Secondary tricuspid regurgitation: incidence, types, and outcomes in atrial fibrillation vs. sinus rhythm.

BACKGROUND AND AIMS: Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. METHODS: Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. RESULTS: Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P < .001), larger right atrial size (median 78 vs. 53 mL, P < .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P < .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. CONCLUSIONS: New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.

Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Cardiac Damage in Early Aortic Stenosis: Is the Valve to Blame?

BACKGROUND: Despite the close association between aortic stenosis (AS) and cardiac damage (CD), it is unclear if CD is limited to patients with moderate and severe AS and which factors affect its progression. Although altered valvular hemodynamic status may drive the development of CD in AS, commonly occurring comorbidities may contribute. OBJECTIVES: The aim of this study was to determine the prevalence of and factors associated with CD in mild AS. METHODS: This retrospective study included 9,611 patients with mild AS (peak aortic valve velocity [Vmax] 2-3 m/s and description of abnormal aortic valve) from 2010 through 2021. CD was staged using the Genereux classification. RESULTS: All but 20% (n = 1,901; stage 0) of patients with mild AS demonstrated CD: 1,613 (17%) stage 1, 4,843 (50%) stage 2, 891 (9%) stage 3, and 363 (4%) stage 4. Patients with higher stages had more comorbidities (hypertension, heart failure, ischemic heart disease, stroke, peripheral arterial disease, chronic kidney disease, chronic pulmonary disease, and diabetes mellitus) but had valvular hemodynamic status similar to those without CD. CD stage did not worsen with higher Vmax range (stage >1 in 64% with Vmax <2.5 m/s vs 61% with Vmax ≥2.5 m/s) but increased with the number of comorbidities, with stage >1 occurring in 50%, 53%, 60%, 66%, 72%, and 73% in the presence of 0, 1, 2, 3, 4, and 5 or more comorbidities, respectively. CONCLUSIONS: CD was highly prevalent in patients with mild AS. Among patients with mild AS, there was no relationship between the degree of CD and AS severity; instead, CD was highly associated with comorbidities.

Prognostic Value of Aortic Valve Calcification in Nonsevere Aortic Stenosis with Preserved Ejection Fraction.

BACKGROUND: Aortic valve calcification(AVC) is prognostic in patients with aortic stenosis(AS). We assessed the AVC prognostic value in nonsevere AS patients. METHODS AND RESULTS: We conducted a retrospective study of 395 patients with nonsevere AS, LV ejection fraction ≥50%. The Agatston method was used for computed tomography AVC assessment. The log-rank test determined the best AVC cutoffs for survival under medical surveillance: 1185 AU in men and 850 in women, lower than the established-cutoffs for severe AS(2064AU in men and 1274 in women). Patients were divided into three AVC groups based on these cutoffs: low(<1185 AU men and <850 women), sub-severe(1185-2064AU men and 850-1274 women) and severe(>2064AU men and >1274 women). Of 395 patients(mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention(AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1[0.7-4.9]years. Compared to the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score(all p ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups(all p ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC(all p ≤ 0.01), but not in the low AVC groups. CONCLUSIONS: Sub-severe AVC is a robust risk-stratification parameter in patients with nonsevere AS and may inform AVI timing.

Prevalence and Prognostic Implications of Pulmonary Hypertension in Patients With Severe Aortic Regurgitation.

