Effect of empagliflozin on cardiac remodelling in South Asian and non-South Asian individuals: insights from the EMPA-HEART CardioLink-6 randomised clinical trial.

BACKGROUND: This exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial examined whether the previously reported benefit of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) mass (LVM) regression differs between individuals of South Asian and non-South Asian ethnicity. METHODS: EMPA-HEART CardioLink-6 was a double-blind, placebo-controlled clinical trial that randomised 97 individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to either empagliflozin 10 mg daily or placebo for 6 months. LV parameters and function were assessed using cardiac magnetic resonance imaging. The 6-month changes in LVM and LV volumes, all indexed to baseline body surface area, for South Asian participants were compared to those for non-South Asian individuals. RESULTS: Compared to the non-South Asian group, the South Asian sub-cohort comprised more males, was younger and had a lower median body mass index. The adjusted difference for LVMi change over 6 months was -4.3 g/m2 (95% confidence interval [CI], -7.5, -1.0; P = 0.042) for the South Asian group and -2.3 g/m2 (95% CI, -6.4, 1.9; P = 0.28) for the non-South Asian group (Pinteraction = 0.45). There was no between-group difference for the adjusted differences in baseline body surface area-indexed LV volumes and LV ejection fraction. CONCLUSIONS: There was no meaningful difference in empagliflozin-associated LVM regression between South Asian and non-South Asian individuals living with T2DM and CAD in the EMPA-HEART CardioLink-6 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02998970 (First posted on 21/12/ 2016).

Surgical aortic valve replacement provides better left ventricular mass regression than transcatheter aortic valve replacement in patients with small aortic annulus.

OBJECTIVES: This study aimed to evaluate the incidence of patient-prosthesis mismatch (PPM) and degree of left ventricular (LV) mass regression after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) in patients with small aortic annulus (defined as annular diameter of ≤ 21 mm). METHODS: We retrospectively analyzed echocardiographic findings in total of 277 patients with aortic stenosis and small aortic annulus (63 underwent SAVR and 214 underwent TAVR) between October 2013 and March 2019. PPM was defined as an effective orifice area index (EOAI) ≤ 0.85 cm2/m2. LV mass regression was evaluated as percentage change in LV mass index (LVMI) from baseline to the 1-year follow-up. RESULTS: The median EOAI before discharge was slightly larger in the TAVR group than in the SAVR group (1.09 vs. 1.07 cm2/m2; P = 0.030). However, the incidence of PPM before discharge (9.4 vs. 12.7%; P = 0.438) and at the 1-year follow-up (11.7 vs. 11.1%; P = 0.901) was similar between groups. Mild or greater paravalvular leakage (PVL) after the procedure was more frequent in the TAVR group (11.7 vs. 0%; P = 0.002). Reduction in LVMI was significantly higher in the SAVR group (19.3 vs. 6.4%; P < 0.001). Multivariate analysis demonstrated that reduction in LVMI was positively associated with higher baseline transaortic pressure gradient (P < 0.001) and higher baseline LVMI (P < 0.001) and negatively associated with older age (P < 0.001) and mild or greater PVL (P < 0.001). CONCLUSIONS: SAVR provides better LV mass regression than TAVR with a comparable rate of PPM in patients with small aortic annulus.

Extent of Left Ventricular Mass Regression and Impact of Global Left Ventricular Afterload on Cardiac Events and Mortality after Aortic Valve Replacement.

