Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial.

BACKGROUND: The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. METHODS: The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). CONCLUSIONS: Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.

Comparing the pooled cohort equations and coronary artery calcium scores in a symptomatic mixed Asian cohort.

Background: The value of pooled cohort equations (PCE) as a predictor of major adverse cardiovascular events (MACE) is poorly established among symptomatic patients. Coronary artery calcium (CAC) assessment further improves risk prediction, but non-Western studies are lacking. This study aims to compare PCE and CAC scores within a symptomatic mixed Asian cohort, and to evaluate the incremental value of CAC in predicting MACE, as well as in subgroups based on statin use. Methods: Consecutive patients with stable chest pain who underwent cardiac computed tomography were recruited. Logistic regression was performed to determine the association between risk factors and MACE. Cohort and statin-use subgroup comparisons were done for PCE against Agatston score in predicting MACE. Results: Of 501 patients included, mean (SD) age was 53.7 (10.8) years, mean follow-up period was 4.64 (0.66) years, 43.5% were female, 48.3% used statins, and 50.0% had no CAC. MI occurred in 8 subjects while 9 subjects underwent revascularization. In the general cohort, age, presence of CAC, and ln(Volume) (OR = 1.05, 7.95, and 1.44, respectively) as well as age and PCE score for the CAC = 0 subgroup (OR = 1.16 and 2.24, respectively), were significantly associated with MACE. None of the risk factors were significantly associated with MACE in the CAC > 0 subgroup. Overall, the PCE, Agatston, and their combination obtained an area under the receiver operating characteristic curve (AUC) of 0.501, 0.662, and 0.661, respectively. Separately, the AUC of PCE, Agatston, and their combination for statin non-users were 0.679, 0.753, and 0.734, while that for statin-users were 0.585, 0.615, and 0.631, respectively. Only the performance of PCE alone was statistically significant (p = 0.025) when compared between statin-users (0.507) and non-users (0.783). Conclusion: In a symptomatic mixed Asian cohort, age, presence of CAC, and ln(Volume) were independently associated with MACE for the overall subgroup, age and PCE score for the CAC = 0 subgroup, and no risk factor for the CAC > 0 subgroup. Whilst the PCE performance deteriorated in statin versus non-statin users, the Agatston score performed consistently in both groups.

Prognosis of patients with hypertrophic cardiomyopathy and low-normal left ventricular ejection fraction.

OBJECTIVE: To investigate whether low-normal left ventricular ejection fraction (LVEF) is associated with adverse outcomes in hypertrophic cardiomyopathy (HCM) and evaluate the incremental value of predictive power of LVEF in the conventional HCM sudden cardiac death (SCD)-risk model. METHODS: This retrospective study included 1858 patients with HCM from two tertiary hospitals between 2008 and 2019. We classified LVEF into three categories: preserved (≥60%), low normal (50%-60%) and reduced (<50%); there were 1399, 415, and 44 patients with preserved, low-normal, and reduced LVEF, respectively. The primary outcome was a composite of SCD, ventricular tachycardia/fibrillation and appropriate implantable cardioverter-defibrillator shocks. Secondary outcomes were hospitalisation for heart failure (HHF), cardiovascular death and all-cause death. RESULTS: During the median follow-up of 4.09 years, the primary outcomes occurred in 1.9%. HHF, cardiovascular death, and all-cause death occurred in 3.3%, 1.9%, and 5.3%, respectively. Reduced LVEF was an independent predictor of SCD/equivalent events (adjusted HR (aHR) 5.214, 95% CI 1.574 to 17.274, p=0.007), adding predictive value to the HCM risk-SCD model (net reclassification improvement 0.625). Compared with patients with HCM with preserved LVEF, those with low-normal and reduced LVEF had a higher risk of HHF (LVEF 50%-60%, aHR 2.457, 95% CI 1.423 to 4.241, p=0.001; LVEF <50%, aHR 7.937, 95% CI 3.315 to 19.002, p<0.001) and cardiovascular death (LVEF 50%-60%, aHR 2.641, 95% CI 1.314 to 5.309, p=0.006; LVEF <50%, aHR 5.405, 95% CI 1.530 to 19.092, p=0.009), whereas there was no significant association with all-cause death. CONCLUSIONS: Low-normal LVEF was an independent predictor of HHF and cardiovascular death in patients with HCM.