Background: Pulmonary hypertension (PH) has been shown to be associated with worse outcomes in patients with aortic regurgitation (AR) in small older studies. Objectives: The authors sought to evaluate the prevalence of PH in patients with severe AR, its impact on mortality and symptoms, and regression after aortic valve replacement (AVR). Methods: A total of 821 consecutive patients with chronic ≥ moderate-severe AR on echocardiography from 2004 to 2019 were retrospectively analyzed. PH was defined as right ventricular systolic pressure (RVSP) >40 mm Hg on transthoracic echocardiogram (mild-moderate PH: RVSP 40-59 mm Hg, severe PH: RVSP > 60 mm Hg). Clinical and echocardiographic data were extracted from the electronic medical record and echocardiographic reports. The diastolic function and filling pressures were manually assessed and checked, and the left ventricular (LV) volumes were traced by a level 3-trained echocardiographer. The primary objectives were prevalence of PH in patients with ≥ moderate-severe AR, its risk associations and impact on all-cause mortality as the primary outcome. Secondary outcomes were impact of PH on symptoms and change in RVSP at discharge post-AVR. Logistic and Cox proportional hazards regression were used to analyze these outcomes. Results: The mean age was 61.2 ± 17 years, and 162 (20%) were women. Mild-moderate PH was present in 91 (11%) patients and severe PH in 27 (3%). Larger LV size, elevated LV filling pressures, and ≥ moderate tricuspid regurgitation were associated with PH. During follow-up of 7.3 (6.3-7.9) years, 188 patients died. Compared to those without PH, risk of mortality was higher in mild-moderate PH (adjusted HR: 1.59 (95% CI: 1.07-2.36) (P = 0.021)) and severe PH (adjusted HR: 2.90 (95% CI: 1.63-5.15) (P < 0.001)). Symptoms were also more prevalent in those with PH (P = 0.004). Of 396 patients who underwent AVR during the study period, 57 had PH. AVR similarly improved survival in patients without and with PH (P for interaction = 0.23), and there was regression in RVSP (≥8 mm Hg drop) at discharge post-AVR in 35/57 (61%) patients with PH. Conclusions: PH was present in 14% of patients with AR and was associated with higher mortality and symptoms. The survival benefit of AVR was similar in patients without and with PH.

Transgender Women Exhibit a Distinct Stress Echocardiography Profile Compared With Age-Matched Cisgender Counterparts: The Mayo Clinic Women's Heart Clinic Experience.

BACKGROUND: Stress echocardiographic (SE) testing is an important modality in cardiovascular risk stratification and obstructive coronary artery disease assessment. Binary sex-based parameters are classically used for the interpretation of these studies, even among transgender women (TGW). Coronary artery disease is a leading cause of morbidity and mortality in this population. Yet, it remains unclear whether TGW exhibit a distinct stress testing profile from their cisgender counterparts. METHODS: Using a matched case-control study design, the authors compared the echocardiographic stress testing profiles of TGW (n = 43) with those of matched cisgender men (CGM; n = 84) and cisgender women (CGW; n = 86) at a single center. Relevant data, including demographics, comorbidities, and cardiac testing data, were manually extracted from the patients' charts. RESULTS: The prevalence of hypertension and dyslipidemia was similar between TGW and CGW and lower than that of CGM (P = .003 and P = .009, respectively). The majority of comorbidities and laboratory values were similar. On average, TGW had higher heart rates than CGM (P = .002) and had lower blood pressures than CGM and CGW (P < .05). TGW's double product and metabolic equivalents were similar to those among CGW and lower than those of CGM (P = .016 and P = .018, respectively). On echocardiography, left ventricular end-diastolic and end-systolic diameters among TGW were similar to those of CGW but lower than those of CGM (P = .023 and P = .018, respectively). Measures of systolic and diastolic function, except for exercise mitral valve E/e' ratio, which was lower in TGW than CGW (P = .029), were largely similar among the three groups. There was no difference in the wall motion score index, and therefore, no difference in the percentage of positive SE test results. CONCLUSIONS: This study shows, for the first time, that TGW have a SE profile that is distinct from that of their cisgender counterparts. Larger, multicenter, prospective studies are warranted to further characterize the SE profile of TGW.

Utilizing median and maximum QTc values improves prediction of breakthrough cardiac events in pediatric long QT syndrome.

