Reduction In Left Ventricular Ejection Fraction Research Articles

Phase 3 Open-Label Study Evaluating the Efficacy and Safety of Mavacamten in Japanese Adults With Obstructive Hypertrophic Cardiomyopathy - The HORIZON-HCM Study.

Mavacamten, a cardiac myosin inhibitor, significantly improved symptoms and cardiac function vs. placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in EXPLORER-HCM. However, the efficacy and safety profiles of mavacamten in Japanese patients are unclear. HORIZON-HCM is a Phase 3 single-arm study in Japanese patients with symptomatic obstructive HCM. The mavacamten starting dose was 2.5 mg; individualized dose titration occurred in Weeks 6-20 based on Valsalva left ventricular outflow tract (LVOT) gradient and resting left ventricular ejection fraction (LVEF). Overall, 38 patients were treated; 36 completed the 30-week primary treatment analysis period. Clinically significant improvements in postexercise LVOT gradient were observed after 30 weeks of treatment (mean change from baseline -60.7 mmHg). Improvements in N-terminal pro B-type natriuretic peptide, New York Heart Association class, and Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score were observed over 30 weeks, and mean LVEF was ≥74% at all visits. Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 63.2% and 7.9% of patients, respectively; none resulted in treatment discontinuation. One patient experienced a transient asymptomatic reduction in LVEF to <50%. No deaths occurred during the study. In Japanese patients with obstructive HCM, mavacamten was associated with similar improvements in LVOT gradients, cardiac biomarkers, and symptoms to those observed in EXPLORER-HCM. Treatment was well tolerated with no new safety concerns.

Evaluation of early cardiotoxicity in HER2-positive breast cancer patients receiving radiotherapy and concurrent trastuzumab.

Overexpression of human epidermal growth factor receptor 2 (HER-2) is associated with aggressive disease in breast cancer. Trastuzumab and radiotherapy are standard treatments for patients with HER-2 + breast cancer, but they may increase the risk of cardiotoxicity. This study aimed to assess early cardiotoxicity in patients receiving radiotherapy (RT) and concurrent trastuzumab. The study included 116 patients with HER-2 + breast cancer who received concurrent treatment with trastuzumab and RT (52 right-side; 64 left-side). Five left ventricular ejection fraction (LVEF) measurements were performed: one before treatment and four subsequent measurements taken at three-month intervals. LVEF was also assessed before (preRT-EF) and after (postRT-EF) radiotherapy. The baseline LVEF was 62.27 ± 5.5%, while the 12-month LVEF was 59.8 ± 5.8% (p < 0.05). In subgroups, post-RT LVEF values ​​were significantly lower than pre-RT LVEF values (p < 0.05). No significant difference was found between the reduction in LVEF for patients receiving 50Gy and 60Gy doses. Moreover, the contribution of regional lymph node irradiation to the decrease in LVEF could not be demonstrated. A positive correlation was found between the total trastuzumab dose and the decrease in LVEF from preRT to postRT. Additionally, a positive correlation was observed between the total taxane dose and the reduction in LVEF from baseline to 9months, both in the overall group and in the left breast cancer group. In our study,it was found that not only trastuzumab but also taxane-based agents could be cardiotoxic. However, no connection was found between RT doses and the decrease in LVEF.

Nutrition Modulation of Cardiotoxicity in Breast Cancer: A Scoping Review

Background/Objectives: Advancements in breast cancer therapeutics, such as anthracyclines, are improving cancer survival rates but can have side effects that limit their use. Cardiotoxicity, defined as damage to the heart caused by cancer therapeutics, is characterised by a significant reduction in left ventricular ejection fraction (LVEF) and symptoms of cardiac dysfunction. Multiple oral supplements exist with antioxidant and anti-inflammatory properties that have the potential to lower cardiotoxicity risk and ameliorate the complications associated with left ventricular dysfunction. In this review, we evaluate the current status of using nutritional interventions to modulate cardiotoxicity. Methods: We used specific keywords to search for articles that met our predetermined inclusion and exclusion criteria to review the evidence and provide insights for future research. Results: Seven studies were identified as eligible for this review: six focused on oral supplementation strategies in breast cancer patients undergoing chemotherapy, and one focused on nutritional counselling and adherence to the Mediterranean diet in breast cancer survivors’ post-treatment. There was a significantly attenuated reduction in LVEF in five studies that monitored cardiometabolic health, and there were significant improvements in blood serum levels of cardiac biomarkers across all studies. Conclusions: Current evidence suggests that appropriate nutritional interventions, alongside chemotherapy, can modulate the risk of cardiotoxic side effects. This highlights the potential of oral antioxidant supplementation and Mediterranean diet counselling to decrease tertiary cancer therapy costs associated with cardiovascular complications.

