Initial Invasive or Conservative Strategy for Stable Coronary Disease.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Natural History of Patients With Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study.

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<0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (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.

Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity.

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.

Prognostic importance of the transmitral pressure gradient in mitral annular calcification with associated mitral valve dysfunction.

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 < 0.001 between groups). MG was independently associated with mortality (adjusted HR 1.064 per 1 mmHg increase, 95% CI 1.049-1.080). MR severity was associated with mortality at low gradients (P < 0.001) but not at higher gradients (P = 0.166 and 0.372 in the mid- and high-gradient groups, respectively). 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.

Left ventricle and mitral valve reverse remodeling in response to cardiac resynchronization therapy in nonischemic cardiomyopathy.

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 (ß = 0.52), and MV coaptation length (ß = -0.34) and septolateral annular diameter (ß = 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 < .05). 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.

Catecholamine response to exercise in patients with non-obstructive hypertrophic cardiomyopathy.

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/m2 , P = 0.03) and maximal left ventricular wall thickness (16 ± 1 vs. 8 ± 1 mm, P < 0.001) but similar body mass index, resting heart rate, peak oxygen consumption (H = 40 ± 13 vs. C = 42 ± 7 ml/kg/min, P = 0.81) and heart rate at the ventilatory threshold (H = 78 ± 6 vs. C = 78 ± 4% peak heart rate, P = 0.92). During incremental effort exercise in both groups, concentrations of adrenaline and noradrenaline were unchanged through low- and moderate-exercise intensity until reaching a catecholamine threshold (H = 82 ± 4 vs. C = 85 ± 3% peak heart rate, P = 0.86) after which levels of both molecules rose rapidly. In patients with mild non-obstructive HCM, plasma catecholamine levels remain stably low at exercise intensities below the ventilatory threshold but rise rapidly at higher intensities of exercise. Routine cardiopulmonary exercise testing may be a useful tool to provide an individualized moderate-intensity exercise prescription for patients with HCM.

The application of appropriate use criteria for transthoracic echocardiography in a cardiac intensive care unit.

BACKGROUND: Appropriate use criteria (AUC) represent an important mechanism by which to promote the rational utilization of healthcare resources. No study to date has been conducted assessing the applicability of current AUC to transthoracic echocardiograms (TTEs) performed in a cardiac intensive care unit (CICU). We analyzed 2 years of consecutive TTEs performed in a CICU at a quaternary-care academic medical center, hypothesizing that current AUC may not adequately describe the role of TTE in a modern CICU. METHODS: Indications for TTEs were independently classified by two investigators in accordance with 2011 AUC. If investigators were unable to assign an AUC classification to a given study, it was deemed to be unclassifiable. Disagreements between investigators were resolved by consensus. Cases in which consensus could not be reached underwent definitive adjudication by a third investigator. RESULTS: Of the 826 TTEs, 619 TTEs were classified as appropriate (74.9%, CI 71.8%-77.9%), 12 as uncertain (1.5%, CI 0.75%-2.5%), 21 as rarely appropriate (2.5%, CI 1.6%-3.9%), and 174 were unable to be classified (21.1%, CI 18.3%-24.0%). The most common unclassifiable indication was "initial evaluation of cardiac structure or function after cardiac arrest of unknown etiology" (n = 101). CONCLUSION: Current AUC for TTEs may not adequately address the complexity of clinical cases encountered in the CICU. In our study of 826 consecutive TTEs, 21.1% were unable to be classified, reflecting the difficulty in applying AUC to this unique clinical environment. Further studies are therefore needed to better delineate the appropriateness of TTEs performed in the CICU.

The effects of cardiac resynchronization therapy on left ventricular and mitral valve geometry and secondary mitral regurgitation in patients with left bundle branch block.

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 < .05 for all). Linear correlations were observed between follow-up MR grade and baseline MV tenting height (r = .44), left atrial volume index (r = .41), LV end-systolic volume index (r = .4), MV tenting area (r = .38), LV ejection fraction (r = -.34), and end-systolic interpapillary muscle distance (r = .34) (P < .05 for all). Multiple regression analysis revealed associations between follow-up MR grade and baseline MV tenting height (ß/mm = 0.42, P = .006) and left atrial volume index (ß/mL/m2  = 0.4, P = .008), independent of QRS duration (ß/ms=-0.07; P = 0.6) and nonischemic cardiomyopathy (ß = -0.34, P = .02). CONCLUSIONS: Cardiac resynchronization therapy in patients with LBBB and secondary MR results in LV and MV geometric reverse remodeling and decreases MR severity. Extent of baseline MV tethering is independently associated with persistent MR at follow-up.

