Left ventricular remodeling response to SGLT2 inhibitors in heart failure: an updated meta-analysis of randomized controlled studies.

BACKGROUND: Randomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF). METHODS AND RESULTS: We performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi. CONCLUSIONS: Treatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.

Burden of Ventricular Arrhythmias in Cardiac Resynchronization Therapy Defibrillation and Implantable Cardioverter-Defibrillator Recipients with Recovered Left Ventricular Ejection Fraction: The Additive Role of Speckle-Tracking Echocardiography.

BACKGROUND: Patients with heart failure undergoing cardiac resynchronization therapy with or without defibrillator function may exhibit recovery of left ventricular ejection fraction (LVEF) during follow-up. Mechanical dispersion (MD; the SD of time to peak longitudinal strain by two-dimensional speckle-tracking echocardiography) is a known predictor of life-threatening ventricular arrhythmias (VAs). Relationships among LVEF recovery, changes in MD, and incidence of VA are still not extensively investigated. METHODS: In this retrospective study, recipients of cardiac resynchronization therapy defibrillation (n = 183) or implantable cardioverter-defibrillators only (n = 87) underwent conventional and speckle-tracking echocardiography, both at baseline and after 10 to 12 months, and were followed clinically. Both a ≥10% increase in LVEF and a final LVEF > 35% defined echocardiographic response (EchoResp). Reduction in MD ≥10 msec defined MD response (MDResp). Risk for appropriate implantable cardioverter-defibrillator therapy for VAs was assessed using a multivariable Cox hazard model. RESULTS: The prevalence of EchoResp+ and MDResp+ was 39% and 46%, respectively. During follow-up (49.8 ± 33.5 months), 74 VA events occurred. The incidence rate (per 100 patient-years) of VAs was lowest in the EchoResp+/MDResp+ group (1.66%; 95% CI, 0.69%-3.99%), highest in the EchoResp-/MDResp- group (12.8%; 95% CI, 9.53%-17.2%; P < .0001), and intermediate in the EchoResp-/MDResp+ (5.5%; 95% CI, 3.3%-9.4%) or EchoResp+/MDResp- (5.3%; 95% CI, 3.0%-9.4%) group. Multivariable analysis showed that higher MD at follow-up (>71.4 msec) was associated with VAs independent of whether final LVEF was below or above the guideline-reported cutoff of 35% (P < .05). CONCLUSIONS: Among ICD recipients, improvements in both left ventricular function and MD are associated with reduced risk for VAs. In patients whose follow-up LVEFs improved to >35%, risk for VAs, although substantially decreased, remained elevated in the presence of still elevated MD.

Global longitudinal strain in heart failure with reduced ejection fraction: Prognostic relevance across disease severity as assessed by automated cluster analysis.

BACKGROUND: Ejection fraction (EF) is still widely used to categorize heart failure (HF) patients but has limitations. Global longitudinal strain (GLS) has emerged as a new prognosticator in HF, independent of EF. AIM: We investigated the incremental predictive benefit of GLS over different risk profiles as identified by automated cluster analysis of simple echocardiographic parameters. METHODS AND RESULTS: In 797 HFrEF patients (age 66 ± 12y; mean EF 30 ± 7%), unsupervised cluster analysis of 10 routine echocardiographic variables (without GLS) was performed. Median follow-up was 37 months. End-point was all-cause mortality. Association between risk profiles, GLS, and mortality was assessed by Cox proportional-hazard modeling with interaction term. Cluster analysis allocated patients to 3 different risk phenogroups (PG): PG-1 (mild diastolic dysfunction [DD], moderate systolic dysfunction, no pulmonary hypertension, normal right ventricular [RV] function); PG-2 (moderate DD, mild pulmonary hypertension, normal RV function); PG-3 (severe DD, advanced systolic dysfunction, pulmonary hypertension, RV dysfunction). Compared to PG-1, PG-2 and PG-3 showed increased adjusted-hazard ratio (1.71; 95% CI:1.05-2.77, P = 0.30; and 2.58; 95% CI:1.50-4.44, P < 0.001, respectively). GLS was independently associated with outcome in the whole population (adjusted-HR: 1.11; 95% CI: 1.05-1.17, P = 0.001); however, profile membership modified the relationship between GLS and outcome which was no longer significant in PG-3 (P for interaction = 0.003). CONCLUSIONS: Within HFrEF populations, clustering of routine echocardiography parameters can automatically identify patients with different risk profiles; further assessment by GLS may be useful for patients with not advanced disease.

