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.

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.

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.

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.

Age, Hypertension, and Exercise Capacity are Independently Associated with Likelihood of Multi-Vessel Disease in Patients Referred for Treadmill Exercise Testing: The Intermediate-High-Workload Treadmill Score (IHWTS).

Background: To identify factors that increase the specificity of the treadmill exercise test (TMET), and develop a novel scoring system which accounts for functional capacity to aid in determining the need for further testing. Methods: We retrospectively evaluated the electronic health records of 600 patients who had positive TMET results and follow-up stress echocardiography from 1-January-2004, through 31-December-2016. Correlations between clinical and aerobic variables and multivessel disease (MVD) were determined. Duke Treadmill Score (DTS) was calculated and compared with a novel scoring system titled the Intermediate-High-Workload Treadmill Score (IHWTS) that used variables associated with MVD. Results: In total, 124 of 600 patients (21%) had coronary catheterization, and 51 of these patients (41%) had MVD. Mean (SD) DTS was -2.10 (6.3) among patients with MVD vs -0.16 (5) among patients without MVD (p = 0.06). Mean (SD) functional aerobic capacity (FAC) was 76% (20%) among patients with MVD vs 90% (21%) among patients without MVD (p < 0.001). Mean (SD) metabolic equivalent (MET) was 7 (2) among patients with MVD vs 8 (2) among patients without MVD (p = 0.002). Only 6 (12%) of patients with MVD achieved 9 MET or greater on TMET. DTS less than 4 did not distinguish between patients with and without MVD (p = 0.67). Age, hypertension and FAC were independently associated with MVD (all p < 0.05). Conclusions: Our novel scoring system IHWTS utilized age, hypertension, and FAC appeared comparable to DTS to risk-stratify patients regardless of baseline symptoms. Clinical parameters such as hypertension along with exercise functional capacity should be considered when evaluating a positive TMET result in patients that achieve an intermediate-high workload > 5 Metabolic Equivalents (METs).

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.

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.

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.

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.

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.

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, Incidence, and Outcomes of Diastolic Dysfunction in Isolated Tricuspid Regurgitation: Perhaps Not Really "Isolated"?

BACKGROUND: In the absence of left-sided cardiac/pulmonary disease, functional tricuspid regurgitation (FTR) is referred to as isolated or idiopathic. Relationships between left ventricular diastolic dysfunction (DD) and FTR remain unknown. OBJECTIVES: The purpose of this study was to investigate the prevalence, incidence, and outcome of DD in patients with idiopathic FTR. METHODS: Adults without structural heart disease were identified. Severe DD was defined by ≥3 of 4 abnormal DD parameters (medial e', medial E/e', TR velocity, left atrial volume index) and ≥ moderate DD by ≥2. Propensity-score matching was performed (3:1) between each less-than-severe TR group and severe TR based on age, sex, body mass index, and comorbidities. RESULTS: Among 30,428 patients, FTR was absent in 73%, mild in 22%, moderate in 4%, and severe in 0.4%. In the propensity-matched sample, severe DD was present in 2%, 6%, 9%, and 13% patients, and ≥ moderate DD in 11%, 18%, 28%, and 48%, respectively (P < 0.001). The probability of heart failure with preserved ejection fraction using the H2FPEF score increased with increasing FTR (median 29.7%, 45.5%, 61.4%, and 88.7%, respectively), as did the prevalence of impaired left atrial strain <24% (35%, 48%, and 69% in mild, moderate, and severe TR). Incident severe and ≥ moderate DD developed more frequently with increasing FTR (HR: 8.45 [95% CI: 2.60-27.50] and HR: 2.82 [95% CI: 1.40-5.69], respectively for ≥ moderate vs no FTR) over a median of 3.0 years. Findings were confirmed in patients without lung disease or right ventricular enlargement. Over a median of 5.0 years, patients with ≥ moderate FTR and DD had the greatest risk of worse outcomes (multivariable P < 0.001). The association between TR and adverse outcomes was significantly diminished in the absence of DD. CONCLUSIONS: Diastolic dysfunction, increased heart failure with preserved ejection fraction probability, and impaired left atrial strain are commonly present in patients with idiopathic FTR, suggesting that the latter may not be truly isolated. Patients with FTR without DD or heart failure are at increased risk of incident DD. Patients with FTR and DD display worse outcomes.

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.

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.

Staging Extramitral Cardiac Damage in Mitral Annular Calcification With Mitral Valve Dysfunction.