Serial changes in left and right ventricular global longitudinal strain in symptomatic obstructive hypertrophic cardiomyopathy treated with mavacamten: insights from VALOR-HCM trial

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, reduces the need for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients and symptoms. As a cardiac myosin inhibitor, mavacamten’s mechanism of action reduces myocardial hypercontractility. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function and can complement left ventricular ejection fraction (LVEF). Objective We sought to assess serial changes in LV and right ventricular (RV)-GLS in patients enrolled in the VALOR-HCM study. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean 60 years, 51% male, LVEF 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). LV and RV-GLS assessment was performed according to the current American and European guideline recommendations using a vendor-neutral post processing software. Non-foreshortened apical (4, 3 and 2-chamber) views were used to obtain peak value of LV-GLS. For RV-GLS, RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. Results Serial changes in LVEF, average LV-GLS, and RV-GLS (4-chamber and free wall) from baseline to week 56 are shown in the Figure. Despite preserved LVEF at baseline, average baseline LV-GLS was abnormal. There were significant and continued improvements in LV-GLS in the total group from baseline to week 56. 12 patients had transient reduction in LVEF (&amp;lt;50%) requiring temporary drug interruption (permanent discontinuation in 3). The LV-GLS in this subgroup was worse at baseline compared to the total study population, with no significant worsening from baseline through week 56. In the overall population, excluding these 12 patients, LV-GLS demonstrated an improvement sustained through week 56. Both free wall and 4-chamber RV-GLS were abnormal at baseline and remained unchanged from baseline to week 56. Conclusions In the VALOR-HCM trial, despite hypercontractile LVEF at baseline, average baseline LV-GLS was worse than normal reference values. Treatment with mavacamten resulted in an improvement in LV-GLS from baseline through Week 56 (with no significant worsening of LV-GLS in the subgroup who experienced any reduction in LVEF &amp;lt;50%), suggesting a favorable long-term impact on regional LV systolic function due to the reduction of cardiac hypercontractility. Additionally, there was no significant detrimental impact on RV systolic function on serial GLS assessment.Serial changes in LV and RV GLS in VALOR

Long-term safety and efficacy of mavacamten in obstructive hypertrophic cardiomyopathy: up to 3.5-year follow-up results of the EXPLORER cohort of MAVA-Long-Term Extension study

