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Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes during a median of 3.2 years. Extended follow-up for mortality is ongoing. Methods: ISCHEMIA participants were randomized to an initial invasive strategy added to guideline-directed medical therapy or a conservative strategy. Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and noncardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models, and Bayesian methods. Undetermined deaths were classified as cardiovascular as prespecified in the trial protocol. Results: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23% women, 16% Hispanic, 4% Black, 42% with diabetes, and median ejection fraction 0.60. A total of 557 deaths accrued during a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 noncardiovascular deaths, and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate, 12.7% in invasive strategy, 13.4% in conservative strategy; adjusted hazard ratio, 1.00 [95% CI, 0.85–1.18]). There was a lower 7-year rate cardiovascular mortality (6.4% versus 8.6%; adjusted hazard ratio, 0.78 [95% CI, 0.63–0.96]) with an initial invasive strategy but a higher 7-year rate of noncardiovascular mortality (5.6% versus 4.4%; adjusted hazard ratio, 1.44 [95% CI, 1.08–1.91]) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. Conclusions: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of noncardiovascular mortality with an initial invasive strategy during a median follow-up of 5.7 years. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04894877.

Background: The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. Methods: We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). Results: Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis ( P P 6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. Conclusions: Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.

The prevalence of mitral annular calcium (MAC) is increasing in our aging population. However, data regarding prognostication in MAC-related mitral valve (MV) disease remain limited. This retrospective observational study aims to explore the prognostic impact of systolic pulmonary artery pressure (SPAP) in MAC-related MV dysfunction and define its determinants. We identified 4,384 patients (mean age 78 ± 11 years and 69% female) with MAC-related MV dysfunction (documented transmitral gradient ≥3 mm Hg) from a large institutional echocardiographic database between 2001 and 2019. In Cox regression analysis, higher SPAP strongly associated with all-cause mortality, independent of cardiovascular risk factors and indices of MV dysfunction (adjusted hazard ratio 1.22 per 10 mm Hg SPAP increase, 95% confidence interval 1.17 to 1.27). Patients with SPAP ≥50 mm Hg had significantly higher mortality compared with SPAP50 mm Hg (log-rank p0.001), a finding that was consistent across different transmitral gradient subgroups (≤5, 5 to 10, and ≥10 mm Hg). Independent determinants of SPAP included the mean transmitral gradient, mitral regurgitation severity, left ventricular ejection fraction, and ≥moderate aortic stenosis (adjusted p0.05), and atrial fibrillation and left atrial dimension. The impact of concomitant mitral regurgitation on SPAP decreased at higher transmitral gradients and was no longer significant at gradients ≥10 mm Hg (p = 0.100). In conclusion, SPAP strongly associates with mortality in MAC, independent of cardiovascular risk factors and indices of MAC-related MV dysfunction. These findings suggest an incremental role for SPAP in the risk stratification and prognostication in this increasingly prevalent condition with expanding the scope of possible interventions.

IntroductionRight ventricular (RV) dysfunction is associated with increased mortality across a spectrum of cardiovascular diseases. The role of obesity in RV dysfunction and adverse outcomes is unclear.MethodsWe examined patients undergoing right heart catheterization between 2005-2016 in a hospital-based cohort. Linear regression was used to examine the association of obesity with hemodynamic indices of RV dysfunction [pulmonary artery pulsatility index (PAPi), right atrial pressure: pulmonary capillary wedge pressure ratio (RAP:PCWP), RV stroke work index (RVSWI)]. Cox models were used to examine the association of RV function measures with clinical outcomes.ResultsAmong 8285 patients (mean age 63 years, 40% women), higher BMI was associated with worse indices of RV dysfunction, including lower PAPi (β -0.26, SE 0.01, p ConclusionsPatients with obesity had worse hemodynamic measured indices of RV function across a broad hospital-based sample. While RV dysfunction was associated with worse clinical outcomes including mortality and HF hospitalization, this association was especially pronounced among individuals with higher BMI.

Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS.This study aimed to detail the role of GCS and GRS in ICI myocarditis.In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death.Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n=42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P< 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P< 0.001). Over a median follow-up of 30days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95%CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95%CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95%CI: 0.70-0.91]) and GRS (AUC: 0.76 [95%CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95%CI: 0.58-0.82]), LVEF (AUC: 0.69 [95%CI: 0.56-0.81]), and age (AUC: 0.54 [95%CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002).GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

Clinical outcomes for the overall severe aortic stenosis (AS) patient population are not well described because those medically managed are not included in procedural registries, and AS severity is not identifiable from administrative data. We aim to assess whether transcatheter aortic valve implantation (TAVI) availability has been associated with overall changes in survival for the whole AS patient population. This is important because patients with AS in real-world practice may differ from those included in randomized controlled trials, potentially attenuating the purported treatment efficacy estimated in trials. Classic severe AS patients (mean gradient ≥40 mmHg) were identified from an echocardiography database. Survival was defined as time since severe AS diagnosis until death. We first compared survival among all patients before and after TAVI availability in 2008. To further understand mechanism, we then assessed whether any survival changes were attributable to TAVI with extended Cox regression models comparing survival among TAVI, surgical aortic valve replacement, and medically managed patients. 3663 classic severe AS patients were included in the study. Median survival years for all patients were greater during the TAVI-era than Pre-TAVI-era (11.5 vs 6.8, 5-year-HR = 0.8, time-varying effect p0.0001), and increased median survival was greatest for patients age 65 to74 (11.5 vs 9.5, 5-year-HR = 0.7, time-varying effect p = 0.045). TAVI patients age 65 to 74 had the lowest risk of death compared to medically managed patients (HR = 0.2, 95% CI = [0.1, 0.3], p0.0001). In conclusion, in the TAVI-era, overall survival for patients with severe AS has doubled. This improvement is most marked for patients 65 to 74 years of age.

Detection of ≥50% diameter stenosis left main coronary artery disease (LMD) has prognostic and therapeutic implications. Noninvasive stress imaging or an exercise tolerance test (ETT) are the most common methods to detect obstructive coronary artery disease, though stress test markers of LMD remain ill-defined.The authors sought to identify markers of LMD as detected on coronary computed tomography angiography (CTA), using clinical and stress testing parameters.This was a post hoc analysis of ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), including randomized and nonrandomized participants who had locally determined moderate or severe ischemia on nonimaging ETT, stress nuclear myocardial perfusion imaging, or stress echocardiography followed by CTA to exclude LMD. Stress tests were read by core laboratories. Prior coronary artery bypass grafting was an exclusion. In a stepped multivariate model, the authors identified predictors of LMD, first without and then with stress testing parameters.Among 5,146 participants (mean age 63 years, 74% male), 414 (8%) had LMD. Predictors of LMD were older age (P 0.001), male sex (P 0.01), absence of prior myocardial infarction (P 0.009), transient ischemic dilation of the left ventricle on stress echocardiography (P = 0.05), magnitude of ST-segment depression on ETT (P = 0.004), and peak metabolic equivalents achieved on ETT (P = 0.001). The models were weakly predictive of LMD (C-index 0.643 and 0.684).In patients with moderate or severe ischemia, clinical and stress testing parameters were weakly predictive of LMD on CTA. For most patients with moderate or severe ischemia, anatomical imaging is needed to rule out LMD. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

ObjectiveTo use echocardiographic and clinical features to develop an explainable clinical risk prediction model in patients with aortic stenosis (AS), including those with low-gradient AS (LGAS), using machine learning (ML).MethodsIn 1130 patients with moderate or severe AS, we used bootstrap lasso regression (BLR), an ML method, to identify echocardiographic and clinical features important for predicting the combined outcome of all-cause mortality or aortic valve replacement (AVR) within 5 years after the initial echocardiogram. A separate hold out set, from a different centre (n=540), was used to test the generality of the model. We also evaluated model performance with respect to each outcome separately and in different subgroups, including patients with LGAS.ResultsOut of 69 available variables, 26 features were identified as predictive by BLR and expert knowledge was used to further reduce this set to 9 easily available and input features without loss of efficacy. A ridge logistic regression model constructed using these features had an area under the receiver operating characteristic curve (AUC) of 0.74 for the combined outcome of mortality/AVR. The model reliably identified patients at high risk of death in years 2–5 (HRs ≥2.0, upper vs other quartiles, for years 2–5, pConclusionIn two separate longitudinal databases, ML identified prognostic features and produced an algorithm that predicts outcome for up to 5 years of follow-up in patients with AS, including patients with LGAS. Our algorithm, the Aortic Stenosis Risk (ASteRisk) score, is available online for public use.