Prediction of Deterioration of Left Ventricular Function Using 3-Dimensional Speckle-Tracking Echocardiography in Patients With Left Bundle-Branch Block.

Background Previous studies have demonstrated that 2-dimensional (2D) global longitudinal strain (GLS) is associated with cardiovascular outcomes in patients with left bundle-branch block. However, the predictive value of 3-dimensional (3D) speckle-tracking echocardiography has not yet been investigated in these patients. Methods and Results The authors retrospectively identified 290 patients with left bundle-branch block who underwent echocardiography more than twice. Using speckle-tracking echocardiography, 2D-GLS, 3D-GLS, 3D-global circumferential strain, 3D global radial strain, and 3D global area strain were acquired. The association between 2D and 3D strains and the follow-up left ventricular (LV) ejection fraction (LVEF) was analyzed. The study population was divided into 2 sets: a group with preserved LVEF (baseline LVEF ≥40%) and a group with reduced LVEF (baseline LVEF <40%). After a median follow-up of 29.1 months (interquartile range, 13.1-53.0 months), 14.9% of patients progressed to LV dysfunction in the group with preserved LVEF, and 51.0% of patients showed improved LV function in the group with reduced LVEF. Multivariable analysis of 2D and 3D strains revealed that higher 2D-GLS (odds ratio [OR], 0.65 [95% CI, 0.54-0.78], P<0.001) was highly associated with maintaining LVEF in patients with preserved LVEF. However, a lower 3D-global circumferential strain (OR, 0.61 [95% CI, 0.47-0.78], P<0.001) showed a strong association with persistently reduced LVEF in patients with reduced LVEF. Conclusions Although 2D-GLS showed a powerful predictive value for the deterioration of LV function in the preserved LVEF group, 3D strain, especially 3D-global circumferential strain, can be helpful to predict consistent LV dysfunction in patients with left bundle-branch block who have reduced LVEF.

Long-term outcomes in distinct phenogroups of patients with primary mitral regurgitation undergoing valve surgery.

OBJECTIVES: Patients with mitral regurgitation (MR) may be heterogeneous with different risk profiles. We aimed to identify distinct phenogroups of patients with severe primary MR and investigate their long-term prognosis after mitral valve (MV) surgery. METHODS: The retrospective cohort of patients with severe primary MR undergoing MV surgery (derivation, n=1629; validation, n=692) was analysed. Latent class analysis was used to classify patients into subgroups using 15 variables. The primary outcome was all-cause mortality after MV surgery. RESULTS: During follow-up (median 6.0 years), 149 patients (9.1%) died in the derivation cohort. In the univariable Cox analysis, age, female, atrial fibrillation, left ventricular (LV) end-systolic dimension/volumes, LV ejection fraction, left atrial dimension and tricuspid regurgitation peak velocity were significant predictors of mortality following MV surgery. Five distinct phenogroups were identified, three younger groups (group 1-3) and two older groups (group 4-5): group 1, least comorbidities; group 2, men with LV enlargement; group 3, predominantly women with rheumatic MR; group 4, low-risk older patients; and group 5, high-risk older patients. Cumulative survival was the lowest in group 5, followed by groups 3 and 4 (5-year survival for groups 1-5: 98.5%, 96.0%, 91.7%, 95.6% and 83.4%; p<0.001). Phenogroups had similar predictive performance compared with the Mitral Regurgitation International Database score in patients with degenerative MR (3-year C-index, 0.763 vs 0.750, p=0.602). These findings were reproduced in the validation cohort. CONCLUSION: Five phenogroups of patients with severe primary MR with different risk profiles and outcomes were identified. This phenogrouping strategy may improve risk stratification when optimising the timing and type of interventions for severe MR.

Evaluating the Coronary Artery Disease Consortium Model and the Coronary Artery Calcium Score in Predicting Obstructive Coronary Artery Disease in a Symptomatic Mixed Asian Cohort.

