Reverse Cardiac Remodeling Research Articles

The Pathophysiology and New Advancements in the Pharmacologic and Exercise-Based Management of Heart Failure With Reduced Ejection Fraction: A Narrative Review.

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome whose management has significantly evolved based on the pathophysiology and disease process. It is widely prevalent, has a relatively high mortality rate, and is comparatively more common in men than women. In HFrEF, the series of maladaptive processes that occur lead to an inability of the muscle of the left ventricle to pump blood efficiently and effectively, causing cardiac dysfunction. The neurohormonal and hemodynamic adaptations play a significant role in the advancement of the disease and are critical to guiding the treatment and management of HFrEF. The first-line therapy, which includes loop diuretics, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, hydralazine/isosorbide-dinitrate, and mineralocorticoid receptor antagonists (MRAs), has been proven to provide symptomatic relief and decrease mortality and complications. The newly recommended drugs for guideline-based therapy, angiotensin receptor/neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors, soluble guanylate cyclase, and myosin activators and modulators have also been shown to improve cardiac function, reverse cardiac remodeling, and reduce mortality rates. Recent studies have demonstrated that exercise-based therapy has resulted in an improved quality of life, exercise capacity, cardiac function, and decreased hospital readmission rates, but it has not had a considerable reduction in mortality rates. Combining multiple therapies alongside holistic advances such as exercise therapy may provide synergistic benefits, ultimately leading to improved outcomes for patients with HFrEF. Although first-line treatment, novel pharmacologic management, and exercise-based therapy have been shown to improve prognosis, the existing literature suggests a need for further studies evaluating the long-term effects of MRA and ARNI.

Sizing SGLT2 Inhibitors Up: From a Molecular to a Morpho-Functional Point of View.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, have recently been shown to reduce cardiovascular death and hospitalization in patients with heart failure, representing a revolutionary therapeutic tool. The purpose of this review is to explore their multifaceted mechanisms of actions, beyond their known glucose reduction power. The cardioprotective effects of gliflozins seem to be linked to the maintenance of cellular homeostasis and to an action on the main metabolic pathways. They improve the oxygen supply for cardiomyocytes with a considerable impact on both functional and morphological myocardial aspects. Moreover, multiple molecular actions of SGLT2i are being discovered, such as the reduction of both inflammation, oxidative stress and cellular apoptosis, all responsible for myocardial damage. Various studies showed controversial results concerning the role of SGLT2i in reverse cardiac remodeling and the lowering of natriuretic peptides, suggesting that their overall effect has yet to be fully understood. In addition to this, advanced imaging studies evaluating the effect on all four cardiac chambers are lacking. Further studies will be needed to better understand the real impact of their administration, their use in daily practice and how they can contribute to benefits in terms of reverse cardiac remodeling.

Effect of sodium-glucose cotransporter 2 inhibitors on left atrial remodeling and prognosis in patients with type 2 diabetes and heart failure with reduced ejection fraction.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been found to minimize hospitalization for heart failure and cardiovascular death. Cardiac reverse remodeling may be a mechanism responsible for the favorable clinical efficacy of SGLT2is on heart failure. To date, few studies have examined their effects on the left atrium. Therefore, the purpose of this study was to explore whether SGLT2is improve left atrial adverse remodeling in patients with type 2 diabetes and heart failure with reduced ejection fraction (HFrEF). A single-center, retrospective, observational study was conducted. Consecutive patients with type 2 diabetes and HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University for acute decompensated heart failure between 1 January 2019 and 1 March 2022 were identified. On the basis of their treatment strategies, the enrolled participants were classified into SGLT2i and non-SGLT2i groups. The primary end point was all-cause mortality. Changes in left atrial echocardiographic indices from baseline to follow-up were also assessed. A total of 198 patients (mean age: 63.96 ± 12.11 years, 20.71% women) were included. Greater reductions from baseline were seen with SGLT2i in the left atrial diameter (P < 0.001), left atrial superior-inferior diameter (P = 0.027), left atrial transverse diameter (P = 0.020), left atrial volume (P = 0.005), and left atrial volume index (P = 0.004). Moreover, 48 cases (48.48%) in the SGLT2i group and 33 (33.33%) in the non-SGLT2i group showed left atrial reverse remodeling (P = 0.003). Survival analysis demonstrated significantly lower overall mortality in the SGLT2i group compared with the non-SGLT2i group. This study found that SGLT2i therapy promoted left atrial structure reverse remodeling. This beneficial effect may be a vital mechanism by which SGLT2i improved clinical outcomes in patients with HFrEF.