Background: The pulmonary artery pulsatility index (PAPi), calculated from the ratio of the pulmonary artery pulse pressure to right atrial pressure, is a predictor of right ventricular failure after inferior myocardial infarction and left ventricular assist device implantation. Whether PAPi is associated with adverse outcomes across a heterogeneous population is unknown. Methods: We examined consecutive patients undergoing right heart catheterization between 2005 and 2016 in a hospital-based cohort. Multivariable Cox models were utilized to examine the association between PAPi and all-cause mortality, major adverse cardiac events, and heart failure hospitalizations. Results: We studied 8285 individuals (mean age 63 years, 39% women) with median PAPi across quartiles 1.7, 2.8, 4.2, and 8.7, who were followed over a mean follow-up of 6.7±3.3 years. Patients in the lowest PAPi quartile had a 60% greater risk of death compared with the highest quartile (multivariable-adjusted hazard ratio, 1.60 [95% CI, 1.36–1.88], P P P P Conclusions: Compared with the highest PAPi quartile, patients in PAPi quartiles 1 to 3 had a greater risk of all-cause mortality, major adverse cardiac events, and heart failure hospitalizations, with greatest risk observed in the lowest quartile. A low PAPi, even at values higher than previously reported, may serve an important role in identifying high-risk individuals across a broad spectrum of cardiovascular disease.

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. Methods: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory–interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest). Results: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61–1.30]; severe ischemia HR, 0.83 [95% CI, 0.57–1.21]; P =0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86–1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98–1.91]; P =0.04 for trend, P =NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06–6.98]) and MI (HR, 3.78 [95% CI, 1.63–8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%–12.4%]), but 4-year all-cause mortality was similar. Conclusions: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01471522.

Background: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. Methods: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did. Results: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P P =0.46) or ISCHEMIA stress echocardiography participants ( P =0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029). Conclusions: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02347215.

Stress echocardiography (SE) assesses for flow-limiting coronary artery disease (CAD) and requires expertise to interpret. Clinical trials use core laboratories to ensure that interpretations are accurate and reproducible. We determined agreement between site and core laboratory SE interpretations

Supplemental Digital Content is available in the text., Background: Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina). Methods: One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling. Results: At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (Pinteraction=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina (Pinteraction=0.116), physical limitation (Pinteraction=0.461), quality of life (Pinteraction=0.689), EuroQOL 5 quality-of-life score (Pinteraction=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (Pinteraction=0.693), and treadmill exercise time (Pinteraction=0.426). Conclusions: The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

Background Patients with isolated tricuspid regurgitation (TR) in the absence of left-sided valvular dysfunction are often managed nonoperatively. Objectives The purpose of this study was to assess the impact of surgery for isolated TR, comparing survival for isolated severe TR patients who underwent surgery with those who did not. Methods A longitudinal echocardiography database was used to perform a retrospective analysis of 3,276 adult patients with isolated severe TR from November 2001 to March 2016. All-cause mortality for patients who underwent surgery versus those who did not was analyzed in the entire cohort and in a propensity-matched sample. To assess the possibility of immortal time bias, the analysis was performed considering time from diagnosis to surgery as a time-dependent covariate. Results Of 3,276 patients with isolated severe TR, 171 (5%) underwent tricuspid valve surgery, including 143 (84%) repairs and 28 (16%) replacements. The remaining 3,105 (95%) patients were medically managed. When considering surgery as a time-dependent covariate in a propensity-matched sample, there was no difference in overall survival between patients who received medical versus surgical therapy (hazard ratio: 1.34; 95% confidence interval: 0.78 to 2.30; p = 0.288). In the subgroup that underwent surgery, there was no difference in survival between tricuspid repair versus replacement (hazard ratio: 1.53; 95% confidence interval: 0.74 to 3.17; p = 0.254). Conclusions In patients with isolated severe TR, surgery is not associated with improved long-term survival compared to medical management alone after accounting for immortal time bias.