Background The utility of a given pretest probability score in predicting obstructive coronary artery disease (CAD) is population dependent. Previous studies investigating the additive value of coronary artery calcium (CAC) on pretest probability scores were predominantly limited to Western populations. This retrospective study seeks to evaluate the CAD Consortium (CAD2) model in a mixed Asian cohort within Singapore with stable chest pain and to evaluate the incremental value of CAC in predicting obstructive CAD. Methods and Results Patients who underwent cardiac computed tomography and had chest pain were included. The CAD2 clinical model comprised of age, sex, symptom typicality, diabetes, hypertension, hyperlipidemia, and smoking status and was compared with the CAD2 extended model that added CAC to assess the incremental value of CAC scoring, as well as to the corresponding locally calibrated local assessment of the heart models. A total of 522 patients were analyzed (mean age 54±11 years, 43.1% female). The CAD2 clinical model obtained an area under the curve of 0.718 (95% CI, 0.668-0.767). The inclusion of CAC score improved the area under the curve to 0.896 (95% CI, 0.867-0.925) in the CAD2 models and from 0.767 (95% CI, 0.721-0.814) to 0.926 (95% CI, 0.900-0.951) in the local assessment of the heart models. The locally calibrated local assessment of the heart models showed better discriminative performance than the corresponding CAD2 models (P<0.05 for all). Conclusions The CAD2 model was validated in a symptomatic mixed Asian cohort and local calibration further improved performance. CAC scoring provided significant incremental value in predicting obstructive CAD.

Prognostic implication of left ventricular hypertrophy regression after antihypertensive therapy in patients with hypertension.

Background: Left ventricular (LV) hypertrophy (LVH) in patients with hypertension is a significant risk factor for cardiovascular mortality and morbidity. However, the prognostic implication of LVH regression after antihypertensive therapy has not been clearly investigated. Methods: Patients who underwent echocardiography at the time of the diagnosis of hypertension and repeated echocardiography at an interval of 6-18 months were retrospectively identified. LVH was defined as LV mass index (LVMI) >115 g/m2 (men) and >95 g/m2 (women). LVH regression was defined as LVH at initial echocardiography with normal geometry or concentric LV remodeling at follow-up echocardiography. Cardiovascular mortality, hospitalization for heart failure (HHF), coronary revascularization, stroke, and aortic events were analyzed according to changes in LVMI and geometry. Results: Of 1,872 patients, 44.7% (n = 837) had LVH at the time of diagnosis; among these, 30.7% showed LVH regression. The reduction in LVMI was associated with the reduction in BP, especially in those with LVH at baseline. During follow up (median, 50.4 months; interquartile range, 24.9-103.2 months), 68 patients died of cardiovascular causes, 127 had HHF, and 162 had vascular events (coronary revascularization, stroke, and aortic events). Persistent or newly developed LVH during antihypertensive therapy was a significant predictor of cardiovascular mortality and events, especially HHF. On multivariable analysis, women, diabetes, atrial fibrillation, coronary artery disease, larger LVMI and end-diastolic dimension, and less reduction in systolic BP were associated with persistent or newly developed LVH. Conclusion: LVH regression in patients with hypertension is associated with a reduction in cardiovascular events and can be used as a prognostic marker.

Prognostic value of lower bone mineral density in predicting adverse cardiovascular disease in Asian women.

OBJECTIVE: We investigated whether the evaluation of bone mineral density (BMD) provides independent and incremental prognostic value for predicting atherosclerotic cardiovascular disease (ASCVD) in women. METHODS: A total of 12 681 women aged 50-80 years (mean, 63.0±7.8 years) who underwent dual-energy X-ray absorptiometry were retrospectively analysed. We assessed the hazard ratio (HR) for ASCVD events (ASCVD death, non-fatal myocardial infarction and ischaemic stroke) according to the BMD or a clinical diagnosis of osteopenia or osteoporosis, with adjustment for clinical risk factors, including age, body mass index, hypertension, type 2 diabetes, hyperlipidaemia, current smoking and previous fracture. We also evaluated whether the addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors improved the prediction for ASCVD events. RESULTS: In total, 468 women (3.7%) experienced ASCVD events during follow-up (median, 9.2 years). Lower BMD at the lumbar spine, femur neck and total hip was independently associated with higher risk for ASCVD events (adjusted HR per 1-standard deviation decrease in BMD: 1.16, p<0.001; 1.29, p<0.001; 1.38, p<0.001; respectively). A clinical diagnosis of osteoporosis was also independently associated with higher risk for ASCVD events (adjusted HR: 1.79, p<0.001). The addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors demonstrated significant incremental value in discriminating ASCVD events (addition of total hip BMD, p for difference <0.001). CONCLUSION: The evaluation of BMD provides independent and incremental prognostic value for ASCVD in women and thus may improve risk stratification in women.

