increase in heart rate (HR)≥ 30 bpm or HR>120 bpm 10-min post-tilt and without orthostatic hypotension. Patients were grouped by sex (male: n=48 and female: n=259). Predicted peak values were calculated and independent t-tests were used to compare between-group differences. Results: There were no significant differences between males and females for age (28±8 vs 27±7, years) or body mass index (24±5 vs 24±5, kg/m 2 ) (both p>0.05). The time between diagnosis and CPET was not significantly different between males and females (21±113 vs 44±280 days, p>0.05). Resting HR was lower in male patients (76±17 vs 85±18 bpm, p<0.05). At peak exercise, there was no difference in respiratory exchange ratio (1.18±.2 vs 1.17±0.1, p>0.05). Males had significantly lower peak HR (171±22 vs 176±19 bpm) and lower percent (%) predicted peak HR (88±12 vs 93±13 %) (both p<0.05) compared to females. Peak oxygen consumption (VO 2 peak) was significantly higher in males (29.2±8 vs 24.9±7 mL/kg/min), however; % predicted VO 2 peak was lower in males (65±17 vs 71±18 %) (both p<0.05). Peak oxygen (O 2 ) pulse was higher in males (14±4 vs 9±2 mL/beat, p<0.05) with no difference in % predicted peak O 2 pulse (73±17 vs 78±17 %, p>0.05). Conclusion: These data suggest male patients achieved a lower peak HR, % predicted peak HR, and % predicted VO 2 peak than female patients. Both male and female patients utilized a similar % predicted peak O 2 pulse. These findings suggest male POTS patients demonstrate more impaired exercise tolerance compared to female patients. Additional research is needed to fully elucidate the underpinning physiologic mechanisms responsible for impaired exercise tolerance in POTS and the apparent sex differences in exercise capacity.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is estimated to occur in 120,000 US adults and remains underdiagnosed. However, awareness of ATTR-CM has improved following the introduction of new diagnostic tools and disease-modifying treatments. Hence, patients (pts) enrolled in contemporary clinical trials could be at an earlier stage of the disease than pts in past clinical studies. Aim: To assess temporal trends in the baseline risk of pts with ATTR-CM enrolled in clinical trials. Methods: Embase, MEDLINE, CENTRAL, and conference websites were searched on November 23, 2023, for peer-reviewed articles and abstracts. Randomized and single-arm clinical trials examining treatments for ATTR-CM were included, and baseline characteristics and outcomes in pts treated with placebo (PBO) were compared across studies. Results: We reviewed 39 publications derived from 4 randomized and 4 single-arm trials. Studies enrolled pts between 2008 and 2021, although 1 study (INOCARD, 2022) did not report years of enrollment. Several baseline characteristics were comparable across studies, including sex, age, race/ethnicity, genotype, and troponin I level. NYHA class at baseline varied with year of enrollment, with fewer NYHA class III pts in recent trials (Figure). Recent trials also showed a trend toward lower NT-proBNP levels (medians ranging from 1911-3178 pg/mL) and higher eGFR levels (means ranging from 54.7-69.0 mL/min/1.73 m 2 ). In PBO groups, all-cause mortality (ACM) rates at 12 months dropped from 9% in ATTR-ACT (enrolled 2013-2015) to 6.9% in ATTRibute-CM (enrolled 2019-2020) and 5.6% in APOLLO-B (enrolled 2019-2021); ACM rates at 30 months dropped from 42.9% in ATTR-ACT to 25.7% in ATTRibute-CM. Conclusions: This systematic review found that disease-modifying treatments and diagnostic advances have led to earlier diagnosis of pts with ATTR-CM. Recent clinical trials appear to have enrolled pts with a better prognosis. Comparisons of results across these trials are limited and should acknowledge the potential impact of variability in baseline risks among trial populations.