Association between Dapagliflozin, Cardiac Biomarkers and Cardiac Remodeling in Patients with Diabetes Mellitus and Heart Failure.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of antidiabetic drugs that have shown favorable effects in heart failure (HF) patients, irrespective of the left ventricular ejection fraction (LVEF). Recent studies have demonstrated the beneficial effects of empagliflozin on cardiac function and structure; however, less is known about dapagliflozin. The purpose of the current work was to investigate the association between the use of dapagliflozin and cardiac biomarkers as well as the cardiac structure in a cohort of patients with HF and diabetes mellitus (DM). The present work was an observational study that included 118 patients (dapagliflozin group n = 60; control group n = 58) with HF and DM. The inclusion criteria included: age > 18 years, a history of DM and HF, regardless of LVEF, and hospitalization for HF exacerbation within the previous 6 months. The exclusion criteria were previous treatment with SGLT2i or glucagon-like peptide-1 receptor agonists, a GFR< 30 and life expectancy < 1 year. The evaluation of patients (at baseline, 6 and 12 months) included a clinical assessment, laboratory blood tests and echocardiography. The Mann-Whitney test was used for the comparison of continuous variables between the two groups, while Friedman's analysis of variance for repeated measures was used for the comparison of continuous variables. Troponin (p < 0.001) and brain natriuretic peptide (BNP) (p < 0.001) decreased significantly throughout the follow-up period in the dapagliflozin group, but not in the control group (p > 0.05 for both). The LV end-diastolic volume index (p < 0.001 for both groups) and LV end-systolic volume index (p < 0.001 for both groups) decreased significantly in the dapagliflozin and the control group, respectively. The LVEF increased significantly (p < 0.001) only in the dapagliflozin group, whereas the global longitudinal strain (GLS) improved in the dapagliflozin group (p < 0.001) and was impaired in the control group (p = 0.021). The left atrial volume index decreased in the dapagliflozin group (p < 0.001) but remained unchanged in the control group (p = 0.114). Lastly, the left ventricular mass index increased significantly both in the dapagliflozin (p = 0.003) and control group (p = 0.001). Dapagliflozin, an SGLT2i, was associated with a reduction in cardiac biomarkers and with reverse cardiac remodeling in patients with HF and DM.

The impact of echocardiographic indexation to evaluate cardiac reverse remodeling throughout pregnancy and postpartum

Introduction and objectivesEchocardiography guidelines suggest normalizing left ventricular (LV) volumes and mass (LVM) to body size. During pregnancy, continuous weight variation impacts on body surface area (BSA) calculation, limiting the longitudinal analysis of cardiac remodeling (CR) and reverse remodeling (RR) variables. Our aim was to identify the most common indexing methodologies in the literature on pregnant populations through a systematic review; and, to compare four scaling methods: (i) none (absolute values); (ii) indexing to the BSA before pregnancy; (iii) allomeric indexing; and (iv) indexing to BSA measured at the same day of cardiac assessment, using an illustrative example. MethodsWe performed a systematic review of CR and RR during pregnancy and post-partum, using two databases. We included studies reporting longitudinal echocardiographic analysis of cardiac chamber volumes in humans. We used a prospective cohort study of healthy pregnant women who underwent four echocardiographic evaluations during pregnancy and postpartum, as an illustrative example. ResultsTwenty-seven studies were included, most studies indexed to BSA measured at each evaluation moment (n=21). Within-subjects design was the most reported to analyse longitudinal data (n=17). Indexation to the pre-pregnancy BSA or application of allometric indexes revealed a higher effect than BSA measured at each evaluation and an equal effect to not indexing using within-subjects design. The within-subjects designs also revealed a higher effect size value than the between-subjects design for longitudinal analysis of LVM adaptations during pregnancy and postpartum. Conclusion(s)This study concludes that indexation methods do not impact the clinical interpretation of longitudinal echocardiographic assessment but highlights the need to harmonize normalization procedures during pregnancy.