BACKGROUND Secondary mitral regurgitation (MR) is common in patients with left bundle branch block (LBBB) undergoing cardiac resynchronization therapy (CRT). We aimed to define CRT effects on left ventricular (LV) and mitral valve (MV) geometry, and their correlation with MR severity. METHODS Forty-one patients with LBBB and ≥mild secondary MR underwent CRT between 2009 and 2012, and had baseline and follow-up echocardiograms available. Repeated measure and linear regression analyses were performed to assess for changes in MV and LV geometry and MR severity, and associations with follow-up MR grade. RESULTS The mean age and baseline QRS duration were 65.5 ± 14.9 years and 160 ± 24 ms. At a mean follow-up of 2.6 ± 1.8 years, there was an increase in LV ejection fraction and reductions in LV end-systolic volume index, MR grade, and end-systolic interpapillary muscle distance (P

Biykem Bozkurt, MD, FACC, FAHA, Chair Hani Jneid, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, FACC, FAHA H. Vernon Anderson, MD, FACC, FAHA Lauren Gilstrap, MD[∗][1] Grant N. Graham, MD[∗][1] Gail K. Jones, MD[∗][1] David Kao, MD[∗][1] Leo Lopez, MD, FACC, FAHA, FASE[∗][1

Introduction: The pulmonary artery pulsatility index (PAPi), calculated from the ratio of pulmonary artery pulse pressure to right atrial pressure, was initially described as a novel predictor of right ventricular failure after inferior myocardial infarction or left ventricular assist device implantation. Whether PAPi is associated with adverse outcomes in broader samples is unknown. Hypothesis: A lower PAPi is associated with mortality in a broad population referred for right heart catheterization. Methods: We examined consecutive patients undergoing right heart catheterization between 2005-2016 in a hospital-based cohort. The following exclusion criteria were applied: shock or cardiac arrest within 24 hours of catheterization, presence of mechanical circulatory support, prior cardiac transplant, prior valvular surgery, or those with missing key clinical covariates. Multivariable Cox models were utilized to examine the association between PAPi and mortality. Analyses were adjusted for age, sex, BMI, hypertension, diabetes, prior myocardial infarction, and prior heart failure. Results: We studied 8559 patients with mean age 63 years and 40% women. We found that patients in the lowest quartile of PAPi were younger, with greater proportion of men, and higher BMI, yet similar NT-proBNP compared with other quartiles ( Table 1 ). Over 12.5 years of follow-up, there were 2441 death events. Patients in the lowest PAPi quartile had a 31% greater risk of death compared with the highest quartile (multivariable adjusted HR 1.31, 95% CI 1.15-1.48, p0.05 vs quartile 4 for both). Conclusions: Patients in the lowest PAPi quartile had a 31% increased risk of all-cause mortality in a broad population referred for right heart catheterization. These findings highlight a potential role for PAPi in identifying high-risk individuals across a spectrum of disease.

Background Cardiac resynchronization therapy (CRT) improves left heart geometry and function in nonischemic cardiomyopathy (NICMP). We aimed to detail the effects of CRT on left ventricular (LV) and mitral valve (MV) remodeling using 2-dimensional transthoracic echocardiography. Methods Forty-five consecutive patients with NICMP who underwent CRT implantation between 2009 and 2012, and had pre-CRT and follow-up echocardiograms available, were included. Paired t test, linear and logistic regression, and Kaplan-Meier survival analyses were used for statistical assessment. Results The mean age and QRS duration were 60 years and 157 ms, respectively, and 13 (28.9%) were female. At a mean follow-up of 3 years, there were 22 (48.9%) "CRT responders" (≥15% reduction in LV end-systolic volume index [LVESVi]). Significant improvements were observed in LV ejection fraction (26.3% vs 34.3%) and LVESVi (87.7 vs 71.1 mL/m2 ), as well as mitral regurgitation vena contracta width, MV tenting height and area, and end-systolic interpapillary muscle distance. Five-year actuarial survival was 87.5%. Multivariate regression analyses revealed the pre-CRT LVESVi (β = 0.52), and MV coaptation length (β = -0.34) and septolateral annular diameter (β = 0.25) as good correlates of follow-up LVESVi. Variables associated with CRT response were pre-CRT MV coaptation length (OR 1.75, 95% CI 1.0-3.1) and posterior leaflet tethering angle (OR 1.07, 95% CI 1.0-1.14), irrespective of baseline QRS morphology and duration (all P Conclusions Cardiac resynchronization therapy improves LV and MV geometry and function in half of patients with NICMP, which is paralleled by decreased mitral regurgitation severity. The extent of pre-CRT LV remodeling and MV tethering are associated with CRT response.