Background: About 25% of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) have chronic total occlusion (CTO) at non-culprit artery. However, the prognostic impact of CTO in these patients is still unclear. Aims: We aimed to investigate the impact of CTO at non-culprit artery on 1-year mortality in patients with AMI-CS using the multicenter registry of cardiogenic shock. Methods: A total of 1,247 patients presented with cardiogenic shock (CS) were enrolled in the SMART-RESCUE registry between January 2014 and December 2018. After exclusion of non-ischemic cause shock, ischemic cardiomyopathy, failed or no revascularization, vasospasm, and patients undergoing coronary artery bypass surgery, 695 patients underwent percutaneous coronary intervention (PCI). Among these, we analyzed 536 patients with multivessel disease (MVD) according to the presence of CTO at non-culprit artery. The study endpoint was a 1-year all-cause mortality. We also examined the incidence of 1-year cardiac death, and in-hospital death or renal replacement therapy (RRT). Results: A 141 patients (26.3%) of study population had CTO lesion at non-culprit artery. The CTO group had more patients with diabetes mellitus, and lesser patients with ST-elevation myocardial infarction. Although initial left ventricular ejection fraction was lower in CTO group (28.5 vs. 34.1%, P=0.005), initial systolic blood pressure (73.8 vs. 73.2 mmHg, P=0.822) and the level of lactate (6.6 vs. 6.4 mmol/L, P=0.804) were similar in both groups. Venoarterial extracorporeal membrane oxygenation was applied in 206 patients (38.4%), and its use rate was comparable in 2 groups (40.4 vs. 37.7%, P=0.571). Pre- (32.9 vs. 22.9, P <0.001) and post-PCI SYNTAX score (16.7 vs. 5.3, P <0.001) was significantly higher in CTO group. In CTO group, 53 patients (37.6%) had CTO at left main or left anterior descending artery, and only 19 patients (13.5%) in CTO group received PCI for CTO. In multivariate analysis, all-cause mortality at 1-year was significantly higher in CTO group (51.8 vs. 40.5%, hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.09-1.90, P=0.011). The incidences of 1-year cardiac death (45.4 vs. 32.4%, HR 1.55, 95% CI 1.15-2.10, P=0.004) and in-hospital death or RRT (46.8 vs. 36.5%, P=0.031) were also higher in CTO group. Conclusions: Non-culprit CTO lesion was associated with higher 1-year mortality in patients with AMI-CS and multivessel disease.

Background: There is suspicion that estrogen may protect against atherosclerosis. Women who experience menarche earlier, and thus have earlier estrogen exposure, might develop atherosclerosis later. The relationship between menarche age and the onset of angina pectoris, a symptom of coronary artery disease, remains unknown. Goal: This study aims to find the correlation between menarche age and the onset age of angina pectoris, and the association between early menarche (onset of menarche ≤ 10 y/o) and early onset of angina pectoris (onset of angina pectoris ≤ 40 y/o). Methods: A cross-sectional study using a population from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). The question collects self-reported data on onset of menarche and onset of angina pectoris. The relationship between menarche age and age in onset of angina pectoris was analyzed by linear and logistic regression analysis. Multivariate analysis adjusted for race, age, body mass index (BMI), smoking , diabetes mellitus (DM), hypertension, and dyslipidemia status. Results: Among 4,816 females who reported their menarche age, 88(1.8 %) have had an angina pectoris. The study involved 82 females who reported both the age of menarche and the age of onset of angina pectoris. The mean ± SD of the age at menarche and the age at onset of angina pectoris was 12.53 ± 1.79 y/o and 51.66 ± 15.16 y/o, respectively. The study found a significant association between the menarche age and the age at onset of angina pectoris. After adjusting for confounders, we found that every 1-year increase in the age of menarche will delay the onset of angina pectoris by 1.43 years, with a 95% CI of 0.01 to 2.86.(Table 1A,Graph 1A-1B) We also found that early menarche has a significantly increased risk 2.8 times (95%CI: 1.3, 6.2) of early onset of angina pectoris.After adjusting for confounders, the association became even stronger. The odds ratio (OR) increased to 3.3 (95%CI: 1.4, 8.0), indicating that women with early menarche were 3.3 times more likely to experience early angina pectoris compared to those with later menarche.(Table 2A) Conclusion: In contrast to our hypothesis, age at menarche is positively associated with onset of angina pectoris. The earlier onset of menarche is linked to the earlier onset of angina pectoris. We suspected that factors beyond estrogen levels may contribute to this unexpected finding. Additional studies are needed to examine the cause of this correlation.