Left ventricular mass predicts cardiac reverse remodelling in patients treated with empagliflozin

BackgroundThe cardiovascular (CV) benefits of sodium-glucose transport protein 2 inhibitors have been attributed, in part, to cardiac reverse remodelling. The EMPA-HEART CardioLink-6 study reported that sodium-glucose cotransporter-2 inhibition for 6 months with empagliflozin was associated with a significant reduction in left ventricular mass indexed to body surface area (LVMi). In this sub-analysis, we evaluated whether baseline LVMi may influence how empagliflozin affects cardiac reverse remodelling.MethodsA total of 97 patients with type 2 diabetes and coronary artery disease were randomized to empagliflozin (10 mg/d) or matching placebo for 6 months. The study cohort was divided into those whose baseline LVMi was ≤ 60 g/m2 and those who had a baseline LVMi > 60 g/m2. Subgroup comparisons were conducted using a linear regression model adjusted for baseline values (ANCOVA) that included an interaction term between LVMi subgroup and treatment.ResultsBaseline LVMi was 53.3 g/m2 (49.2–57.2) and 69.7 g/m2 (64.2–76.1) for those with baseline ≤ 60 g/m2 (n = 54) and LVMi > 60 g/m2 (n = 43) respectively. The adjusted difference of LVMi regression between those randomized to empagliflozin and placebo were − 0.46 g/m2 (95% CI: −3.44, 2.52, p = 0.76) in the baseline LVMi ≤ 60 g/m2 subgroup and − 7.26 g/m2 (95% CI: −11.40, −3.12, p = 0.0011) in the baseline LVMi > 60 g/m2 subgroup (p-for-interaction = 0.007). No significant associations were found between baseline LVMi and 6-month change in LV end systolic volume-indexed (p-for-interaction = 0.086), LV end diastolic volume-indexed (p-for-interaction = 0.34), or LV ejection fraction (p-for-interaction = 0.15).ConclusionsPatients with higher LVMi at baseline experienced greater LVM regression with empagliflozin.

Impact of new-onset arrhythmia on cardiac reverse remodeling following transcatheter aortic valve replacement: computed tomography-derived left ventricular and atrial strains.

Patients who undergo transcatheter aortic valve replacement (TAVR) are at risk for new-onset arrhythmia (NOA) that may require permanent pacemaker (PPM) implantation, resulting in decreased cardiac function. We aimed to investigate the factors that are associated with NOA after TAVR and to compare pre- and post-TAVR cardiac functions between patients with and without NOA using CT-derived strain analyses. We included consecutive patients who underwent pre- and post-TAVR cardiac CT scans six months after TAVR. New-onset left bundle branch block, atrioventricular block, and atrial fibrillation/flutter lasting over 30days after the procedure and/or the need for PPM diagnosed within 1year after TAVR were regarded as NOA. Implant depth and left heart function and strains were analyzed using multi-phase CT images and compared between patients with and without NOA. Of 211 patients (41.7% men; median 81years), 52 (24.6%) presented with NOA after TAVR, and 24 (11.4%) implanted PPM. Implant depth was significantly deeper in the NOA group than in the non-NOA group (- 6.7 ± 2.4 vs. - 5.6 ± 2.6mm; p = 0.009). Left ventricular global longitudinal strain (LV GLS) and left atrial (LA) reservoir strain were significantly improved only in the non-NOA group (LV GLS, - 15.5 ± 4.0 to - 17.3 ± 2.9%; p < 0.001; LA reservoir strain, 22.3 ± 8.9 to 26.5 ± 7.6%; p < 0.001). The mean percent change of the LV GLS and LA reservoir strains was evident in the non-NOA group (p = 0.019 and p = 0.035, respectively). A quarter of patients presented with NOA after TAVR. Deep implant depth on post-TAVR CT scans was associated with NOA. Patients with NOA after TAVR had impaired LV reserve remodeling assessed by CT-derived strains. New-onset arrhythmia (NOA) following transcatheter aortic valve replacement (TAVR) impairs cardiac reverse remodeling. CT-derived strain analysis reveals that patients with NOA do not show improvement in left heart function and strains, highlighting the importance of managing NOA for optimal outcomes. • New-onset arrhythmia following transcatheter aortic valve replacement (TAVR) is a concern that interferes with cardiac reverse remodeling. • Comparison of pre-and post-TAVR CT-derived left heart strain provides insight into the impaired cardiac reverse remodeling in patients with new-onset arrhythmia following TAVR. • The expected reverse remodeling was not observed in patients with new-onset arrhythmia following TAVR, given that CT-derived left heart function and strains did not improve.