Coronary Artery Lumen Segmentation Using Location-Adaptive Threshold in Coronary Computed Tomographic Angiography: A Proof-of-Concept.

OBJECTIVE: To compare the lumen parameters measured by the location-adaptive threshold method (LATM), in which the inter- and intra-scan attenuation variabilities of coronary computed tomographic angiography (CCTA) were corrected, and the scan-adaptive threshold method (SATM), in which only the inter-scan variability was corrected, with the reference standard measurement by intravascular ultrasonography (IVUS). MATERIALS AND METHODS: The Hounsfield unit (HU) values of whole voxels and the centerline in each of the cross-sections of the 22 target coronary artery segments were obtained from 15 patients between March 2009 and June 2010, in addition to the corresponding voxel size. Lumen volume was calculated mathematically as the voxel volume multiplied by the number of voxels with HU within a given range, defined as the lumen for each method, and compared with the IVUS-derived reference standard. Subgroup analysis of the lumen area was performed to investigate the effect of lumen size on the studied methods. Bland-Altman plots were used to evaluate the agreement between the measurements. RESULTS: Lumen volumes measured by SATM was significantly smaller than that measured by IVUS (mean difference, 14.6 mm³; 95% confidence interval [CI], 4.9-24.3 mm³); the lumen volumes measured by LATM and IVUS were not significantly different (mean difference, -0.7 mm³; 95% CI, -9.1-7.7 mm³). The lumen area measured by SATM was significantly smaller than that measured by LATM in the smaller lumen area group (mean of difference, 1.07 mm²; 95% CI, 0.89-1.25 mm²) but not in the larger lumen area group (mean of difference, -0.07 mm²; 95% CI, -0.22-0.08 mm²). In the smaller lumen group, the mean difference was lower in the Bland-Altman plot of IVUS and LATM (0.46 mm²; 95% CI, 0.27-0.65 mm²) than in that of IVUS and SATM (1.53 mm²; 95% CI, 1.27-1.79 mm²). CONCLUSION: SATM underestimated the lumen parameters for computed lumen segmentation in CCTA, and this may be overcome by using LATM.

Breast Arterial Calcification is Associated with the Progression of Coronary Atherosclerosis in Asymptomatic Women: A Preliminary Retrospective Cohort Study.

We evaluated whether breast arterial calcification (BAC) is associated with the progression of coronary atherosclerosis in asymptomatic women. This retrospective observational cohort study analysed asymptomatic women from the BBC registry. In 126 consecutive women (age, 54.5 ± 7.0 years) who underwent BAC evaluation and repeated coronary computed tomography angiography (CCTA) examinations, the coronary arterial calcification score (CACS) and segment stenosis score (SSS) were evaluated to assess the progression of coronary arterial calcification (CAC) and coronary atherosclerotic plaque (CAP). CAC and CAP progression were observed in 42 (33.3%) and 26 (20.6%) women, respectively (median interscan time, 4.3 years), and were associated with the presence of BAC and a higher BAC score at baseline. Women with BAC demonstrated higher CAC and CAP progression rates and showed higher chances for CAC and CAP progression during follow-up (p < 0.001 for both). In multivariable analyses, the BAC score remained independently associated with both CAC and CAP progression rates after adjustment for clinical risk factors (ß = 0.087, p = 0.029; and ß = 0.020, p = 0.010, respectively) and with additional adjustment for baseline CACS (ß = 0.080, p = 0.040; and ß = 0.019, p = 0.012, respectively) or SSS (ß = 0.079, p = 0.034; and ß = 0.019, p = 0.011, respectively). Thus, BAC may be related to the progression of coronary atherosclerosis and its evaluation may facilitate decision-making.