Prognostic Value of Noninvasive Cardiovascular Testing in Patients With Stable Chest Pain: Insights From the PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).

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<0.001). In CTA, 54.0% of events (n=74/137) occurred in patients with nonobstructive CAD (1%-69% stenosis). Prevalence of obstructive CAD and myocardial ischemia was low (11.9% versus 12.7%, respectively), with both findings having similar prognostic value (hazard ratio, 3.74; 95% confidence interval [CI], 2.60-5.39; and 3.47; 95% CI, 2.42-4.99). When test findings were stratified as mildly, moderately, or severely abnormal, hazard ratios for events in comparison with normal tests increased proportionally for CTA (2.94, 7.67, 10.13; all P<0.001) but not for corresponding functional testing categories (0.94 [P=0.87], 2.65 [P=0.001], 3.88 [P<0.001]). The discriminatory ability of CTA in predicting events was significantly better than functional testing (c-index, 0.72; 95% CI, 0.68-0.76 versus 0.64; 95% CI, 0.59-0.69; 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.

Outcomes of anatomical versus functional testing for coronary artery disease.

BACKGROUND: Many patients have symptoms suggestive of coronary artery disease (CAD) and are often evaluated with the use of diagnostic testing, although there are limited data from randomized trials to guide care. METHODS: We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. RESULTS: The mean age of the patients was 60.8±8.3 years, 52.7% were women, and 87.7% had chest pain or dyspnea on exertion. The mean pretest likelihood of obstructive CAD was 53.3±21.4%. Over a median follow-up period of 25 months, a primary end-point event occurred in 164 of 4996 patients in the CTA group (3.3%) and in 151 of 5007 (3.0%) in the functional-testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; P=0.75). CTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%, P=0.02), although more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%). The median cumulative radiation exposure per patient was lower in the CTA group than in the functional-testing group (10.0 mSv vs. 11.3 mSv), but 32.6% of the patients in the functional-testing group had no exposure, so the overall exposure was higher in the CTA group (mean, 12.0 mSv vs. 10.1 mSv; P<0.001). CONCLUSIONS: In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550.).

Effects of cardiac resynchronization therapy after inferior myocardial infarction on secondary mitral regurgitation and mitral valve geometry.

BACKGROUND: The effects of cardiac resynchronization therapy (CRT) on secondary mitral regurgitation (MR), and mitral valve (MV) and left ventricular (LV) geometry, in patients with prior inferior myocardial infarction is not clearly defined. We assessed these outcomes utilizing two-dimensional echocardiography, and analyzed echocardiographic geometric variables that may correlate with follow-up MR severity. METHODS: Between 2009 and 2012, 229 CRT were implanted. Twenty-two had prior inferior myocardial infarction, ≥mild MR at baseline, and serial echocardiography. A left bundle branch block was present in 12 (54.5%) patients. The pre-CRT and follow-up echocardiograms were analyzed for: (1) MR severity; (2) MV and LV geometry; and (3) LV remodeling. RESULTS: The median follow-up time was 2.2 years (interquartile range, 0.7-4). In 16 patients without an inferior myocardial scar, there was a reduction in MR jet area/left atrial area ratio (33.2% vs 25.8%; P = 0.06) and MR grade (2.3 vs 1.8; P = 0.05), and an increased LV ejection fraction (26.1% vs 30.9%; P = 0.04) and end-systolic posterior ventricular sulcus-anterolateral papillary muscle angle (133.9 vs 143.9 degrees; P = 0.01). In six patients with scar, there was no change in LV or MR parameters. Regression analysis revealed linear associations between baseline MV tenting height (r = 0.57; P = 0.006), LV end-diastolic diameter index (r = 0.5; P = 0.02), mitral septolateral annular diameter (r = 0.48; P = 0.03), and MV tenting area (r = 0.46; P = 0.03), with follow-up MR jet area/left atrial area ratio. CONCLUSIONS: In patients with prior inferior myocardial infarction and no scar, CRT is associated with decreased MR severity, and improved papillary muscle alignment and LV systolic function at follow-up.

Assessment of Tricuspid Annular Motion by Speckle Tracking in Anesthetized Patients Using Transesophageal Echocardiography.