Effects of sacubitril/valsartan on atrial function and structure as treatment response indicators in patients with heart failure with reduced ejection fraction: an observational prospective study

Abstract Funding Acknowledgements Type of funding sources: None. Background Sacubitril/valsartan (Sac/Val) has been shown to improve mortality and reduce hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), also through reverse cardiac remodeling. However, temporal changes of functional and structural left atrial parameters, including speckle tracking (ST) analysis, have not been comprehensively characterized yet. Purpose This prospective study sought to: (1) evaluate the impact of Sac/Val on echo parameters, focusing on left atrial function and structure metrics, at two timepoints, 6 and 12 months, after treatment initiation; (2) assess the predictive role of these factors on Sac/Val response at 12 months, including LVEF and biomarker outcomes. Methods From January 2020 to September 2021, HFrEF patients from Policlinico Universitario Agostino Gemelli IRCSS outpatient HF service with indication to Sac/Val treatment were prospectively enrolled; subjects with history of atrial fibrillation and more than moderate mitral regurgitation were excluded. Echocardiographic evaluation was performed before Sac/Val, at 6 and 12 months after treatment initiation. Patients with improvement in left ventricular ejection fraction (LVEF) ≥ 35% and with N-terminal pro-b-type natriuretic peptide (NT pro-BNP) reduction below 1000 pg/mL were considered responders. Results Sixty-six patients (50 males, 16 females) with an age of 64 ± 12 years were finally enrolled, of which 41% were affected by chronic ischemic heart disease. At enrollment, 19 subjects were in New York Heart Association class III-IV, median NT-proBNP was 3063.00 pg/mL and mean LVEF was 30.3±7.7%. LA-EF was 27.8±12.8%, while Left Atrio-ventricular coupling index (LACi) was 0,30±0,12. At ST echocardiography, LV GLS was -8,2±3,0% and LA reservoir strain (LARS) 11,60%. All structural and functional LA parameters significantly improved at T1 and T2: at T2, LARS was 22,51%, LA-EF 37,4±15,8% and LACi 0,28±0,12 (respectively p &amp;lt;0,001, p = 0,05, p = 0,018 compared to baseline). No differences were detected according to dysfunction etiology. Improvements were larger among patients who achieved the pre-specified outcome. LA reservoir strain was the best predictor of positive changes in LVEF and NT-proBNP. Conclusions Precise characterization of LA structural and functional parameters, including ST analysis, may help identifying patients experiencing the highest benefit from Sac/Val, therefore guiding treatment in the HFrEF population.

The role of T1 mapping and Extracellular Volume (ECV) in predicting cardiac reverse remodelling and response to Heart Failure with reduced Ejection Fraction (HFrEF) therapy

Abstract Funding Acknowledgements Type of funding sources: None. Background Adverse cardiac remodelling results from an insult such as myocardial infarction, or as seen in Heart Failure (HF), maladaptive neurohormonal activation. Reverse remodelling describes improvement in cardiac geometry; the left ventricle (LV) recovers more normal structure with improved function and prognosis. Cardiovascular Magnetic Resonance imaging (CMR) allows gold standard assessment of LV volumes and function, diffuse and focal fibrosis and estimation of extracellular volume (ECV) by T1 mapping. Purpose Elevated T1 and ECV values are associated with worse outcome in many cardiac conditions. We conducted the first prospective study to investigate whether T1 mapping and ECV can predict cardiac reverse remodelling in response to treatment, in a cohort of patients hospitalised with a new HF diagnosis. Methods This was a single centre observational study. Inclusion criteria were admission with new HF, LVEF ≤50% or elevated NTproBNP and being treated with intravenous furosemide. Only patients with Heart Failure with reduced Ejection Fraction (HFrEF) and EF &amp;lt;40% on baseline echocardiography were included in this analysis. 36 consecutive eligible participants were included and had both echocardiogram and CMR studies to establish anatomy, function, and myocardial tissue characteristics at baseline. Participants were treated according to international HF guidelines and underwent reviews and repeat echocardiography at 6, 12–18 and 24–30 months. "Responders" to guideline directed HFrEF therapy were defined as those who had an increase in LVEF of ≥10% to a value of ≥40% between their baseline and latest follow-up echocardiogram. Baseline CMR volumes, function, presence of Late Gadolinium Enhancement (LGE), septal and whole heart T1 and ECV values were compared between responder and non-responder groups. Results Median follow-up was 26 months. 27 (75%) participants were responders to therapy. There were no differences in baseline characteristics between groups. There was high uptake of HFrEF medical therapy in both groups. (Table 1) There was no significant difference found between septal or whole heart T1 or ECV values between responder and non-responder groups. There was a trend towards lower whole heart ECV values (29% vs. 35%; p = 0.06) in the responder group but this did not reach statistical significance. (Figure 1) Overall, there was no difference in rates of LGE presence between groups but there was a significantly higher proportion of participants with non-ischaemic LGE pattern in the responder group compared to non-responder group (48% vs 11%; p = 0.05). Conclusions In this cohort of patients hospitalised with a new HFrEF diagnosis, the majority demonstrated reverse remodelling in response to therapy by 26 months. Whole heart ECV (%) as a surrogate marker for fibrosis calculated by whole heart T1 mapping may play a role in understanding which patients are likely to respond to HF therapy but further larger studies are required.