BACKGROUND: Mitral annular calcification (MAC) is a progressive degenerative process associated with comorbidities and increased mortality. A staging system that considers extramitral cardiac damage in MAC may help improve patient selection for mitral valve interventions. OBJECTIVES: This study sought to develop a transthoracic echocardiogram (TTE)-based cardiac staging system in patients with MAC and significant mitral valve dysfunction and assess its prognostic utility. METHODS: We retrospectively evaluated all adults who underwent TTE over 1 year at Mayo Clinic with MAC and significant mitral valve dysfunction defined as mitral stenosis and/or at least moderate mitral regurgitation. Patients were categorized into 5 stages according to extramitral cardiac damage by TTE. All-cause mortality and heart failure hospitalization were assessed. RESULTS: For the 953 included patients, the mean age was 76.2 ± 10.7 years, and 54.0% were women. Twenty-eight (2.9%) patients were classified in stages 0 to 1, 499 (52.4%) in stage 2, 115 (12.1%) in stage 3, and 311 (32.6%) in stage 4. At the 3.8-year follow-up, mortality was significantly higher in patients in stages 2 to 4 compared to stages 0 to 1 and increased with each stage. Survival differences were maintained after adjustment for age, diabetes mellitus, and glomerular filtration rate. The rate of heart failure hospitalization was significantly higher in stages 3 and 4 compared to stages 0 to 1. Similar results were observed in subgroup analysis in patients with moderate or severe MAC, predominant mitral stenosis, or predominant mitral regurgitation. CONCLUSIONS: Using the proposed extramitral cardiac damage staging system in patients with MAC and significant mitral valve dysfunction, more advanced stages are associated with higher mortality.

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.

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.

Prevalence, sex differences, and implications of pulmonary hypertension in patients with apical hypertrophic cardiomyopathy.

Introduction: Apical hypertrophic cardiomyopathy (ApHCM) is a subtype of hypertrophic cardiomyopathy (HCM) that affects up to 25% of Asian patients and is not as well understood in non-Asian patients. Although ApHCM has been considered a more "benign" variant, it is associated with increased risk of atrial and ventricular arrhythmias, apical thrombi, stroke, and progressive heart failure. The occurrence of pulmonary hypertension (PH) in ApHCM, due to elevated pressures on the left side of the heart, has been documented. However, the exact prevalence of PH in ApHCM and sex differences remain uncertain. Methods: We sought to evaluate the prevalence, risk associations, and sex differences in elevated pulmonary pressures in the largest cohort of patients with ApHCM at a single tertiary center. A total of 542 patients diagnosed with ApHCM were identified using ICD codes and clinical notes searches, confirmed by cross-referencing with cardiac MRI reports extracted through Natural Language Processing and through manual evaluation of patient charts and imaging records. Results: In 414 patients, echocardiogram measurements of pulmonary artery systolic pressure (PASP) were obtained at the time of diagnosis. The mean age was 59.4 ± 16.6 years, with 181 (44%) being females. The mean PASP was 38 ± 12 mmHg in females vs. 33 ± 9 mmHg in males (p < 0.0001). PH as defined by a PASP value of > 36 mmHg was present in 140/414 (34%) patients, with a predominance in females [79/181 (44%)] vs. males [61/233 (26%), p < 0.0001]. Female sex, atrial fibrillation, diagnosis of congestive heart failure, and elevated filling pressures on echocardiogram remained significantly associated with PH (PASP > 36 mmHg) in multivariable modeling. PH, when present, was independently associated with mortality [hazard ratio 1.63, 95% CI (1.05-2.53), p = 0.028] and symptoms [odds ratio 2.28 (1.40, 3.71), p < 0.001]. Conclusion: PH was present in 34% of patients with ApHCM at diagnosis, with female sex predominance. PH in ApHCM was associated with symptoms and increased mortality.

Postdevelopment Performance and Validation of the Artificial Intelligence-Enhanced Electrocardiogram for Detection of Cardiac Amyloidosis.

BACKGROUND: We have previously applied artificial intelligence (AI) to an electrocardiogram (ECG) to detect cardiac amyloidosis (CA). OBJECTIVES: In this validation study, the authors observe the postdevelopment performance of the AI-enhanced ECG to detect CA with respect to multiple potential confounders. METHODS: Amyloid patients diagnosed after algorithm development (June 2019-January 2022) with a 12-lead ECG were identified (n = 440) and were required to have CA. A 15:1 age- and sex-matched control group was identified (n = 6,600). Area under the receiver operating characteristic (AUC) was determined for the cohort and subgroups. RESULTS: The average age was 70.4 ± 10.3 years, 25.0% were female, and most patients were White (91.3%). In this validation, the AI-ECG for amyloidosis had an AUC of 0.84 (95% CI: 0.82-0.86) for the overall cohort and between amyloid subtypes, which is a slight decrease from the original study (AUC 0.91). White, Black, and patients of "other" races had similar algorithm performance (AUC >0.81) with a decreased performance for Hispanic patients (AUC 0.66). Algorithm performance shift over time was not observed. Low ECG voltage and infarct pattern exhibited high AUC (>0.90), while left ventricular hypertrophy and left bundle branch block demonstrated lesser performance (AUC 0.75 and 0.76, respectively). CONCLUSIONS: The AI-ECG for the detection of CA maintained an overall strong performance with respect to patient age, sex, race, and amyloid subtype. Lower performance was noted in left bundle branch block, left ventricular hypertrophy, and ethnically diverse populations emphasizing the need for subgroup-specific validation efforts.