Patient-prosthesis mismatch (PPM) causes a high transvalvular pressure gradient and residual left ventricular (LV) hypertrophy, consequently influencing long-term results. This study aimed to find the relationships between hemodynamic parameters and LV mass regression and determine the risk predictors of major adverse cardiovascular and cerebral events (MACCE) after aortic valve replacement (AVR) for aortic stenosis. Methods and Results: Preoperative and postoperative Doppler echocardiography data were evaluated for 120 patients after AVR. The patients' mean age was 67.7 years; 55% of the patients were male. Forty-four (37%) patients suffered from MACCE during a mean follow-up period of 3.6 ± 2 years. The following hemodynamic parameters at follow-up were associated with lower relative indexed LV mass (LVMI) regression: lower postoperative indexed effective orifice area, greater mean transvalvular pressure gradient (MPG), greater stroke work loss (SWL), and concentric or eccentric LV remodeling mode. The following hemodynamic parameters at follow-up were associated with a higher risk of MACCE: higher valvuloarterial impedance (ZVA), greater SWL, greater MPG, greater relative wall thickness, greater LVMI, and hypertrophic LV remodeling mode. Lower relative LVMI regression was associated with a higher risk of MACCE (hazard ratio, 1.01: 95% confidence interval, 1.003-1.03). The corresponding cutoff of relative LVMI regression was -14%. Conclusions: Changes in hemodynamic parameters were independently associated with relative LVMI regression. Impaired reverse remodeling and persistent residual LV hypertrophy were independent risk predictors of MACCE. An LVMI regression lower than 14% indicated higher MACCE. A postoperative ZVA greater than 3.5 mmHg/mL/m2 was an independent risk predictor of cardiac events and mortality after AVR. Preventive strategies should be used at the time of the operation to avoid PPM.

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.

Mineralocorticoid Receptor Antagonist Improves Cardiac Structure in Type 2 Diabetes: Data From the MIRAD Trial.

OBJECTIVES: This study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD). BACKGROUND: MRA activation is associated with cardiac fibrosis and increased left ventricular mass (LVM), which is an independent predictor of adverse CVD, including heart failure in patients with type 2 diabetes. METHODS: A prespecified analysis of secondary endpoints in a randomized, double-blinded clinical trial of 140 patients with type 2 diabetes at high risk of or established CVD. Patients were randomized to receive high-dose eplerenone therapy (100 mg-200 mg) or placebo as an add-on to standard care for 26 weeks. Indexed LVM (LVMi) and T1 time were measured using cardiac magnetic resonance (CMR) imaging. Biomarkers included N-terminal pro-B-type natriuretic peptide (NT-proBNP), pro-collagen type I N-terminal propeptide (P1NP), and type III N-terminal propeptide (P3NP). RESULTS: Of 140 patients in the MIRAD trial, 104 patients were subject to CMR imaging (eplerenone: 54 patients; placebo: 50 patients). Mean LVMi at baseline was 74.2 ± 16 g/m2. The treatment effect (ie, between-group differences) was a decrease of 3.7 g/m2 following the eplerenone treatment (95% CI: -6.7 to -0.7; P = 0.017), with a corresponding decrease in absolute LVM. Plasma NT-proBNP concentrations decreased by 22% (P = 0.017) using eplerenone compared with placebo, and P1NP decreased 3.3 ng/mL (P = 0.019). No differences in T1 times or P3NP concentrations were observed between groups. CONCLUSIONS: The addition of high-dose eplerenone in high-risk type 2 diabetes was associated with a clear reduction in LVMi and in NT-proBNP and P1NP levels, which may suggest a clinical benefit in heart failure prevention. (EU Clinical trials: Mineralocorticoid Receptor Antagonists in Type 2 Diabetes [MIRAD]; 2015-002519-14).

Comparison of Aortic Gradient and Ventricular Mass after Valve Replacement for Aortic Stenosis with Rapid Deployment, Sutureless, and Conventional Bioprostheses.