PO-02-240 IMPACTS OF DAPAGLIFLOZIN ON STRUCTURAL REMODELING AND ARRHYTHMOGENICITY IN CARDIORENAL SYNDROME

Chronic kidney disease (CKD) patients revealed cardiac structural and electrical remodeling. The interaction between the heart and kidney leads to cardiorenal syndrome. Dapagliflozin (DAPA) reduces cardiovascular (CV) events in heart failure (HF). However, the efficacy of DAPA on cardiorenal syndrome is questionable. We aimed to investigate the electrophysiology (EP) properties and cardiac reverse remodeling of dapagliflozin in CKD rabbits with HF. Eighteen New Zealand white rabbits were randomized into the sham (n=6), CKD (n=6), CKD-DAPA (n=6) groups. The rabbits in the CKD and CKD-DAPA groups were created by 5/6 nephrectomy method with follow-up echocardiogram to confirm HF. The CKD-DAPA group received oral dapagliflozin 1 mg/kg/day for 4 weeks. All rabbits received an echocardiogram, blood samples, and EP study. Myocardium was harvested for Trichrome stain. The creatinine levels of the CKD and CKD-DAPA levels were significantly higher than those in the sham group (2.31±0.21 vs. 1.32±0.11 mg/dL; 2.29±0.13 vs. 1.32±0.11 mg/dL, both p<0.01), respectively. The CKD and CKD-DAPA rabbits showed a significantly reduced left ventricular ejection fraction when compared to the sham group (47.4±0.81 vs. 53.3±1.47 %; 48.41±1.50, both p<0.01), respectively. Baseline rhythm showed sinus rhythm in all rabbits and no spontaneous arrhythmias were found. The RR interval in the CKD group was significantly longer than those in the sham and CKD-DAPA groups (Figure A). The effective refractory period (ERP) of all cardiac chambers revealed no difference among those in the 3 groups, respectively (Figure B). In the atrial inducibility test, 2 rabbits in the CKD-DAPA group revealed inducible atrial arrhythmia. In the ventricular inducibility test, all rabbits revealed inducible ventricular arrhythmia (VA). The CKD group had a significantly higher VA inducibility than the sham (32.00±10.95 vs. 0.00±0.00 %, p<0.001) and CKD-DAPA (32.00±10.95 vs. 0.00±0.00 %, p<0.001) groups, respectively. The CKD group had a significantly larger area of fibrotic tissue than the sham and CKD-DAPA group (Figure C). The CKD-DAPA group had a significantly larger area of fibrotic tissue than the sham group (Figure C). Figure D demonstrated the collagen deposition (blue) in the myocardium in the 3 groups. Dapagliflozin led to decreased VA inducibility and reversed cardiac structural remodeling in CKD rabbits. Dapagliflozin potentially reduced the risk of arrhythmogenicity in cardiorenal syndrome.

Enhanced Cardiac Reverse Remodeling after Pulmonary Artery Denervation Combined with Mitral and Maze Surgery

Background: The study evaluates the effectiveness of cardiac reverse remodeling in patients after surgical treatment of high pulmonary hypertension (PH) in patients with mitral valve disease and Atrial Fibrillation (AF).

Optimal Heart Rate May Improve Systolic and Diastolic Function in Patients with Fontan Circulation.

(1) Background: The optimal heart rate, at which the E-wave and A-wave stand adjacent without any overlaps in the Doppler transmitral flow echocardiography, is associated with maximum cardiac output and favorable clinical outcomes in adult patients with systolic heart failure. However, the clinical implication of the echocardiographic overlap length in patients with Fontan circulation remains unknown. We investigated the relationship between heart rate (HR) and hemodynamics in Fontan surgery patients with and without beta-blockers. (2) Methods and Results: A total of 26 patients (median age 1.8 years, 13 males) were enrolled. At baseline, the plasma N-terminal pro-B-type natriuretic peptide was 2439 ± 3483 pg/mL, the fraction area change was 33.5 ± 11.4%, the cardiac index was 3.55 ± 0.90 L/min/m2, and the overlap length was 45.2 ± 59.0 msec. Overlap length was importantly decreased after the one-year follow-up (7.60 ± 78.57 msec, p = 0.0069). Positive correlations were noted between the overlap length and A-wave and E/A ratio (p = 0.0021 and p = 0.0046, respectively). Ventricular end-diastolic pressure was significantly correlated with the overlap length in non-beta-blocker patients (p = 0.0483). (3) Conclusion: Overlap length may reflect the status of ventricular dysfunction. Hemodynamic preservation at lower HR could be critical for cardiac reverse remodeling.