Noninvasive detection of coronary vasospastic angina using a double-acquisition coronary CT angiography protocol in the presence and absence of an intravenous nitrate: a pilot study.

OBJECTIVES: To evaluate the feasibility of a double-acquisition coronary CT angiography (CCTA) protocol in the presence and absence of an intravenous (IV) vasodilator infusion for detecting vasospastic angina. METHODS: Twenty patients with a high clinical probability of vasospastic angina were enrolled. All subjects underwent baseline CCTA without a vasodilator in the early morning followed by a catheterized coronary angiography with ergonovine provocation test. Within 3 days, all subjects underwent repeat CCTA during a continuous IV infusion of nitrate. Vasospastic angina as detected by CCTA was defined as significant stenosis (≥50 %) with negative remodelling without definite plaques or diffuse small diameter (<2 mm) of a major coronary artery with a beaded appearance on baseline CT that completely dilated on IV nitrate CT. The CCTA results were compared to the catheterized ergonovine provocation test as the reference standard. RESULTS: Among 20 patients, the catheterized ergonovine provocation test detected vasospasm in 15 patients. The sensitivity, specificity, positive predictive value and negative predictive value of CCTA in a per-patient-based analysis were 73, 100, 100 and 56 %, respectively. CONCLUSIONS: Double-acquisition CCTA in the presence and absence of IV infusion of nitrate allows noninvasive detection of vasospastic angina with moderate sensitivity and high specificity. KEY POINTS: • Limited data exist regarding the efficacy of CCTA in detecting vasospastic angina. • We propose a double-acquisition CCTA protocol with and without IV nitrate injections. • This protocol provides 100% specificity and moderate sensitivity (73%) in spasm detection.

Current roles and future applications of cardiac CT: risk stratification of coronary artery disease.

Cardiac computed tomography (CT) has emerged as a noninvasive modality for the assessment of coronary artery disease (CAD), and has been rapidly integrated into clinical cares. CT has changed the traditional risk stratification based on clinical risk to image-based identification of patient risk. Cardiac CT, including coronary artery calcium score and coronary CT angiography, can provide prognostic information and is expected to improve risk stratification of CAD. Currently used conventional cardiac CT, provides accurate anatomic information but not functional significance of CAD, and it may not be sufficient to guide treatments such as revascularization. Recently, myocardial CT perfusion imaging, intracoronary luminal attenuation gradient, and CT-derived computed fractional flow reserve were developed to combine anatomical and functional data. Although at present, the diagnostic and prognostic value of these novel technologies needs to be evaluated further, it is expected that all-in-one cardiac CT can guide treatment and improve patient outcomes in the near future.

Impaired myocardial perfusion reserve in patients with fatty liver disease assessed by quantitative myocardial perfusion magnetic resonance imaging.

BACKGROUND: The purpose of this study was to determine whether the presence of fatty liver is associated with an alteration in myocardial perfusion reserve (MPR). METHODS AND RESULTS: A retrospective analysis of 65 asymptomatic subjects who underwent both plain abdominal computed tomography and cardiac magnetic resonance imaging (MRI), and who had normal left ventricular wall motion, no regional myocardial ischemia and no myocardial scar on MRI was performed. Stress and rest myocardial perfusion MRI were analyzed by Patlak plot method to quantify myocardial blood flow (MBF) and MPR in 16 myocardial segments. Fatty liver was detected in 18 (28%) of the 65 subjects. No significant difference was found in rest-MBF between subjects with and without fatty liver (1.2 ± 0.75 vs. 1.1 ± 0.67 ml·min(-1)·g(-1), P=0.59). However, MPR was significantly lower in subjects with fatty liver than the non-fatty liver subjects (2.3 ± 0.74 vs. 3.3 ± 1.4, P<0.001). Subjects with fatty liver had a higher prevalence of MPR <2.5 (78% vs. 38%, P<0.005) and higher triglyceride levels (206 ± 61 vs. 92 ± 37 mg/dl, P<0.001). Multivariate analysis revealed the presence of fatty liver as a significant predictor of reduced MPR with an odds ratio of 8.2 (P<0.01). CONCLUSIONS: Nonalcoholic fatty liver disease is related to reduced MPR, suggesting impaired coronary microcirculation.