Abstract Introduction Mavacamten safety and efficacy in patients with obstructive hypertrophic cardiomyopathy (HCM) was demonstrated in the phase 3 EXPLORER-HCM trial. Long-term safety and efficacy of mavacamten in patients with obstructive HCM is being studied in the MAVA-Long-Term Extension (LTE) study (NCT03723655). Purpose To present long-term safety and efficacy data from the EXPLORER cohort of MAVA-LTE up to week 180 (data cutoff: August 31, 2023). Methods Patients who completed EXPLORER-HCM could enroll in MAVA-LTE following washout. All patients received mavacamten 5 mg at baseline; dose titration to 2.5, 10, or 15 mg was based on site-read echocardiographic evaluation of Valsalva left ventricular outflow tract (LVOT) gradient and left ventricular ejection fraction (LVEF). Following titration, patients were assessed at 12-week intervals between weeks 24 to 156; week 180 was the first visit following a 24-week interval. Results At the data cutoff, 211 of 231 patients who enrolled in MAVA-LTE were on treatment; 185 and 99 patients had reached week 156 and 180, respectively (median [interquartile range (IQR)] time on study: 166 [160–189] weeks; total exposure: 739 patient-years). Sustained improvements from baseline to weeks 156 and 180 were observed in mean (standard deviation [SD]) resting LVOT gradient (−40.2 [32.8] mmHg, n=187; and −40.3 [32.7] mmHg, n=94; respectively), Valsalva LVOT gradient (−55.3 [37.3] mmHg, n=184; and −55.3 [33.7] mmHg, n=91) (Figure 1), and median (IQR) N-terminal pro B-type natriuretic peptide levels (−504 [−1160, −143] ng/L, n=179; and −562 [−1162.5, −209] ng/L, n=88). Improvements from baseline to weeks 144 and 180 were sustained in mean (SD) left atrial volume index (−3.5 [10.4] mL/m2, n=193; and −5.5 [9.7] mL/m2, n=62; respectively). At week 156 and 180, 53.5% and 66.3% of patients, respectively, were in New York Heart Association class I. Mean (SD) LVEF decreased from baseline to week 180 (−11.0% [8.9%]; n=93) but the mean (63.9%) remained within normal range. Overall, 33 patients (14.3%) experienced atrial fibrillation, 14 patients (6.1%) experienced cardiac failure episodes, 13 patients (5.6%) permanently discontinued treatment owing to adverse events and 20 patients (8.7%) experienced transient reductions in LVEF &amp;lt; 50% (range: 30–48%), of whom 6 (2.6%) experienced LVEF &amp;lt; 40% (Figure 2). Of these 20 patients (13 from the placebo group in EXPLORER-HCM), all recovered LVEF ≥ 50% following treatment interruption and 14 reinitiated medication. In total, 5 patients died during the study (all deaths unrelated to mavacamten). Conclusions Long-term mavacamten treatment in patients with obstructive HCM resulted in sustained improvements in echocardiographic measures, symptoms, and biomarkers. Treatment was well-tolerated; no new safety signals were observed. Transient and reversible reductions in LVEF were observed in a small proportion of patients during long-term therapy.

Long term outcomes of patients with decompensated aortic stenosis undergoing urgent transcatheter aortic valve implantation: a TAVI-NOR subs-study

Abstract Background Aortic stenosis (AS) is a progressive disease, which untreated leads to irreversible myocardial damage and potentially death. Patients with AS may present with acute decompensation (ADAS) even during active surveillance. Purpose In this TAVI-NOR sub-study, we investigate the clinical profile, risk factors, epidemiology and long-term outcomes of patients treated with TAVI after presenting with ADAS compared to stable patients who underwent elective TAVI (no ADAS). Method A total of 600 patients with severe AS consecutively treated with TAVI between January 2012 and July 2019 were enrolled in TAVI-NOR study. Predictors and long-term clinical outcomes were explored in binary logistic and Cox regression models. Results A total of 68 patients (11.3%) received urgent TAVI due to acute hospitalization with ADAS. Age (80±8.0 years vs 81±6.0 years, p=0.662), gender (56% males vs 50% males, p=0.361) and other comorbidities at baseline such as cardiovascular disease, chronic lung disease and atrial fibrillation (AF) were comparable in patients with ADAS and no ADAS (n=532) (p&amp;gt;0.05 for all). However, patients with ADAS had greater symptom burden (NYHA III-IV 81% vs 51%, p&amp;lt;0.001), lower blood pressure, higher heart rate and lower estimated glomeruli filtration rate (52.0±10.8 vs 54.6±9.8 mL/min/1.73m2, p&amp;lt;0.045). They had also higher prevalence of ECG left ventricular (LV) hypertrophy (40% vs 27%, p=0.027), more often reduced LV ejection fraction (&amp;lt;50%) (41% vs 16%, p&amp;lt;0.001), lower stroke volume (39±11 ml/m2 vs 42±11 ml/m2 vs, p=0.030) a trend of abnormal ECG (p=0.055) and longer hospital stay (11.5 ±8.7 days 6.6± 4.9 days, p&amp;lt;0.001). Patients with ADAS were comparable with no ADAS in terms of early short-term (&amp;lt;30 days) all-cause mortality (p&amp;gt;0.05). Although 1-year mortality was comparable (1.5% in ADAS vs 2.1% in no ADAS, p&amp;gt;0.99), mid- to late-term mortality rates were significantly higher in patient with ADAS receiving urgent TAVI, with 3-, 5- and 7 years mortality of 22% vs 11%, p=0.008; 46% vs 29%, p=0.005; 53% vs 39%, p=0.033, respectively. In a Kaplan-Meier analysis, event-free survival was significantly reduced for patients with ADAS undergoing urgent TAVI compared with stable patients undergoing elective TAVI HR 1.63, 95% CI 1.15-2.31, p=0.006), confirmed by a multivariable-adjusted model (HR 1.54; 95% CI 1.05-2.25, p=0.026) independent of age, gender, AF, LV ejection fraction and time from diagnosis to TAVI (Fig). Conclusion Patients with AS presenting with acute decompensation and treated with urgent TAVI had excellent short-term survival. This was irrespective of increased symptom burden, adversely remodeled and functionally reduced LV at baseline. These findings might explain the observed higher mid- and long-term mortality compared with stable patients undergoing elective TAVI. It is essential to identify patients at risk of acute decompensation and treat them timely before irreversible myocardial damage occur.