BACKGROUND: The use of rapid deployment and sutureless aortic prostheses is increasing. Previous reports have shown promising results on haemodynamic performance and mortality rates. However, the impact of these bioprostheses on left ventricular mass (LVM) regression remains unknown. We decided to study the changes in remodelling and LVM regression in isolated severe aortic stenosis treated with conventional or Perceval® or Intuity® valves. METHOD AND RESULTS: From January 2011 to January 2016, 324 bioprostheses were implanted in our centre. The collected characteristics were divided into 3 groups: conventional valves, Perceval®, and Intuity®, and they were analysed after 12 months. There were 183 conventional valves (56%), 72 Perceval® (22%), and 69 Intuity® (21.2%). The statistical analysis showed significant differences in transprosthetic postoperative peak gradient (23 [18-29] mm Hg vs. 21 [16-29] mm Hg and 18 [14-24] mm Hg, p < 0.001), ventricular mass electrical criteria regression (Sokolow and Cornell products), and 1-year survival (90 vs. 93% and 97%, log rank p value = 0.04) in conventional, Perceval®, and Intuity® groups. CONCLUSIONS: We observed differences in haemodynamic, electrocardiographic, and echocardiographic parameters related to the different types of prosthesis. Patients with the Intuity® prosthesis had the highest reduction in peak aortic gradient and the higher ventricular mass regression. Besides, patients with the Intuity® prosthesis had less risk of mortality during follow-up than the other two groups. Further studies are needed to confirm these findings.

Prognostic impact of left ventricular mass regression after transcatheter aortic valve replacement in patients with left ventricular hypertrophy.

BACKGROUND: Paravalvular regurgitation (PVR) has been known to be the primary determinant of poor left ventricular (LV) mass regression after transcatheter aortic valve replacement (TAVR). However, the incidence of significant PVR has been reduced considerably as TAVR technology evolved rapidly. This study aimed to investigate the time course and impact of LV mass index (LVMi) regression on long-term clinical outcomes in severe aortic stenosis (AS) patients without significant PVR after TAVR. METHODS: Of 412 patients who underwent TAVR, 146 who had LV hypertrophy (LVMi ≥115 g/m2 for men and ≥ 95 g/m2 for women) at baseline and were alive at one year after TAVR were enrolled. The primary outcome was cardiovascular deaths and the impact of LVMi regression on clinical outcomes were examined. The patients with significant PVR were excluded. RESULTS: During a median follow-up of 40 months (interquartile range, 26-58 months), 9 (6.2%) cardiovascular deaths, 21 (14.4%) all-cause deaths, and 9 (6.2%) hospitalizations occurred. In the multivariable analysis, the percentage change of LVMi was an independent predictor of cardiovascular deaths (adjusted hazard ratio [HR], 1.03; 95% confidential interval [CI], 1.01-1.05; P = 0.010), and composite outcome of cardiovascular deaths and rehospitalization for heart failure (adjusted HR, 1.02; 95% CI, 1.00-1.04; P = 0.022). Baseline LVMi, eccentric hypertrophy, and TAVR-induced left bundle branch block were independently associated with LVMi regression. CONCLUSIONS: In patients with severe AS who received successful TAVR without significant PVR, the degree of LVMi regression is an independent predictor of postoperative outcomes after TAVR.

Regression of Left Ventricular Mass After Transcatheter Aortic Valve Replacement: The PARTNER Trials and Registries.

BACKGROUND: Greater early left ventricular mass index (LVMi) regression is associated with fewer hospitalizations 1 year after transcatheter aortic valve replacement (TAVR). The association between LVMi regression and longer-term post-TAVR outcomes is unclear. OBJECTIVES: The purpose of this study was to determine the association between LVMi regression at 1-year post-TAVR and clinical outcomes between 1 and 5 years. METHODS: Among intermediate- and high-risk patients who received TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries and were alive at 1 year, we included patients with baseline moderate or severe left ventricular hypertrophy (LVH) and paired measurements of LVMi at baseline and 1 year. The associations between LVMi regression (percent change between baseline and 1 year) and death or rehospitalization from 1 to 5 years were examined. RESULTS: Among 1,434 patients, LVMi was 146 g/m2 (interquartile range [IQR]: 133 to 168 g/m2) at baseline and decreased 14.5% (IQR: 4.2% to 26.1%) to 126 g/m2 (IQR: 106 to 148 g/m2) at 1 year. After adjustment, greater LVMi regression at 1 year was associated with lower all-cause death (adjusted hazard ratio [aHR]: 0.95 per 10% decrease in LVMi; 95% confidence interval [CI]: 0.91 to 0.98; p = 0.004; aHR of the quartile with greatest vs. least LVMi regression: 0.61; 95% CI: 0.43 to 0.86; p = 0.005). Severe LVH at 1 year was observed in 39%, which was independently associated with increased all-cause death (aHR of severe LVH vs. no LVH: 1.71; 95% CI: 1.20 to 2.44; p = 0.003). Similar associations were found for rates of cardiovascular mortality and rehospitalization. CONCLUSIONS: Among patients with moderate or severe LVH treated with TAVR who are alive at 1 year, greater LVMi regression at 1 year is associated with lower death and hospitalization rates to 5 years. These findings may have implications for the timing of valve replacement and the role of adjunctive medical therapy after TAVR.