Background: Despite expert opinion recommending patient-tailored cardiac rehabilitation (CR) after acute aortic dissection, both patient participation in CR and the associated risk factor modification after CR following aortic dissection repair are poorly understood. Objectives: To describe the characteristics of patients referred to CR, as well as the enrollment rate and outcomes of those referred to CR following thoracic aortic dissection. Methods: We reviewed electronic health records of adults (≥18) discharged alive following thoracic aortic dissection surgery across the Mayo Clinic Enterprise (01/01/2020-11/15/2022) with follow-up to 05/15/2024 (IRB #24-001141). Data are presented using summary statistics. Results: During the study period, 85 patients were included (median [IQR] age: 65 [50-75] years; 40% female; Table 1 ). Across 84% (N=71) who were referred to CR at discharge, 55% (N=39) enrolled. In those patients referred versus not referred to CR, the prevalence of type A dissection (75% vs. 43%), end-organ involvement (27% vs. 0%), and underlying CAD (54% vs. 21%) were greater while current tobacco use (9% vs. 29%) was lower. Of those enrolled at Mayo Clinic (N=16), CR was started 35 (28-65) days following surgery. These patients completed 21 (13-30) CR sessions at an exercise intensity of 59% (50-65%) maximum predicted heart rate. CR was discontinued in 44% (N=7) due to non-cardiac reasons ( Table 2 ). Of the 9 patients who completed CR, general health status (Dartmouth index: 19 [17-21] vs. 26 [22-34]), depressive symptoms (PHQ-9: 1 [0-1] vs. 4 [1-4]), and exercise capacity (6MWT: 214 [196-244] vs. 384 [305-597] meters) improved ( Table 2 ). There were no reported complications or deaths, with stable aortic sizes reported at 18 months. Conclusions: CR improves functional capacity and well-being without complications in patients after thoracic aortic dissection surgery. Further investigation is needed to better assess CR efficacy and usage in this population.

Background: Atrial functional mitral regurgitation (AFMR) constitutes ~25% of ≥moderate MR and has been associated with a high prevalence and incidence of HFpEF. Transcatheter edge-to-edge repair (TEER) has shown effectiveness in improving symptoms in AFMR, but its impact on mortality and HF hospitalizations is unknown. Objective: Evaluate rates of mortality and HF hospitalizations in patients with ≥moderate AFMR treated with TEER and compare them to conservative management. Methods: Consecutive adults with ≥moderate AFMR (functional MR with left atrial enlargement, ejection fraction≥50%, and absent >mild left ventricular enlargement) were identified retrospectively. Ecxlusion criteria were previous cardiac surgery, ≥moderate aortic regurgitation/stenosis, infiltrative/hypertrophic cardiomyopathy, regional wall motion abnormalities or malignancy. Propensity score matching was performed (1:1 ratio) between patients treated with TEER and patients treated conservatively based on age, sex, EuroScore II, effective regurgitant orifice area, and the integrative MR severity. To ensure similar technique in evaluation in the 2 groups, variables were obtained from the closest transthoracic echocardiogram before TEER in the TEER group [median 65 (IQR 29-111) days]. Results: Overall, 46 patients with ≥moderate AFMR treated by TEER and 46 treated conservatively were included, Table 1 . Patients undergoing TEER had more frequent atrial fibrillation and NYHA class ≥III. MR improved to ≤moderate in 93% of patients undergoing TEER on procedural transesophageal echocardiography, Figure 1 . On 1–3-month post-TEER follow-up, 64% had NYHA class I/II (vs 33% pre-TEER), Figure 1 . Over median 2.2 (IQR 1.2-3.1) years, 32 patients died (rate 13%/year in each group, log-rank p=0.85), Figure 2 . When adjusted for baseline NYHA, rates of HF hospitalizations were not different between the groups (Wald-test p-value=0.48). Residual ≥moderate AFMR in the TEER group was not associated with mortality (log-rank p=0.83), but ≥1 class improvement of NYHA in patients with baseline NYHA >1 was associated with decreased mortality, Figure 2 . Conclusion: MR severity and NYHA class improved with TEER for AFMR, and improved NYHA class was associated with decreased mortality. However, the association of TEER with decreased risk of mortality or HF hospitalization remains unproven, and larger randomized studies are needed to evaluate the potential role of TEER on these outcomes in AFMR.