Superior Prognostic Value of Right Ventricular Free Wall Compared to Global Longitudinal Strain in Patients With Heart Failure.

BACKGROUND: Global right ventricular (RV) longitudinal strain (RVGLS) and free wall RV longitudinal strain (RVFWS) have both been advocated as sensitive tools to evaluate RV function and predict prognosis in patients with heart failure and reduced ejection fraction (HFrEF). However, because the interventricular septum is an integral part of the left ventricle (LV) also, RVGLS might be influenced by LV dysfunction. Thus, we compared the prognostic performance of either RV strain parameter in HFrEF patients, also taking into account the degree of LV systolic dysfunction. METHODS: In 288 prospectively enrolled outpatients with stable HFrEF, RVGLS and RVFWS were assessed by speckle-tracking and LV systolic function by global longitudinal strain and LV ejection fraction. Patients were followed up for 30.2 ± 23.0 months; the primary endpoint was all-cause death/heart failure-related hospitalization. Prognostic performance was assessed by C-statistic and net reclassification improvement. RESULTS: There were 95 events during follow-up. By univariable analysis, both RVGLS (hazard ratio × 1 SD, 1.60; 95% CI, 1.29-1.99; P < .0001) and RVFWS (hazard ratio × 1 SD, 1.82; 95% CI, 1.45-2.29; P < .0001) were associated with outcome, and both remained significant after correction for EMPHASIS risk score, New York Heart Association class, natriuretic peptides, and therapy. However, after further correction for LV systolic function parameters, only RVFWS remained significantly associated with outcome (P < .01). A basic prediction model was improved by adding RVFWS (net reclassification improvement 0.390; P < .05), but not RVGLS. CONCLUSIONS: Although both RVGLS and RVFWS have prognostic value, RVFWS better predicts outcome in HFrEF patients, mainly because it is less influenced by LV longitudinal dysfunction.

Left Atrial Reservoir Function and Outcome in Heart Failure With Reduced Ejection Fraction.

Background Left atrial (LA) volume is a marker of cardiac remodeling and prognosis in heart failure (HF) with reduced ejection fraction (EF), but LA function is rarely measured or characterized. We investigated determinants and prognostic impact of LA reservoir function in patients with HF with reduced EF. Methods and Results In 405 patients with stable HF with reduced EF (EF, ≤40%) in sinus rhythm, we assessed LA reservoir function by both LA total EF (by phasic volume changes) and peak atrial longitudinal strain (PALS; by speckle tracking echocardiography); LA functional index was also calculated. During follow-up (median, 30 months; Q1-Q3, 13-52), 139 patients (34%) reached the composite end point (all-cause death/HF hospitalization). Median PALS was 15.5% (interquartile range, 11.2-20.6). By univariable analysis, all LA function parameters significantly predicted outcome ( P <0.01 for all), with PALS showing the highest predictive accuracy (area under the curve, 0.75; sensitivity, 73%; specificity, 70%). Impaired PALS was associated with greater left ventricular and LA volumes, worse left ventricular EF, left ventricular global longitudinal strain, right ventricular systolic function, and more severe diastolic dysfunction. After multivariable adjustment (including LA volume and left ventricular global longitudinal strain), PALS, but not LA total EF or LA functional index, remained significantly associated with outcome (hazard ratio per 1-SD decrease, 1.38; 95% CI, 1.05-1.84; P=0.030). Adding PALS to a base model, including age, sex, LA volume, EF, E/E' ratio, and global longitudinal strain, provided incremental predictive value (continuous net reclassification improvement, 0.449; P=0.0009). Conclusions In HF with reduced EF, assessment of LA reservoir function by PALS allows powerful prognostication, independently of LA volume and left ventricular longitudinal contraction.

Fibrosis assessment by integrated backscatter and its relationship with longitudinal deformation and diastolic function in heart failure with preserved ejection fraction.