INTRODUCTION: Although prior studies indicate that a QTc > 500 ms on a single baseline 12-lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS. METHODS: We performed a retrospective analysis of 433 patients with LQTS evaluated, risk-stratified, and undergoing active guideline-based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF-terminating ICD shock, and sudden cardiac death (SCD). RESULTS: During the median follow-up of 5.5 years (interquartile range [IQR] = 3-9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c-statistic = 0.93-0.95). Patients in the high-risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%-81%) when compared to patients in both medium-risk (93%-97%) and low-risk (98%-99%) groups. CONCLUSIONS: The risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12-lead ECGs are at the highest risk of BCE while on guideline-directed medical therapy.

Calf rEF: Impact of Calf Muscle Pump Dysfunction With Reduced Ejection Fraction on All-Cause Mortality.

OBJECTIVE: To evaluate mortality outcomes by varying degrees of reduced calf muscle pump (CMP) ejection fraction (EF). PATIENTS AND METHODS: Consecutive adult patients who underwent venous air plethysmography testing at the Mayo Clinic Gonda Vascular Laboratory (January 1, 2012, through December 31, 2022) were divided into groups based on CMP EF for the assessment of all-cause mortality. Other venous physiology included measures of valvular incompetence and clinical venous disease (CEAP [clinical presentation, etiology, anatomy, and pathophysiology] score). Mortality rates were calculated using the Kaplan-Meier method. RESULTS: During the study, 5913 patients met the inclusion criteria. During 2.84-year median follow-up, there were 431 deaths. Mortality rates increased with decreasing CMP EF. Compared with EF of 50% or higher, the hazard ratios (95% CIs) for mortality were as follows: EF of 40% to 49%, 1.4 (1.0 to 2.0); EF of 30% to 39%, 1.6 (1.2 to 2.4); EF of 20% to 29%, 1.7 (1.2 to 2.4); EF of 10% to 19%, 2.4 (1.7 to 3.3) (log-rank P≤.001). Although measures of venous valvular incompetence did not independently predict outcomes, venous disease severity assessed by CEAP score was predictive. After adjusting for several clinical covariates, both CMP EF and clinical venous disease severity assessed by CEAP score remained independent predictors of mortality. CONCLUSION: Mortality rates are higher in patients with reduced CMP EF and seem to increase with each 10% decrement in CMP EF. The mortality mechanism does not seem to be impacted by venous valvular incompetence and may represent variables intrinsic to muscular physiology.

Association of cardiac biomarkers with long-term cardiovascular events in a community cohort.

MATERIALS AND METHODS: The study assessed major adverse cardiac events (MACE) (myocardial infarction, coronary artery bypass graft, percutaneous intervention, stroke, and death. Cox proportional hazards models assessed apolipoprotein AI (ApoA1), apolipoprotein B (ApoB), ceramide score, cystatin C, galectin-3 (Gal3), LDL-C, Non-HDL-C, total cholesterol (TC), N-terminal B-type natriuretic peptide (NT proBNP), high-sensitivity cardiac troponin (HscTnI) and soluble interleukin 1 receptor-like 1. In adjusted models, Ceramide score was defined by from N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)] and N-lignoceroyl-sphingosine [Cer(24:0)]. Multi-biomarker models were compared with C-statistics and Integrated Discrimination Index (IDI). RESULTS: A total of 1131 patients were included. Adjusted NT proBNP per 1 SD resulted in a 31% increased risk of MACE/death (HR = 1.31) and a 31% increased risk for stroke/MI (HR = 1.31). Adjusted Ceramide per 1 SD showed a 13% increased risk of MACE/death (HR = 1.13) and a 29% increased risk for stroke/MI (HR = 1.29). These markers added to clinical factors for both MACE/death (p = 0.003) and stroke/MI (p = 0.034). HscTnI was not a predictor of outcomes when added to the models. DISCUSSION: Ceramide score and NT proBNP improve the prediction of MACE and stroke/MI in a community primary prevention cohort.

In a community cohort, where a wide range of biomarkers were evaluated, Ceramide score provided additive value over traditional cardiac risk factors alone for predicting stroke/MI. NT ProBNP provided additive value in prediction of MACE/death. Other biomarkers failed to improve the discrimination of these models.