Sex-specific association of NT-proBNP with clinically inapparent structural heart disease in the general population: results from the STAAB study

Abstract Background Guidelines recommend echocardiography in subjects beyond defined levels of natriuretic peptides. The ACC/AHA guidelines on heart failure (HF) state echocardiographic signs of structural heart disease (SHD) that define the precursor stage B of heart failure. Purpose To study the age- and sex-specific association between echocardiographically assessed structural heart disease (echoSHD) and NT-proBNP levels in the general population. Methods The STAAB study investigates precursor stages of HF in the general population of a medium-sized city in Germany (source population 124,297 inhabitants as of 2011 census). Study participants were recruited between 12/2013 and 10/2017 from the source population without preceding HF diagnosis, stratified for sex and age (30-79 years). For this analysis, we excluded participants with previously diagnosed coronary artery disease. EchoSHD was accepted if one of the following criteria, diagnosed according to current echo guidelines, was detectable at echocardiography: left ventricular (LV) hypertrophy, LV dilation, reduced LV ejection fraction, moderate-to-severe LV valve disease, and LV diastolic dysfunction. Results Of 4,649 subjects analysed (93.6% of STAAB participants, age 30-79 years, 53.5% women), 863 (18.6%) had echoSHD. NT-proBNP depended strongly on age and sex (figure). Frequencies of echoSHD varied between women (23.0%) and men (13.5%; P&amp;lt;0.001). EchoSHD was associated with increased NT-proBNP levels in both women (geometric mean ratio 1.18, 95%CI 1.09–1.27, P&amp;lt;0.001; figure) and men (ratio 1.62, 1.46–1.79, P&amp;lt;0.001); P&amp;lt;0.001 for different ratios in both sexes. Of note, age did not influence these ratios as well as their difference (P=0.34 and P=0.95, resp.). Conclusion Clinically inapparent echoSHD was associated with higher levels of NT-proBNP, of a magnitude that was relevant in men. The sex difference in the strength of this relationship might be due to different pathophysiological processes leading to SHD and ultimately HF in women and men. It might also indicate the need for adopted definitions of echoSHD in women. Our results further point towards the need of age- and sex-specific NT-proBNP thresholds.NTproBNP according to sex, age, and SHD

Five-year outcomes with self-expanding versus balloon-expandable transcatheter aortic valve replacement in patients with left ventricular systolic dysfunction