The effect of sodium-glucose cotransporter-2 inhibitors on cardiac structure remodeling and function: A meta-analysis of randomized controlled trials

BackgroundIt has been proven that sodium-glucose co-transporter 2 inhibitors (SGLT2is) improve the prognosis of patients with heart failure, independent of the presence of diabetes mellitus. Whether SGLT2 inhibitors affect cardiac structural remodeling and cardiac function is still uncertain. MethodsWe included published randomized controlled trials (RCTs) to compare the effect of SGLT2is and control therapy in patients with or without heart failure. The meta-analysis was performed using Review Manager 5.3 software. ResultsA total of 15 RCTs with a total of 1343 patients were selected for this meta-analysis, 663 of whom were on SGLT2is treatment and 680 of whom were in the control group. SGLT2is significantly improved heart rate (HR) [MD: -2.74, 95% CI (-4.71, -0.77), P = 0.006], left atrium volume index (LAVi) [MD: -1.99, 95% CI (-3.23,-0.75), P = 0.002], E/e’ [MD: -1.47, 95% CI (-1.83,-1.10), P<0.00001], left ventricular mass index (LVMi) [MD: -2.38, 95% CI (-4.35, -0.40), P = 0.02], left ventricular end-systolic volume (LVESV) [MD: -6.50, 95% CI (-11.15,-1.84), P = 0.006], and left ventricular ejection fraction (LVEF) [MD: 1.78, 95% CI (0.56,3.01), P = 0.004] in the total population. Subgroup analysis indicated that compared with other SGLT2is, empagliflozin significantly decreased LVEDV, LVESV,LVMi, LAVi, E/e’, and increased LVEF (P<0.05). In addition, the cardiac anti-remodeling effects of SGLT2 are particularly significant in patients with heart failure. ConclusionOur study showed that SGLT2is, particularly empagliflozin, significantly reverse cardiac remodeling in patients with heart failure. Empagliflozin may be a potentially promising agent to reverse cardiac remodeling in clinical practice.

Cardiac Reverse Remodeling in Ischemic Heart Disease with Novel Therapies for Heart Failure with Reduced Ejection Fraction.

Despite the improvements in the treatment of coronary artery disease (CAD) and acute myocardial infarction (MI) over the past 20 years, ischemic heart disease (IHD) continues to be the most common cause of heart failure (HF). In clinical trials, over 70% of patients diagnosed with HF had IHD as the underlying cause. Furthermore, IHD predicts a worse outcome for patients with HF, leading to a substantial increase in late morbidity, mortality, and healthcare costs. In recent years, new pharmacological therapies have emerged for the treatment of HF, such as sodium-glucose cotransporter-2 inhibitors, angiotensin receptor-neprilysin inhibitors, selective cardiac myosin activators, and oral soluble guanylate cyclase stimulators, demonstrating clear or potential benefits in patients with HF with reduced ejection fraction. Interventional strategies such as cardiac resynchronization therapy, cardiac contractility modulation, or baroreflex activation therapy might provide additional therapeutic benefits by improving symptoms and promoting reverse remodeling. Furthermore, cardiac regenerative therapies such as stem cell transplantation could become a new therapeutic resource in the management of HF. By analyzing the existing data from the literature, this review aims to evaluate the impact of new HF therapies in patients with IHD in order to gain further insight into the best form of therapeutic management for this large proportion of HF patients.

Evaluation of early left-sided cardiac reverse remodeling under combined therapy of sacubitril-valsartan and spironolactone compared with angiotensin-converting enzyme inhibitors and spironolactone.