Invasive Cardiac Hemodynamics in Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Symptomatic limitations in apical hypertrophic cardiomyopathy may occur because of diastolic dysfunction with resultant elevated left ventricular filling pressures, cardiac output limitation to exercise, pulmonary hypertension (PH), valvular abnormalities, and/or arrhythmias. In this study, the authors aimed to describe invasive cardiac hemodynamics in a cohort of patients with apical hypertrophic cardiomyopathy. METHODS AND RESULTS: Patients presenting to a comprehensive hypertrophic cardiomyopathy center with apical hypertrophic cardiomyopathy were identified (n=542) and those who underwent invasive hemodynamic catheterization (n=47) were included in the study. Of these, 10 were excluded due to postmyectomy status or incomplete hemodynamic data. The mean age was 56±18 years, 16 (43%) were women, and ejection fraction was preserved (≥50%) in 32 (91%) patients. The most common indication for catheterization was dyspnea (48%) followed by suspected PH (13%), and preheart transplant evaluation (10%). Elevated left ventricular filling pressures at rest or exercise were present in 32 (86%) patients. PH was present in 30 (81%) patients, with 6 (20%) also having right-sided heart failure. Cardiac index was available in 25 (86%) patients with elevated resting filling pressures. Of these, 19 (76%) had reduced cardiac index and all 6 with right-sided heart failure had reduced cardiac index. Resting hemodynamics were normal in 8 of 37 (22%) patients, with 5 during exercise; 3 of 5 (60%) patients had exercise-induced elevation in left ventricular filling pressures. CONCLUSIONS: In patients with apical hypertrophic cardiomyopathy undergoing invasive hemodynamic cardiac catheterization, 86% had elevated left ventricular filling pressures at rest or with exercise, 81% had PH, and 20% of those with PH had concomitant right-sided heart failure.

Progression of Mild Mitral Annulus Calcification to Mitral Valve Dysfunction and Impact on Mortality.

BACKGROUND: Mitral annulus calcification (MAC) represents a degenerative process resulting in calcium deposition in the mitral valve apparatus. Mitral annulus calcification is associated with adverse clinical outcomes. We sought to examine the long-term significance of mild MAC and its relationship to subsequent mitral valve dysfunction (MVD) and mortality in patients without MVD on the initial echocardiogram. METHODS: A total of 1,420 patients with mild MAC and no MVD at baseline and 1 or more follow-up echocardiograms at least 1 year after the baseline echocardiogram were included in the analysis. For patients with >1 echocardiogram during follow-up, the last echocardiogram was used. The same criteria were used to identify 6,496 patients without MAC. Mitral valve dysfunction was defined as mitral regurgitation (MR) and/or mitral stenosis (MS) of moderate or greater severity. Mixed disease was defined as the concurrent presence of both moderate or greater MS and MR. The primary end point was development of MVD, and the secondary end point was all-cause mortality. RESULTS: For patients with mild MAC, age was 74 ± 10 years and 528 (37%) were female. Over a median follow-up of 4.7 (interquartile range, 2.7-6.9) years, 215 patients with mild MAC developed MVD, including MR in 170 (79%), MS in 37 (17%), and mixed disease in 8 (4%). In a multivariable regression model compared to patients without MAC, the presence of mild MAC was independently associated with increased mortality (hazard ratio = 1.43; 95% CI 1.24, 1.66; P < .001). Kaplan-Meier 4-year survival rates were 80% and 90% for patients with mild MAC and no MAC, respectively. CONCLUSIONS: Mild MAC observed on transthoracic echocardiography is an important clinical finding with prognostic implications for both valvular function and mortality.

Artificial intelligence of arterial Doppler waveforms to predict major adverse outcomes among patients with diabetes mellitus.