BACKGROUND: The perioperative assessment of right ventricular (RV) function remains a challenge. Tricuspid annular plane systolic excursion (TAPSE) using M-mode is a widely used measure of RV function. However, accurate alignment of the ultrasound beam with the direction of annular movement can be difficult with transesophageal echocardiography (TEE) to measure TAPSE, precluding effective use of M-mode to measure annular excursion. Tracking of specular reflectors in the myocardium may provide an angle-independent method to assess annular motion with TEE. We hypothesized that TEE speckle tracking of the lateral tricuspid annular motion represents a comparable measurement to the well-validated M-mode TAPSE on transthoracic echocardiogram (TTE), and may be considered as a reasonable alternative to TAPSE. METHODS: This is a prospective, observational cohort study. We included all patients, who were in sinus rhythm, with a preoperative TTE within 3 months of scheduled cardiac surgery that required intraoperative TEE. Tissue motion annular displacements (TMAD) of the lateral (L), septal (S), and midpoint (M) tricuspid annulus were measured (QLAB Cardiac Motion Quantification; Philips Medical, Andover, MA) after induction of general anesthesia. This was compared to the preoperative M-mode TAPSE on TTE. RESULTS: Seventy-two consecutive patients who met eligibility requirements were enrolled from September to November 2016. Twelve were excluded due to poor image quality, allowing TMAD to be analyzed in 60 patients. TMAD was analyzed offline and TMAD analysis was able to track tricuspid annular motion in all patients. The mean TMAD (L), TMAD (S), and TMAD (M) were 17.4 ± 5.2, 10.2 ± 4.8, and 14.2 ± 4.8 mm, respectively. TMAD (L) showed close correlation with M-mode TAPSE on TTE (r = 0.87, 95% confidence interval, 0.79-0.92; P < .01). All patients with a preoperative TAPSE <17 mm had a TMAD (L) <17 mm, while 71% of those with a TAPSE ≥ 17 mm had a TMAD (L) ≥ 17 mm. There was strong positive correlation between TMAD (L) and intraoperative RV fractional area change (r = 0.86, 95% confidence interval, 0.77-0.91; P < .01). Reproducibility analysis of TMAD within and across observers showed excellent correlation. CONCLUSIONS: TMAD is a quick and angle-independent method to quantitatively assess RV longitudinal function by TEE. It correlates strongly with M-mode TAPSE on TTE. Because TMAD and TAPSE were not simultaneously measured in this study, their correlation is subject to differences in loading conditions, general anesthesia, and changes in the disease process. TMAD may be easily applied in routine clinical settings and its role in the perioperative environment deserves to be further explored.

Impact of cardiac resynchronization therapy on mitral valve apparatus geometry and clinical outcomes in patients with secondary mitral regurgitation.

BACKGROUND: Cardiac resynchronization therapy (CRT) may improve secondary mitral regurgitation (MR) in patients with cardiomyopathy. The effects on mitral valve (MV) and left ventricular (LV) geometry, however, have not been clearly defined. METHODS: Between 2009 and 2012, 229 CRT implants were performed at a single academic center. Seventy-one had ≥mild MR at baseline and serial echocardiography, without subsequent MV intervention. The pre-CRT and follow-up echocardiograms were retrospectively reviewed for (1) MV and LV geometry measurements; (2) MR grade; and (3) LV remodeling indices. RESULTS: The mean age was 67 ± 15 years, and the cardiomyopathy was ischemic in 37 (52%). At a mean follow-up of 4.0 ± 1.9 years, there were significant improvements in LV ejection fraction and size, MR grade, MV tenting area and anterior leaflet tethering angle, and end-systolic interpapillary muscle distance (IPMD), and reductions in moderate-to-severe or severe MR (27% vs 15%; P = .04) and New York Heart Association functional class III/IV symptoms (83% vs 41%; P < .001). Multivariable analysis revealed the pre-CRT MV tenting height (OR 1.25, 95% CI 1.01-1.56; P = .04) and end-systolic IPMD (OR 1.14, 95% CI 0.99-1.32; P = .08) as independently associated with moderate or greater MR at follow-up. Finally, at 5 years post-CRT implantation, the estimated survival and freedom from LV assist device or cardiac transplantation was 61%. CONCLUSIONS: CRT results in favorable effects on MV and LV geometry and decreases the prevalence of moderate-to-severe or severe MR and heart failure symptoms. The pre-CRT MV tenting height and IPMD are independently associated with persistent MR at follow-up.

Transient Ischemic Dilatation during Stress Echocardiography: An Additional Marker of Significant Myocardial Ischemia.