Aims The aim of this study was to define the natural history of patients with mitral annular calcification (MAC)-related mitral valve dysfunction and to assess the prognostic importance of mean transmitral pressure gradient (MG) and impact of concomitant mitral regurgitation (MR). Methods and results The institutional echocardiography database was examined from 2001 to 2019 for all patients with MAC and MG ≥3 mmHg. A total of 5754 patients were stratified by MG in low (3–5 mmHg, n = 3927), mid (5–10 mmHg, n = 1476), and high (≥10 mmHg, n = 351) gradient. The mean age was 78 ± 11 years, and 67% were female. MR was none/trace in 32%, mild in 42%, moderate in 23%, and severe in 3%. Primary outcome was all-cause mortality, and outcome models were adjusted for age, sex, and MAC-related risk factors (hypertension, diabetes, coronary artery disease, chronic kidney disease). Survival at 1, 5, and 10 years was 77%, 42%, and 18% in the low-gradient group; 73%, 38%, and 17% in the mid-gradient group; and 67%, 25%, and 11% in the high-gradient group, respectively (log-rank P Conclusion In MAC-related mitral valve dysfunction, mean transmitral gradient is associated with increased mortality after adjustment for age, sex, and MAC-related risk factors. Concomitant MR is associated with excess mortality in low-gradient ranges (3–5 mmHg) but gradually loses prognostic importance at higher gradients, indicating prognostic utility of transmitral gradient in MAC regardless of MR severity.

Background: Inconclusive noninvasive tests complicate the care of patients with suspected coronary artery disease, but their prevalence and impact on management, outcomes, and costs are not well described. Methods: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) patients were randomized to stress testing (n=4533) or computed tomographic angiography (CTA; n=4677). We assessed relationships between inconclusive results, subsequent testing, a composite outcome (death, myocardial infarction, or hospitalization for unstable angina), and healthcare expenditures. Results: Overall, 8.0% of tests were inconclusive (9.7% stress, 6.4% CTA). Compared with negative tests, inconclusive tests were more often referred to a second noninvasive test (stress: 14.6% versus 8.5%, odds ratio [OR], 1.91; CTA: 36.5% versus 8.4%, OR, 5.95; P P P =0.034; CTA: 5.0% versus 2.2%, hazard ratio, 1.85; P =0.044) and positive tests (stress: 8.3% versus 2.0%, hazard ratio, 3.50; CTA: 9.2% versus 2.2%, hazard ratio, 3.66; P Conclusions: Among patients with stable chest pain undergoing a noninvasive test, inconclusive results occurred in 6% of CTA and 10% of stress tests. Compared with those with conclusive negative tests, individuals with inconclusive results more often underwent subsequent testing, had increased medical costs, and experienced worse outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01174550.

Background Aortic valve area (AVA) ≤1.0 cm2 is a defining characteristic of severe aortic stenosis (AS). AVA can be underestimated at low transvalvular flow rate. Yet, the impact of flow rate on prognostic value of AVA ≤1.0 cm2 is unknown and is not incorporated into AS assessment. Objectives This study aimed to evaluate the effect of flow rate on prognostic value of AVA in AS. Methods In total, 1,131 patients with moderate or severe AS and complete clinical follow-up were included as part of a longitudinal database. The effect of flow rate (ratio of stroke volume to ejection time) on prognostic value of AVA ≤1.0 cm2 for time to death was evaluated, adjusting for confounders. Sensitivity analysis was performed to identify the optimal cutoff for prognostic threshold of AVA. The findings were validated in a separate external longitudinal cohort of 939 patients. Results Flow rate had a significant effect on prognostic value of AVA. AVA ≤1.0 cm2 was not prognostic for mortality (p = 0.15) if AVA was measured at flow rates below median (≤242 ml/s). In contrast, AVA ≤1.0 cm2 was highly prognostic for mortality (p = 0.003) if AVA was measured at flow rates above median (>242 ml/s). Findings were irrespective of multivariable adjustment for age, sex, and surgical/transcatheter aortic valve replacement (as time-dependent covariates); comorbidities; medications; and echocardiographic features. AVA ≤1.0 cm2 was also not an independent predictor of mortality below median flow rate in the validation cohort. The optimal flow rate cutoff for prognostic threshold was 210 ml/s. Conclusions Transvalvular flow rate determines prognostic value of AVA in AS. AVA measured at low flow rate is not a good prognostic marker and therefore not a good diagnostic marker for truly severe AS. Flow rate assessment should be incorporated into clinical diagnosis, classification, and prognosis of AS.