OBJECTIVE: Patients with diabetes mellitus (DM) are at increased risk for peripheral artery disease (PAD) and its complications. Arterial calcification and non-compressibility may limit test interpretation in this population. Developing tools capable of identifying PAD and predicting major adverse cardiac event (MACE) and limb event (MALE) outcomes among patients with DM would be clinically useful. Deep neural network analysis of resting Doppler arterial waveforms was used to detect PAD among patients with DM and to identify those at greatest risk for major adverse outcome events. METHODS: Consecutive patients with DM undergoing lower limb arterial testing (April 1, 2015-December 30, 2020) were randomly allocated to training, validation, and testing subsets (60%, 20%, and 20%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict all-cause mortality, MACE, and MALE at 5 years using quartiles based on the distribution of the prediction score. RESULTS: Among 11,384 total patients, 4211 patients with DM met study criteria (mean age, 68.6 ± 11.9 years; 32.0% female). After allocating the training and validation subsets, the final test subset included 856 patients. During follow-up, there were 262 deaths, 319 MACE, and 99 MALE. Patients in the upper quartile of prediction based on deep neural network analysis of the posterior tibial artery waveform provided independent prediction of death (hazard ratio [HR], 3.58; 95% confidence interval [CI], 2.31-5.56), MACE (HR, 2.06; 95% CI, 1.49-2.91), and MALE (HR, 13.50; 95% CI, 5.83-31.27). CONCLUSIONS: An artificial intelligence enabled analysis of a resting Doppler arterial waveform permits identification of major adverse outcomes including all-cause mortality, MACE, and MALE among patients with DM.

Machine Learning for Diagnosis of Pulmonary Hypertension by Echocardiography.

OBJECTIVE: To evaluate a machine learning (ML)-based model for pulmonary hypertension (PH) prediction using measurements and impressions made during echocardiography. METHODS: A total of 7853 consecutive patients with right-sided heart catheterization and transthoracic echocardiography performed within 1 week from January 1, 2012, through December 31, 2019, were included. The data were split into training (n=5024 [64%]), validation (n=1275 [16%]), and testing (n=1554 [20%]). A gradient boosting machine with enumerated grid search for optimization was selected to allow missing data in the boosted trees without imputation. The training target was PH, defined by right-sided heart catheterization as mean pulmonary artery pressure above 20 mm Hg; model performance was maximized relative to area under the receiver operating characteristic curve using 5-fold cross-validation. RESULTS: Cohort age was 64±14 years; 3467 (44%) were female, and 81% (6323/7853) had PH. The final trained model included 19 characteristics, measurements, or impressions derived from the echocardiogram. In the testing data, the model had high discrimination for the detection of PH (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.80 to 0.85). The model's accuracy, sensitivity, positive predictive value, and negative predictive value were 82% (1267/1554), 88% (1098/1242), 89% (1098/1241), and 54% (169/313), respectively. CONCLUSION: By use of ML, PH could be predicted on the basis of clinical and echocardiographic variables, without tricuspid regurgitation velocity. Machine learning methods appear promising for identifying patients with low likelihood of PH.

Re-evaluating the Incidence and Prevalence of Clinical Hypertrophic Cardiomyopathy: An Epidemiological Study of Olmsted County, Minnesota.

OBJECTIVE: To contemporaneously reappraise the incidence-rate, prevalence, and natural history of hypertrophic cardiomyopathy (HCM) in Olmsted County, Minnesota, from 1984 to 2015. PATIENTS AND METHODS: A validated medical-record linkage system collecting information for residents of Olmsted County was used to identify all cases of HCM between January 1, 1984, and December 31, 2015. After adjudication of records from Mayo Clinic and Olmsted Medical Center, data relating to diagnoses and outcomes were abstracted. The calculated incidence rate and prevalence were standardized to the US 1980 White population (age- and sex-adjusted) and compared with a prior study examining the years 1975-1984. RESULTS: Two hundred seventy subjects with HCM were identified. The age- and sex-adjusted incidence rate was 6.6 per 100,000 person-years, and the point prevalence of HCM on January 1, 2016, was 89 per 100,000 population. The incidence rate and point prevalence of HCM on January 1, 2016, standardized to the US 1980 White population (age- and sex-adjusted), were 6.7 (95% CI, 7.1 to 8.8) per 100,000 person-years and 81.5 per 100,000 population, respectively. The incidence rate of HCM increased each decade since the index study. Individuals with HCM had a higher overall standardized mortality rate than the general population with an observed to expected HR of 1.44 (95% CI, 1.21 to 1.71; P<.001) which improved by each decade. CONCLUSION: The incidence and prevalence of HCM are higher than rates reported from a prior study in the same community examining the years 1975-1984, but lower than other study cohorts. The risk of mortality in HCM remains higher than expected, albeit with improvement in rates of mortality observed each decade during the study period.