AIM: Left ventricular (LV) transient ischemic dilatation (TID) is not clear how it relates to inducible myocardial ischemia during stress echocardiography (SE). METHODS AND RESULTS: Eighty-eight SEs were examined from the site certification phase of the ISCHEMIA Trial. LV end-diastolic volume (EDV) and end-systolic volume (ESV) were measured at rest and peak stages and the percent change calculated. Moderate or greater ischemia was defined as ≥3 segments with stress-induced severe hypokinesis or akinesis. Optimum cut points in stress-induced percent EDV and ESV change that identified moderate or greater myocardial ischemia were analyzed. Analysis from percentage distribution identified a > 13% LV volume increase in EDV or a > 9% LV volume increase in ESV as the optimum cutoff points for moderate or greater ischemia. Using these definitions for TID, there were 27 (31%) with TIDESV and 12 (14%) with TIDEDV . By logistic regression analysis and receiver operating characteristic curves, the percent change in ESV had a stronger association with moderate or greater myocardial ischemia than that of EDV change. Compared to those without TIDESV , cases with TIDESV had larger extent of inducible wall-motion abnormalities, lower peak stress LVEF, and higher likelihood of moderate or grater ischemia. For moderate or greater myocardial ischemia detection, TIDESV had a sensitivity of 46%, specificity of 83%, positive predictive value of 70%, and negative predictive value of 64%. CONCLUSION: Transient ischemic dilatation by SE is a marker of extensive myocardial ischemia and can be used as an additional marker of higher risk.

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Renal Response in Patients with Chronic Kidney Disease Predicts Outcome Following Cardiac Resynchronization Therapy.

BACKGROUND: Chronic kidney disease (CKD) severity is associated with increased morbidity and mortality in congestive heart failure. There is a paucity of data regarding renal improvement after cardiac resynchronization therapy (CRT) and its potential impact on clinical outcomes, especially in patients with severe CKD. METHOD: This was a retrospective analysis of a prospectively collected cohort of 260 patients with CKD undergoing CRT at a single center. Renal function was compared before and after CRT. The primary end point was a composite of death, heart transplant, and left ventricular assist device (LVAD), assessed at 5 years. RESULTS: Patients with more severe CKD demonstrated increased risk of death, transplant, or LVAD following CRT (P = 0.015). Renal response (estimated glomerular filtration rate improvement ≥10 mL/min/1.73 m(2) ) was observed in 14% of all patients and 28% of patients with stage IV CKD. Independent predictors of renal response included left ventricular ejection fraction improvement (odds ratio [OR] 1.06, confidence interval [CI] 1.01-1.10), angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (OR 4.31, CI 1.08-17.23), and advanced CKD stage (OR 2.19, CI 1.14-4.23). Renal response independently decreased hazard of the primary outcome (HR 0.24, CI 0.08-0.73, P = 0.01). Renal responders with stage IV CKD had 80% 5-year event-free survival, compared to 0% for nonrenal responders in stage IV (P = 0.03). CONCLUSION: Although severity of CKD is associated with poorer outcome after CRT, improvement in renal function can occur in patients across all CKD stages. Renal responders, including those with stage IV CKD, demonstrate favorable 5-year outcomes. Assessment of renal response may help better prognostic outcomes following CRT.

The value of core lab stress echocardiography interpretations: observations from the ISCHEMIA Trial.

BACKGROUND: Stress echocardiography (SE) is dependent on subjective interpretations. As a prelude to the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial, potential sites were required to submit two SE, one with moderate or severe left ventricular (LV) myocardial ischemia and one with mild ischemia. We evaluated the concordance of site and core lab interpretations. METHODS: Eighty-one SE were submitted from 41 international sites. Ischemia was classified by the number of new or worsening segmental LV wall motion abnormalities (WMA): none, mild (1 or 2) or moderate or severe (3 or more) by the sites and the core lab. RESULTS: Core lab classified 6 SE as no ischemia, 35 mild and 40 moderate or greater. There was agreement between the site and core in 66 of 81 total cases (81%, weighted kappa coefficient [K] =0.635). Agreement was similar for SE type - 24 of 30 exercise (80%, K = 0.571) vs. 41 of 49 pharmacologic (84%, K = 0.685). The agreement between poor or fair image quality (27 of 36 cases, 75%, K = 0.492) was not as good as for the good or excellent image quality cases (39 of 45 cases, 87%, K = 0.755). Differences in concordance were noted for degree of ischemia with the majority of discordant interpretations (87%) occurring in patients with no or mild LV myocardial ischemia. CONCLUSIONS: While site SE interpretations are largely concordant with core lab interpretations, this appears dependent on image quality and the extent of WMA. Thus core lab interpretations remain important in clinical trials where consistency of interpretation across a range of cases is critical. TRIAL REGISTRATION: ClinicalTrials.gov NCT01471522.