BACKGROUND: Dual-source computed tomography (CT) can evaluate left ventricular (LV) dyssynchrony, myocardial scar and coronary venous anatomy in patients undergoing cardiac resynchronization therapy (CRT). OBJECTIVE: We aim to determine if dual-source CT predicts clinical CRT outcomes and reduces intra-procedural time. METHODS: In this prospective study, 54 patients scheduled for CRT (age 63±11, 74% male) underwent pre-procedural CT to assess their venous anatomy as well as CT-derived dyssynchrony metrics and myocardial scar. Based on the 1:1 randomization, the implanting physician had pre-implant knowledge of the venous anatomy in half the patients. In blinded analyses, we measured time-to-maximal wall thickness and inward motion to determine 1) CT global and segmental dyssynchrony and 2) concordance of lead location to regional LV mechanical contraction. Endpoints were 6-month CRT response by Heart Failure Clinical Composite Score and 2-year major adverse cardiac events (MACE). RESULTS: There were 72% CRT responders and 17% with MACE. Two wall motion dyssynchrony indices (global and opposing anteroseptal-inferolateral walls) predicted MACE (p

Coronary computed tomography angiography (CTA) and functional testing strategies for stable chest pain yield similar outcomes; one aspect that may guide test choice is safety.We compared test safety (test complications, incidental findings, and effective radiation dose) between CTA and functional testing as-tested in PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain). In the subgroup whose physicians intended nuclear stress over other functional tests if randomized to the functional arm, we compared radiation dose of CTA versus nuclear stress and identified characteristics associated with dose.Of 9470 patients, none had major and1% had minor complications (CTA: 0.8% [37/4633] vs. functional: 0.6% [27/4837]). CTA identified more incidental findings (11.6% [539/4633] vs. 0.7% [34/4837], p 0.001), most commonly pulmonary nodules (9.4%, 437/4633). CTA had similar 90-day cumulative radiation dose to functional testing. However, in the subgroup whose physicians intended nuclear stress (CTA 3147; nuclear 3203), CTA had lower median index test (8.8 vs. 12.6 mSv, p 0.001) and 90-day cumulative (11.6 vs. 13.1 mSv, p 0.001) dose, independent of patient characteristics. The lowest nuclear doses employed 1-day Tc-99m protocols (12.2 mSv). The lowest CTA doses were at sites performing ≥500 CTAs/year (6.9 mSv) and with advanced (latest available) CT scanners (5.5 mSv).Complications were negligibly rare for both CTA and functional testing. CTA detects more incidental findings. Compared to nuclear stress testing, CTA's lower radiation dose, independent of patient characteristics, makes it an attractive test choice. Radiation dose varies with imaging protocol, indicating opportunities to further reduce dose. (ClinicalTrials.gov number, NCT01174550).

Calcific aortic stenosis (AS) is one of the most common acquired valvular heart diseases in industrialized nations. It is a slowly progressive disease and with the aging population, the prevalence of AS is expected to increase. Doppler echocardiography is used to classify patients based on severity of stenosis. Research efforts on how to better identify and risk-assess these patients are currently underway using advanced imaging modalities and serum biomarkers. Thus far, medications for AS prevention have been unsuccessful. As technology progresses, the assessment of AS will transition from one heavily weighed on echocardiographic gradients to one of active surveillances with multimodality imaging, serum biomarkers and genetic assessment.

Background: Optimal management of patients with stable chest pain relies on the prognostic information provided by noninvasive cardiovascular testing, but there are limited data from randomized trials comparing anatomic with functional testing. Methods: In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain and intermediate pretest probability for obstructive coronary artery disease (CAD) were randomly assigned to functional testing (exercise electrocardiography, nuclear stress, or stress echocardiography) or coronary computed tomography angiography (CTA). Site-based diagnostic test reports were classified as normal or mildly, moderately, or severely abnormal. The primary end point was death, myocardial infarction, or unstable angina hospitalizations over a median follow-up of 26.1 months. Results: Both the prevalence of normal test results and incidence rate of events in these patients were significantly lower among 4500 patients randomly assigned to CTA in comparison with 4602 patients randomly assigned to functional testing (33.4% versus 78.0%, and 0.9% versus 2.1%, respectively; both P P P =0.87], 2.65 [ P =0.001], 3.88 [ P P =0.04). If 2714 patients with at least an intermediate Framingham Risk Score (>10%) who had a normal functional test were reclassified as being mildly abnormal, the discriminatory capacity improved to 0.69 (95% CI, 0.64–0.74). Conclusions: Coronary CTA, by identifying patients at risk because of nonobstructive CAD, provides better prognostic information than functional testing in contemporary patients who have stable chest pain with a low burden of obstructive CAD, myocardial ischemia, and events. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01174550.