Artificial Intelligence of Arterial Doppler Waveforms to Predict Major Adverse Outcomes Among Patients Evaluated for Peripheral Artery Disease.

BACKGROUND: Patients with peripheral artery disease are at increased risk for major adverse cardiac events, major adverse limb events, and all-cause death. Developing tools capable of identifying those patients with peripheral artery disease at greatest risk for major adverse events is the first step for outcome prevention. This study aimed to determine whether computer-assisted analysis of a resting Doppler waveform using deep neural networks can accurately identify patients with peripheral artery disease at greatest risk for adverse outcome events. METHODS AND RESULTS: Consecutive patients (April 1, 2015, to December 31, 2020) undergoing ankle-brachial index testing were included. Patients were randomly allocated to training, validation, and testing subsets (60%/20%/20%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict major adverse cardiac events, major adverse limb events, and all-cause death at 5 years. Patients were then analyzed in groups based on the quartiles of each prediction score in the training set. Among 11 384 total patients, 10 437 patients met study inclusion criteria (mean age, 65.8±14.8 years; 40.6% women). The test subset included 2084 patients. During 5 years of follow-up, there were 447 deaths, 585 major adverse cardiac events, and 161 MALE events. After adjusting for age, sex, and Charlson comorbidity index, deep neural network analysis of the posterior tibial artery waveform provided independent prediction of death (hazard ratio [HR], 2.44 [95% CI, 1.78-3.34]), major adverse cardiac events (HR, 1.97 [95% CI, 1.49-2.61]), and major adverse limb events (HR, 11.03 [95% CI, 5.43-22.39]) at 5 years. CONCLUSIONS: An artificial intelligence-enabled analysis of Doppler arterial waveforms enables identification of major adverse outcomes among patients with peripheral artery disease, which may promote early adoption and adherence of risk factor modification.

Incidence of Severe Adverse Drug Reactions to Ultrasound Enhancement Agents in a Contemporary Echocardiography Practice.

OBJECTIVES: Prior data indicate a very rare risk of serious adverse drug reaction (ADR) to ultrasound enhancement agents (UEAs). We sought to evaluate the frequency of ADR to UEA administration in contemporary practice. METHODS: We retrospectively reviewed 4 US health systems to characterize the frequency and severity of ADR to UEA. Adverse drug reactions were considered severe when cardiopulmonary involvement was present and critical when there was loss of consciousness, loss of pulse, or ST-segment elevation. Rates of isolated back pain and headache were derived from the Mayo Clinic Rochester stress echocardiography database where systematic prospective reporting of ADR was performed. RESULTS: Among 26,539 Definity and 11,579 Lumason administrations in the Mayo Clinic Rochester stress echocardiography database, isolated back pain or headache was more frequent with Definity (0.49% vs 0.04%, P < .0001) but less common with Definity infusion versus bolus (0.08% vs 0.53%, P = .007). Among all sites there were 201,834 Definity and 84,943 Lumason administrations. Severe and critical ADR were more frequent with Lumason than with Definity (0.0848% vs 0.0114% and 0.0330% vs 0.0010%, respectively; P < .001 for each). Among the 3 health systems with >2,000 Lumason administrations, the frequency of severe ADR with Lumason ranged from 0.0755% to 0.1093% and the frequency of critical ADR ranged from 0.0293% to 0.0525%. Severe ADR rates with Definity were stable over time but increased in more recent years with Lumason (P = .02). Patients with an ADR to Lumason since the beginning of 2021 were more likely to have received a COVID-19 vaccination compared with matched controls (88% vs 75%; P = .05) and more likely to have received Moderna than Pfizer-Biotech (71% vs 26%, P < .001). CONCLUSION: Severe and critical ADR, while rare, were more frequent with Lumason, and the frequency has increased in more recent years. Additional work is needed to better understand factors, including associations with recently developed mRNA vaccines, which may be contributing to the increased rates of ADR to UEA since 2021.