Abstract Background The importance of transcatheter heart valve (THV) design on clinical outcome in patients with aortic stenosis (AS) and left ventricular (LV) systolic dysfunction remains unknown. Objectives We aimed to compare 5-year outcomes of patients with severe AS and reduced LV ejection fraction (LVEF), undergoing transcatheter aortic valve replacement (TAVR) with balloon-expandable vs. self-expanding THVs. Methods In an institutional TAVR registry, patients with LVEF &amp;lt;50% who underwent TAVR with either balloon-expandable or self-expanding THVs were included. A 1:1 propensity-score matching was performed to account for baseline differences between groups. Results A total of 759 patients were included between August 2007 and December 2022, and propensity-score matching resulted in 134 pairs. Technical success was achieved in over 85% of patients, and was similar in both groups. Self-expanding THVs were associated with a lower mean transvalvular gradient (7.1 ± 3.7 mmHg vs. 9.9 ± 4.3 mmHg; P &amp;lt;0.001) and a higher incidence of ³mild-to-moderate paravalvular regurgitation (36.3% vs. 11.3%; P &amp;lt;0.001) compared to balloon-expandable THVs. At 5 years, patients treated with a self-expanding THV had higher all-cause mortality than those with a balloon-expandable THV (67.8% vs. 55.8%, Adjusted Hazard Ratio: 1.44; 95% CI: 1.02-2.03; P = 0.037). There were no significant differences in other clinical outcomes up to 5 years between groups. Conclusions In the setting of LV systolic dysfunction, patients treated with a self-expanding THV had higher risk of 5-year mortality compared to patients treated with a balloon-expandable THV.

Longitudinal changes in the prevalence of indicators for the precursor stage B of heart failure: results of the STAAB study

Abstract Background The ACC/AHA guidelines on heart failure (HF) use selected echocardiographic signs of structural heart disease (SHD) as well as NT-proBNP levels to define the precursor stage B of heart failure in asymptomatic individuals. Purpose To study the change in prevalence over time of echocardiographic signs of SHD or elevated NT-proBNP levels in clinically inapparent individuals of the general population. Methods The STAAB study investigates precursor stages of HF in the general population of a medium-sized city in Germany (source population 124,297 inhabitants as of 2011 census). Participants, stratified for sex and age (30-79 years), were recruited between 12/2013 and 10/2017 from the source population if they had no preceding HF diagnosis and were followed for 2-4 years. Echocardiographic signs of SHD were (for exact definitions see table): left ventricular (LV) hypertrophy, LV dilation, reduced LV ejection fraction. Subjects with history of myocardial infarction, significant LV valve disease or symptomatic HF (Framingham criteria) were excluded. Results Of 4,965 subjects included at baseline, 3,684 (74.2%; mean age 55.2 years, 52.7% women) with at least one paired measurement were analysed. The changes observed over time in the prevalence of echocardiographic signs of SHD and elevated NT-proBNP levels are displayed in the table. Prevalences of echocardiographic signs of SHD increased (significantly for LVEF and LV dilation, trend for LV hypertrophy). Addition of NT-proBNP increased the cross-sectional prevalences, but not the change in prevalence of potential HF precursor stages. Conclusion The net incidence of clinically inapparent echocardiographic signs of SHD increased over time at a rate consistent with the prevalence observed for clinically apparent HF in the general population. Of note, not all echocardiographic findings will eventually result in symptomatic HF, and the classification is influenced by measurement errors. However, our data support the concept of HF precursor stages.

Genotype predicts heart failure independent of left ventricular ejection fraction and NT-proBNP levels in hypertrophic cardiomyopathy