Graphical abstract, Highlights • Echocardiography is usually the first imaging modality ordered for evaluation of a cardiac mass. • Although echocardiography cannot define the histopathology of a mass, it can identify the presence, location, and tissue characteristics of the mass, which can thus narrow the differential diagnosis. • Echocardiography is useful in evaluating tumor sequelae such as blood flow obstruction, valvular regurgitation, and myocardial dysfunction.

Purpose Swim training is performed in the prone or supine position and obligates water immersion, factors that may augment cardiac volume loading more than other endurance sports. At present, prospective data defining the cardiac responses to swim training are lacking. We therefore studied myocardial adaptations among competitive swimmers to establish a causal relationship between swim training and left ventricular (LV) remodeling. Methods Collegiate swimmers were studied before and after a 90-d period of training intensification. Transthoracic echocardiography was used to examine LV structural and functional adaptations under resting conditions and during an acute LV afterload challenge generated by isometric handgrip testing (IHGT). A sedentary control population was identically studied with IHGT. Results In response to a discrete period of swim training intensification, athletes (n = 17, 47% female, 19 ± 0.4 yr old) experienced eccentric LV remodeling, characterized by proportionally more chamber dilation than wall thickening, with attendant enhancements of resting LV systolic (LV twist) and diastolic (early and late phase tissue velocities) function. Compared with baseline and controls, athletes posttraining demonstrated greater systolic twist impairment during IHGT. However, training-induced LV dilation coupled with gains in diastolic function offsets this acquired systolic susceptibility to acute afterload, resulting in the relative preservation of stroke volume during IHGT. Conclusion Swim training, a sport characterized by unique cardiac loading conditions, stimulates eccentric LV remodeling with the concomitant augmentation of systolic twist and diastolic relaxation. This volume-mediated cardiac remodeling appears to result in greater systolic susceptibility to acute afterload challenge. Further work is required to establish how training-induced changes in function translate to human performance and whether these are accompanied by physiologic trade-offs with relevance to common forms of heart disease.

KEY POINTS: Intense physical activity, a potent stimulus for sympathetic nervous system activation, is thought to increase the risk of malignant ventricular arrhythmias among patients with hypertrophic cardiomyopathy (HCM). As a result, the majority of patients with HCM deliberately reduce their habitual physical activity after diagnosis and this lifestyle change puts them at risk for sequelae of a sedentary lifestyle: weight gain, hypertension, hyperlipidaemia, insulin resistance, coronary artery disease, and increased morbidity and mortality. We show that plasma catecholamine levels remain stably low at exercise intensities below the ventilatory threshold, a parameter that can be defined during cardiopulmonary exercise testing, but rise rapidly at higher intensities of exercise. These findings suggest that cardiopulmonary exercise testing may be a useful tool to provide an individualized moderate‐intensity exercise prescription for patients with HCM. ABSTRACT: Intense physical activity, a potent stimulus for sympathetic nervous system activation, is thought to increase the risk of malignant ventricular arrhythmias among patients with hypertrophic cardiomyopathy (HCM). However, the impact of exercise intensity on plasma catecholamine levels among HCM patients has not been rigorously defined. We conducted a prospective observational case‐control study of men with non‐obstructive HCM and age‐matched controls. Laboratory‐based cardiopulmonary exercise testing coupled with serial phlebotomy was used to define the relationship between exercise intensity and plasma catecholamine levels. Compared to controls (C, n = 5), HCM participants (H, n = 9) demonstrated higher left ventricular mass index (115 ± 20 vs. 90 ± 16 g/m(2), P = 0.03) and maximal left ventricular wall thickness (16 ± 1 vs. 8 ± 1 mm, P