Persistence of left atrial thrombus in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: We recently demonstrated that patients with atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM) have an increased risk of left atrial (LA) thrombus. In this study, we aimed to evaluate thrombus management, thrombus persistence, and thromboembolic events for HCM and non-HCM patients with AF and LA thrombus. METHODS: From a cohort of 2,155 AF patients undergoing transesophageal echocardiography (TEE) for any indication, this study included 122 patients with LA thrombus (64 HCM patients and 58 non-HCM controls). RESULTS: There was no difference in mean CHA2DS2-VASc scores between HCM and control patients (3.9 ± 2.2 vs 3.8 ± 2.0, p = 0.88). Ten (16%) and 4 (7%) patients in the HCM and control groups, respectively, were in sinus rhythm at the time of TEE identifying the LA thrombus (p = 0.13). In all patients, the anticoagulation strategy was modified after the LA thrombus diagnosis. A total of 36 (56%) HCM patients and 34 (59%) control patients had follow-up TEE at median 90 and 62 days, respectively, after index TEE. The HCM group had significantly higher 90-day rates of persistent LA thrombus compared to the control group (88% vs 29%; p < 0.001). In adjusted models, HCM was independently associated with LA thrombus persistence. Among patients with LA thrombus, the 5-year cumulative incidence of thromboembolic events was 11% and 2% in HCM and control groups, respectively (p = 0.22). CONCLUSIONS: Among patients with AF with LA thrombus identified by TEE, those with HCM appear to have a higher risk of LA thrombus persistence than non-HCM patients despite anticoagulation.

Prevalence and incidence of diastolic dysfunction in atrial fibrillation: clinical implications.

BACKGROUND AND AIMS: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are intimately associated disorders; HFpEF may be overlooked in AF when symptoms are simply attributed to dysrhythmia, and incident AF may identify patients at risk for developing diastolic dysfunction (DD). This study aimed to investigate the prevalence and incidence of DD in patients with new-onset AF compared with sinus rhythm (SR). METHODS: Adults with new-onset AF (n = 1747) or SR (n = 29 623) and no structural heart disease were identified. Propensity score matching was performed (1:3 ratio) between AF and SR based on age, sex, body mass index, and comorbidities. Severe DD (SDD) was defined by ≥3/four abnormal parameters (medial e', medial E/e', tricuspid regurgitation velocity, and left atrial volume index) and ≥moderate DD (>MDD) by ≥2/4. Annualized changes in DD indices were determined. RESULTS: New-onset AF was independently associated with SDD (8% vs. 3%) and ≥MDD (25% vs. 16%); 62% of patients with AF had high-risk H2FPEF scores, and 5% had clinically recognized HFpEF. Over a median follow-up of 3.2 (interquartile range 1.6-5.8) years, DD progressed two-four-fold more rapidly in those with new-onset AF (P < .001 for all). The risk for incident DD was increased in new-onset AF [hazard ratio (95% confidence interval) 2.69 (2.19-3.32) for SDD and 1.73 (1.49-2.02) for ≥MDD]. CONCLUSIONS: Patients with new-onset AF display high-risk features for HFpEF at diagnosis, emphasizing the importance of evaluating for HFpEF among symptomatic patients with AF. Patients with new-onset AF have accelerated progression in DD over time, which may identify patients with preclinical HFpEF, where preventive therapies may be tested.