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is a myocardial disease associated with progression to heart failure. In around 40% of cases, the disease is caused by variants in genes encoding sarcomere proteins. Purpose To evaluate the role of genotype in predicting heart failure (HF) outcomes. Methods In this observational single-centre cohort study, consecutive patients with HCM were assessed for heart failure clinically stratified by genetic status into genotype-elusive which included those with no significant variants (G-) or variants of unknown significance (VUS) and genotype-positive (G+) with pathogenic/likely pathogenic (LP/P) variants. Heart failure endpoint was defined as left ventricular assist device implantation, heart transplantation or heart-failure-related death. The incidence of HF endpoint was compared between genotypes during follow-up using a time-to-event analysis. Results 474 patients (50.9 ±14.5 years, 67.3 males) with HCM (25% with left ventricular (LV) outflow obstruction) were followed for 10.9 years (IQR 5.1-13.5). G+ LP/P patients (201/474 (42.4%)) were younger (45.8. ±14.0 years) compared to G- (225/474 (47.5%), 55.2 ±13.4 years) and VUS (48/474 (10.1%), 52.0 ± 15 years); 29/474 (6.1%) reached the heart failure endpoint. The incidence of heart failure endpoints was 12.4% (25/201) in the G+ LP/P group compared to 1.5% (4/273) in the gene elusive group. A multivariate Cox proportional hazards model including NT-proBNP and LV ejection fraction (LVEF) and genetic status showed that G+ LP/P was associated with increased risk of heart failure outcomes (HR: 5.11, 95% CI: 1.43–18.25, p=0.012). Every 100-unit rise in NT-proBNP was associated with a 41% increase in risk (HR: 1.41, 95% CI: 1.20–1.66, p&amp;lt;0.0001). A one-unit (1%) reduction in LVEF correlated with a 10% increase in heart failure risk (HR: -0.90, 95% CI: 0.87–0.93, p&amp;lt;0.0001). Conclusion(s) Genetic status is a predictor of heart failure outcomes independent of LVEF and NT-proBNP levels in HCM. This underscores the importance of genetic testing in the clinical management of HCM.

Takotsubo Cardiomyopathy After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for a Recurrent Colon Cancer: A Life-Threatening Complication

(1) Background: Takotsubo cardiomyopathy, or stress cardiomyopathy, is an acute heart failure condition with transient left ventricular (LV) motion abnormalities but no significant coronary artery obstruction. It mimics acute coronary syndrome (ACS), with symptoms like chest pain, dyspnea, and ECG changes. (2) Case Report: We present the case of a 44-year-old female with relapsed colon cancer and peritoneal carcinomatosis. After undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), she experienced cardiac arrest from ventricular fibrillation 18 h postoperatively. Echocardiography revealed a reduced LV ejection fraction (20%) and apical akinesia, suggesting a Takotsubo Cardiomyopathy. Intensive resuscitation and inotropic support led to gradual recovery. Coronary angiography confirmed no coronary artery obstruction. (3) Discussion: This case highlights TTS as a rare but severe complication following major oncological surgeries, possibly triggered by both physical and emotional stressors. TTS should be considered in the differential diagnosis of perioperative cardiac events in cancer patients. (4) Conclusions: Prompt recognition and management of TTS in the perioperative period are crucial to improving outcomes, especially in high-risk oncological patients undergoing extensive surgeries.

Mortality related to left ventricular ejection fraction and obstructive coronary artery disease in non-ST-segment elevation myocardial infarction

Abstract Background Extent of coronary artery disease (CAD) and the severity of reduced left ventricular ejection fraction (LVEF) have both been associated with the prognosis after non-ST-segment elevation myocardial infarction (NSTEMI). However, the contemporary mortality associated with the extent of obstructive CAD over a range of LVEF remains uncertain. Purpose The aim of this study was to assess the impact of CAD and LVEF on all-cause death following a first-time NSTEMI. Methods We included consecutive first-time NSTEMI patients undergoing coronary angiography from 2010 to 2021 in Western Denmark. Patients were stratified by extent of obstructive vessel disease (VD; 1, 2, or 3VD) and LVEF (≥51%, 41-50%, or 10-40%). Patients with previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting were excluded. The primary outcome was all-cause death. We calculated 5-year cumulative incidence proportions (CIP) as a measure of absolute risk and adjusted hazard ratios (HR). Results A total of 8,770 patients with first-time NSTEMI and obstructive CAD were examined with coronary angiography. Two-thirds were male and median age was 68 years (Q1-Q3: 58-78). The increase in mortality associated with decreasing LVEF was greater than observed by extent of CAD (Table). Thus, the 5-year mortality increased stepwise by extent of CAD from 14% for 1VD to 31% for 3VD (adjusted HR 1.35, 95% CI:1.19-1.54), but from 12% for LVEF ≥51% to 40% for LVEF 10-40% (adjusted HR 2.32, 95% CI: 2.04-2.65). When combining LVEF and extent of CAD, an increase in 5-year mortality was found from 9% for 1VD and LVEF ≥51% to 46% for 3VD and LVEF 10-40% (risk difference of 37.1%; Figure). Correspondingly, using 1VD and LVEF ≥51% as reference, the adjusted HRs increased gradually with extent of CAD and decline in LVEF to 3.05 (95% CI: 2.51-3.70) for patients with 3VD and LVEF 10-40% (Table). Conclusion In a contemporary all-comers cohort of first-time NSTEMI patients, increasing extent of CAD and declining LVEF are both associated with a gradual increase in 5-year mortality. Our data suggest that the level of LVEF reduction was more strongly associated with 5-year mortality than CAD extent.