Myocardial reflectivity, as assessed by calibrated integrated backscatter (cIB) analysis, is a non-invasive surrogate for the amount of left ventricular (LV) fibrosis. The aim of this study was to assess the myocardial reflectivity pattern in patients with heart failure and preserved ejection fraction (HFpEF), and to evaluate its relationship with longitudinal systolic deformation of LV by 2D-speckle tracking echocardiography, and degree of diastolic dysfunction. Transthoracic echocardiography, myocardial Doppler-derived systolic (Sm) and early diastolic velocity (E'), global longitudinal strain (GLS), and tissue characterization by cIB, were obtained in 86 subjects, 46 with HFpEF, and 40 controls. GLS was significantly impaired in HFpEF patients (-15.4 ± 3.5 % vs -21.5 ± 2.9 % in controls; P < 0.0001). Increased myocardial reflectivity, as evidenced by less negative values of cIB, was also found in HFpEF compared to controls (-21.2 ± 4.4 dB vs -25.3 ± 3.9 dB, P < 0.0001). In HFpEF patients, myocardial reflectivity was positively related to GLS (r = 0.68, P < 0.0001), E/E' ratio (r = 0.38, P = 0.009), and Tau (r = 0.43, P = 0.002), and inversely related to E' velocity (r = -0.46, P = 0.0012). These associations remained significant after adjustment for age, preload and afterload indices. Patients with HFpEF show changes of LV structure consistent with enhanced fibrosis-as evidenced by increased myocardial reflectivity- which parallel the degree of diastolic dysfunction, and of longitudinal systolic dysfunction.

The 'Echo Heart Failure Score': an echocardiographic risk prediction score of mortality in systolic heart failure.

AIMS: Although many transthoracic echocardiographic (TTE) measurements have been shown to predict outcome in heart failure (HF), whether incremental risk prediction is afforded by their combination is unknown. We developed a simple echocardiographic risk score of mortality in HF patients. METHODS AND RESULTS: We performed TTE in 747 systolic HF patients followed-up for 34 ± 23 months. The Cox hazard model was used to evaluate the association between 14 TTE parameters and death. The Echo Heart Failure Score (EHFS) was derived by assigning the value of 1 to each independent predictor when present, and 0 when it was absent, and then by summing the number. The 3-year risk prediction improvement was tested by adding the EHFS to a model containing clinical predictors, and by calculating the C index and net reclassification improvement (NRI). Five baseline TTE variables (end-systolic volume index, left atrial volume index, mitral E-wave deceleration time, tricuspid annular peak systolic excursion, and pulmonary artery systolic pressure) remained independent predictors of mortality. The mortality rate (per 100 patients/year) significantly increased with EHFS ranging from 0 to 5 (EHFS = 0, 2.7%; 1, 5.2%; 2, 10.1%; 3, 13.7%, 4, 29.7%; 5, 36.9%; P < 0.0001). Patients with EHFS ≥3 had a mortality hazard ratio of 3.58 (95% confidence interval 2.74-4.78) compared with EHFS <3. Adding EHFS to the base model improved the C index (from 0.74 to 0.81, P < 0.0001), yielding a continuous NRI of 0.63 (P < 0.0001). CONCLUSIONS: The EHFS, an easily obtainable echo score, improved risk prediction of death over traditional prognostic factors in systolic HF patients, and it may prove useful for risk stratification.

Improvement of myocardial performance (Tei) index closely reflects intrinsic improvement of cardiac function: assessment in revascularized hibernating myocardium.

BACKGROUND: Myocardial performance index (MPI), or Tei index, is an indicator of systolic and diastolic myocardial function. MPI increases in case of cardiac dysfunction; however, whether reversal of left ventricular dysfunction is also reflected by concomitant improvement (i.e., decrease) of MPI is unknown. METHODS: Fifty-two patients with chronic ischemic cardiomyopathy and viable myocardium by dobutamine stress echocardiography were studied by echocardiography before and more than 4 months after cardiac revascularization. Patients were in optimal medical therapy, which remained unchanged following revascularization. RESULTS: At baseline, ejection fraction (EF: 32 ± 6%) and wall motion score index (WMSI: 2.37 ± 0.32) were impaired, and MPI averaged 0.71 ± 0.19. Revascularization markedly improved EF (44 ± 10%, P < 0.0001) and WMSI (1.77 ± 0.44, P < 0.0001). MPI also improved (0.59 ± 0.26, P < 0.0001), and its decrease was significantly correlated with the improvement in EF (r =-0.68, P < 0.0001) and to the extent of viable myocardium (r =-0.45, P = 0.0007). Responders to revascularization (≥5% increase in EF at follow-up, n = 40% and 77%) achieved a significant improvement in MPI at follow-up in contrast with nonresponders (-23 ± 25% vs. 0.02 ± 0.18%, P = 0.001). Improvement in MPI was largely driven by a significant reduction in isovolumic contraction time (P < 0.001) with consequent prolongation of the ejection phase. CONCLUSION: In patients with chronic ischemic cardiomyopathy, MPI improves along with recovery of function, reflecting the intrinsic improvement of viable segments induced by revascularization.