78 patients (mean age 63.4 years, 20 females) with symptomatic heart failure with reduced ejection fraction were randomized to groups of equal numbers, i.e., 39 patients, and started on therapy of S/V + S or ACEI + S. Second evaluations were made after 6-8 weeks of therapy. GLS changed from -7.4% to -9.4% (18% improvement) in both arms equally. More than 50% of patients, initially with very severe systolic dysfunction (GLS > -8%), were reclassified to severe (GLS -8% to -12%). LVEF did not improve in any of the groups. The quality of life measured by MLHFQ and walking distance by 6-MWT increased. Positive correlations between GLS and 6MWT (r = 0.41, p = 0.02) and GLS and MHFLQ (r = 0.42, p = 0.03) were found. The S/V + S subgroup demonstrated improvements in LVEDV (Δ16.7 vs. 4.5 ml), E/e ratio (Δ 2.8 vs. 1.4), and LAVI (Δ 9.4 vs. 8.4 ml/m2) as compared to ACEI + S. GLS, unlike LVEF, detects early changes in LV systolic function after 6-8 weeks of combined therapy, i.e., SV + S and ACE + S. GLS is more useful than LVEF in assessing early response to treatment. The effect of S/V + S and ACEI + S on LV systolic function was comparable, but the improvement in diastolic function as expressed by E/e', LAVI, and LVEDV was more pronounced with S/V + S.

Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), β-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

Reverse cardiac remodeling in patients undergoing combination therapy of transcatheter mitral valve repair.

For patients with severe mitral valve regurgitation (MR), different kinds of transcatheter mitral valve repair (TMVr) exist, targeting the leaflets, annulus, and chordae. The concomitant combination (COMBO) therapy of TMVrs is rarely used as treatment, and there are very few publications about this therapeutic strategy. We evaluated the effect of COMBO-TMVr on the cardiac left chambers and clinical data, including survival. We included 35 patients at high risk who underwent concomitant sequential transcatheter mitral valve edge-to-edge repair (M-TEER) and another TMVr for severe MR in our hospital between March 2015 and April 2018. Of these, 13 had adequate follow-up transthoracic echocardiography (TTE) up to around 1 year after the procedure. Survival for all patients was 83% at 1 year, 71% at 2 years, and 63% at 3 years, respectively. In the 13 patients with adequate TTE follow-up, M-TEER plus either Cardioband (n = 4), Carillon Mitral Contour System (n = 7), or Neochord (n = 2) were used, respectively. Ten patients had secondary, and three patients primary MR. After 1 year, changes [median (Q1, Q3)] of left ventricular (LV) end-systolic diameter of -9.9 cm (-11.1, 0.4), LV end-diastolic diameter of -3.3 cm (-8.5, 0.0), LV end-systolic volume (LVESV) of -17.4 mL (-32.6, -0.4), LV end-diastolic volume (LVEDV) of -13.5 mL (-15.9, -3.2), LV mass of -19.5 g (-24.2, -7.6), and left atrial volume (LAV) index (LAVi) of -16.4 mL (-23.3, -11.3) were observed. A significant reduction was also seen in the change ratios of LVESV, LVEDV, LV mass, and LAVi, respectively. We found that COMBO therapy of TMVr seems feasible and may support reverse remodeling of left cardiac chambers during 1 year after the procedure in a cohort of patients at high risk.

Reverse Cardiac Remodeling Response and Its Effect on Quality of Life After initiation of Sacubitril/valsartan in Heart Failure with Reduced Ejection Fraction

Objective: To evaluate if switching therapy from an angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) to sacubitril/valsartan induces incremental left ventricular (LV) reverse remodeling and the effect of switching on quality of life (QOL) in heart failure with reduced ejection fraction (HFrEF). Methodology: This prospective multicenter study included 100 patients with HFrEF. The patients were subdivided into two equal groups: Group one included patients who were switched to sacubitril/valsartan and group two included patients continued on ACEIs or ARBs as control group. The patients were subjected to medical history taking, clinical examination, heart failure related data, New York Heart Association (NYHA) functional classification, blood samples and chemistry, transthoracic echocardiography (TTE) and quality of life assessment. Results: There was marked improvement in all two dimensional (2D) echocardiography parameters, as left ventricular end-systolic volume (LVESVI), left ventricular end-diastolic volume index (LVEDVI) and left atrium volume index (LAVI) which significantly reduced after 3 months of therapy with significant improvement in LV function (P-value &lt; 0.05). Moreover, mitral regurgitation (MR) severity significantly decreased (P-value &lt; 0.05). Regarding quality of life, there was a significant improvement in QOL. KCCQ score was significantly improved after 3 months of treatment (P-value &lt; 0.05). Conclusion: In HFrEF patients, sacubitril/valsartan significantly improves LV function; furthermore, it induces incremental LV reverse remodeling as well as improves QOL.