Left ventricular mass regression in patients without patient-prosthesis mismatch after aortic valve replacement for aortic stenosis.

OBJECTIVES: The relationship between the degree of a postoperative effective orifice area and temporal regression of a left ventricular mass after aortic valve replacement for aortic stenosis is unclear in patients without patient-prosthesis mismatch. We therefore investigated the relationship and independent predictors of left ventricular mass regression. METHODS: Among 307 consecutive patients who underwent aortic valve replacement for aortic stenosis between 2008 and 2013, 223 patients receiving a periodic inspection by echocardiography for at least 3 consecutive years after surgery without patient-prosthesis mismatch were enrolled in the present study. Temporal regression of left ventricular mass index was compared between two groups that were classified equally according to effective orifice area index obtained at a 1-week postoperative echocardiographic examination: < 1.20 cm2/m2 (n = 112) and > 1.20 cm2/m2 (n = 111). We also determined the predictors affecting left ventricular mass regression. RESULTS: No difference existed in the preoperative left ventricular mass index between the two groups (p = 0.431). Temporal regression of the left ventricular mass index was similar in the two groups. The independent predictors of left ventricular mass regression were male gender (p = 0.007) and preoperative left ventricular mass index (p = 0.003), but valve size was not (p = 0.641). CONCLUSIONS: There was no relationship between the degree of postoperative effective orifice area and temporal regression of the left ventricular mass in patients without patient-prosthesis mismatch. The independent predictors of left ventricular mass regression were male gender and preoperative left ventricular mass index.

Complete transposition of great arteries associated with total anomalous pulmonary venous connection: An unusual cause for early left ventricular myocardial mass regression.

A 24-day-old apparently asymptomatic neonate was found to have complete transposition of great arteries with small patent ductus arteriosus and restrictive patent foramen ovale. The neonate was found to have relatively high saturations (saturations = 88%) despite inadequate mixing communications. Echo findings were suggestive of significant dilatation of right atrium and right ventricle and left ventricular (LV) mass regression. Further echo interrogation revealed coexisting total anomalous pulmonary venous connection (TAPVC) as the cause of relatively high saturations and early LV mass regression. The patient was planned for follow-up and underwent successful Senning repair at the age of 8 months. Hemodynamics and echo findings of this association of TGA with TAPVC have been described in this case report.

Effect of aortic pericardial valve choice on outcomes and left ventricular mass regression in patients with left ventricular hypertrophy.