Cardiac reverse remodeling in primary mitral regurgitation: mitral valve replacement vs. mitral valve repair

BackgroundWhen feasible, guidelines recommend mitral valve repair (MVr) over mitral valve replacement (MVR) to treat primary mitral regurgitation (MR), based upon historic outcome studies and transthoracic echocardiography (TTE) reverse remodeling studies. Cardiovascular magnetic resonance (CMR) offers reference standard biventricular assessment with superior MR quantification compared to TTE. Using serial CMR in primary MR patients, we aimed to investigate cardiac reverse remodeling and residual MR post-MVr vs MVR with chordal preservation. Methods83 patients with ≥ moderate-severe MR on TTE were prospectively recruited. 6-min walk tests (6MWT) and CMR imaging including cine imaging, aortic/pulmonary through-plane phase contrast imaging, T1 maps and late-gadolinium-enhanced (LGE) imaging were performed at baseline and 6 months after mitral surgery or watchful waiting (control group). Results72 patients completed follow-up (Controls = 20, MVr = 30 and MVR = 22). Surgical groups demonstrated comparable baseline cardiac indices and co-morbidities. At 6-months, MVr and MVR groups demonstrated comparable improvements in 6MWT distances (+ 57 ± 54 m vs + 64 ± 76 m respectively, p = 1), reduced indexed left ventricular end-diastolic volumes (LVEDVi; − 29 ± 21 ml/m2 vs − 37 ± 22 ml/m2 respectively, p = 0.584) and left atrial volumes (− 23 ± 30 ml/m2 and − 39 ± 26 ml/m2 respectively, p = 0.545). At 6-months, compared with controls, right ventricular ejection fraction was poorer post-MVr (47 ± 6.1% vs 53 ± 8.0% respectively, p = 0.01) compared to post-MVR (50 ± 5.7% vs 53 ± 8.0% respectively, p = 0.698). MVR resulted in lower residual MR-regurgitant fraction (RF) than MVr (12 ± 8.0% vs 21 ± 11% respectively, p = 0.022). Baseline and follow-up indices of diffuse and focal myocardial fibrosis (Native T1 relaxation times, extra-cellular volume and quantified LGE respectively) were comparable between groups. Stepwise multiple linear regression of indexed variables in the surgical groups demonstrated baseline indexed mitral regurgitant volume as the sole multivariate predictor of left ventricular (LV) end-diastolic reverse remodelling, baseline LVEDVi as the most significant independent multivariate predictor of follow-up LVEDVi, baseline indexed LV end-systolic volume as the sole multivariate predictor of follow-up LV ejection fraction and undergoing MVR (vs MVr) as the most significant (p < 0.001) baseline multivariate predictor of lower residual MR. ConclusionIn primary MR, MVR with chordal preservation may offer comparable cardiac reverse remodeling and functional benefits at 6-months when compared to MVr. Larger, multicenter CMR studies are required, which if the findings are confirmed could impact future surgical practice.

Effects of sacubitril/valsartan on cardiac reverse remodeling and cardiac resynchronization in patients with acute myocardial infarction.

In 2014, the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) has shown that sacubitril/valsartan can reduce the risk of hospitalization and death from cardiovascular causes more effectively than enalapril (an ACEI) in heart failure patients with reduced ejection fraction (HFrEF). Similarly, the PARADIGM-HF trial (Comparison of Sacubitril-Valsartan vs. Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode) came to similar conclusions and extended the PARADIGM-HF trial results in 2019. Since then, numerous new studies have provided further insight in HFrEF, sacubitril/valsartan can reduce N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, increase left ventricular ejection fraction (LVEF), reverse ventricular remodeling, and reduce other non-fatal manifestations of clinical deterioration as compared to ACEI/ARB. However, few trials have compared the effects of these drugs in patients shortly after AMI. Therefore, it is necessary to further explore the clinical efficacy and safety of sacubitril/valsartan vs. valsartan in patients with AMI. We conducted an open-label, prospective, randomized controlled trial to determine the superiority in ameliorating ventricular remodeling and preventing of heart failure in patients with AMI after percutaneous coronary intervention (PCI), 148 patients were randomly assigned (85 to sacubitril/valsartan and 63 to valsartan). LAV, LVDV, and LVSV were all decreased in the sacubitril/valsartan group when compared with before treatment, but there was no difference between the sacubitril/valsartan group and the valsartan group. In addition, compared with before treatment in the sacubitril/valsartan group, the heart global work index (GWI) and the global work efficiency (GWE) increased, while the heart global wasted work (GWW) decreased. Patients in the sacubitril/valsartan group have similar MACE and adverse side effects to those in the valsartan group. Sacubitril/valsartan has the same performance as valsartan in inhibiting ventricular remodeling and preventing heart failure after PCI in patients with AMI, and its clinical application is safe. It provides a clinical foundation for the application of sacubitril/valsartan in patients with AMI.