OBJECTIVES: We sought to assess the effect of 2 contemporary pericardial valves on left ventricular mass regression and clinical outcomes after aortic valve replacement (AVR) in patients with aortic stenosis (AS). METHODS: Patients were followed postoperatively in a dedicated valve clinic. A propensity score was derived for each patient and used to adjust all analyses. Longitudinal analysis was performed using a repeated measures growth curve model. Survival analysis was assessed with a Cox proportional hazards model. RESULTS: Since February 2011, 258 patients with AS and left ventricular hypertrophy underwent AVR with the Trifecta (TR) (St Jude Medical, St Paul, Minn) or Perimount Magna Ease (ME) (Edwards LifeSciences, Irvine, Calif) bioprosthesis. There were longer bypass and crossclamp times and the indexed left ventricular outflow tract was smaller in the TR group. For the TR and ME, respectively, peak (14.4 ± 5.1 mm Hg vs 20.9 ± 7.2 mm Hg; P < .001) and mean (7.3 ± 2.7 mm Hg vs 10.9 ± 4.3 mm Hg; P < .001) gradients were significantly smaller postoperatively in the TR group. There was greater total mass regression (44.3 g/m2; 95% confidence interval [CI], 36.3-52.3 vs 29.5; 95% CI, 20.4-38.5 g/m2; P = .020) and mass regression over time in the TR group compared with the ME group (P = .016). Freedom from readmission, congestive heart failure, and the composite outcome of all-cause mortality, readmission, and congestive heart failure at 2.5 years was significantly improved in the TR group (composite outcome in TR and ME groups, respectively, 90.2; 95% CI, 81.9-94.9 and 78.2; 95% CI, 67.1-86.0; P = .013) CONCLUSIONS: TR use was associated with significantly increased left ventricular mass regression and improved intermediate-term clinical outcome in patients with left ventricular hypertrophy undergoing AVR for AS, compared with use of the ME.

Incidence and sequelae of prosthesis-patient mismatch in transcatheter versus surgical valve replacement in high-risk patients with severe aortic stenosis: a PARTNER trial cohort--a analysis.

BACKGROUND: Little is known about the incidence of prosthesis-patient mismatch (PPM) and its impact on outcomes after transcatheter aortic valve replacement (TAVR). OBJECTIVES: The objectives of this study were: 1) to compare the incidence of PPM in the TAVR and surgical aortic valve replacement (SAVR) randomized control trial (RCT) arms of the PARTNER (Placement of AoRTic TraNscathetER Valves) I Trial cohort A; and 2) to assess the impact of PPM on regression of left ventricular (LV) hypertrophy and mortality in these 2 arms and in the TAVR nonrandomized continued access (NRCA) registry cohort. METHODS: The PARTNER Trial cohort A randomized patients 1:1 to TAVR or bioprosthetic SAVR. Postoperative PPM was defined as absent if the indexed effective orifice area (EOA) was >0.85 cm(2)/m(2), moderate if the indexed EOA was ≥0.65 but ≤0.85 cm(2)/m(2), or severe if the indexed EOA was <0.65 cm(2)/m(2). LV mass regression and mortality were analyzed using the SAVR-RCT (n = 270), TAVR-RCT (n = 304), and TAVR-NRCA (n = 1,637) cohorts. RESULTS: The incidence of PPM was 60.0% (severe: 28.1%) in the SAVR-RCT cohort versus 46.4% (severe: 19.7%) in the TAVR-RCT cohort (p < 0.001) and 43.8% (severe: 13.6%) in the TAVR-NRCA cohort. In patients with an aortic annulus diameter <20 mm, severe PPM developed in 33.7% undergoing SAVR compared with 19.0% undergoing TAVR (p = 0.002). PPM was an independent predictor of less LV mass regression at 1 year in the SAVR-RCT (p = 0.017) and TAVR-NRCA (p = 0.012) cohorts but not in the TAVR-RCT cohort (p = 0.35). Severe PPM was an independent predictor of 2-year mortality in the SAVR-RCT cohort (hazard ratio [HR]: 1.78; p = 0.041) but not in the TAVR-RCT cohort (HR: 0.58; p = 0.11). In the TAVR-NRCA cohort, severe PPM was not a predictor of 1-year mortality in all patients (HR: 1.05; p = 0.60) but did independently predict mortality in the subset of patients with no post-procedural aortic regurgitation (HR: 1.88; p = 0.02). CONCLUSIONS: In patients with severe aortic stenosis and high surgical risk, PPM is more frequent and more often severe after SAVR than TAVR. Patients with PPM after SAVR have worse survival and less LV mass regression than those without PPM. Severe PPM also has a significant impact on survival after TAVR in the subset of patients with no post-procedural aortic regurgitation. TAVR may be preferable to SAVR in patients with a small aortic annulus who are susceptible to PPM to avoid its adverse impact on LV mass regression and survival. (The PARTNER Trial: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894).