Effects of empagliflozin on cardio-renal interaction in heart failure with reduced ejection fraction: results from in-vivo experiments and the CINNAMON-study

Abstract Background Heart failure is often accompanied by renal dysfunction, which indicates a pathophysiological connection between the heart and kidneys. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. Mechanistically, however, it is unclear whether the empagliflozin-dependent renal protection is mediated via the inhibition of renal SGLT2 or rather indirectly via improved cardiac function. Interestingly, in the EMPEROR trials, there was a significant interaction of empagliflozin-dependent kidney protection with systolic contractile dysfunction. We hypothesized that Empagliflozin treatment ameliorates heart failure in response to chronic pressure overload in mice leading to improved renal function. We correlated these findings with data from our prospective, single-armed trial. Methods Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-/-). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Cardiac function was evaluated by echocardiography and kidney function by transdermal FITC-Sinistrin measurement (GFR), urinary albumin/creatinine ratio (UACR) and Siriusred fibrosis staining. Results After 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced left ventricular ejection fraction (LVEF) and diastolic dysfunction. Empagliflozin attenuated changes in LVEF (Fig. A) and improved diastolic dysfunction (data not shown). Interestingly, at 10 weeks, TAC reduced GFR, increased UACR and tended to increase renal fibrosis, which was attenuated by empagliflozin (Fig. B, C and D). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-/-). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-/- mice and Empagliflozin prevented this deterioration similar to WT mice (Fig. E vs. A). Surprisingly, Empagliflozin also prevented GFR deterioration 10 weeks after TAC in mice lacking SGLT2 (SGLT2-/-) with comparable magnitude as in WT mice (Fig. F), suggesting that the reno-protective effect of Empagliflozin was independent from renal SGLT2 inhibition. The effect of empagliflozin on the heart and kidney was also investigated in patients with HF (prospective, single-arm CINNAMON-study, DRKS00031101). After 180 days of Empagliflozin treatment (10 mg), there was a significant improvement in LVEF, NT-proBNP levels and KCCQ-12 Scores (Fig. G-I) and the effects on UACR and GFR are subject of investigation. Conclusion This is the first study investigating the role of SGLT2 in Empagliflozin-dependent kidney protection of mice that develop heart failure after TAC. Importantly, empagliflozin treatment prevented deterioration of LVEF and GFR independent of the presence of SGLT2 in mice and improved cardiac markers and quality of life in patients.

Effect of Vericiguat on Left Ventricular Reverse Remodeling in Patients Who Have Heart Failure With Reduced Ejection Fraction - Special Focus on Patients Without Quadruple Medical Therapy.

A novel cardioprotective drug, vericiguat, reduces the risk of cardiovascular mortality for patients already on guideline-directed medical therapy. However, the effect of vericiguat on left ventricular (LV) reverse remodeling in patients with reduced LV ejection fraction (LVEF) with or without guideline-directed medical therapy, known as quadruple medical therapy, remains undetermined. This study comprised 73 heart failure (HF) patients with reduced LVEF (<45%) from 5 institutions in Japan. Echocardiography was performed before and 6.1±3.9 months after administration of vericiguat. LV reverse remodeling was observed in all patients (LV end-diastolic volume 156.1±52.6 vs. 139.3±60.0 mL; P<0.001; LV end-systolic volume 108.1±41.2 vs. 91.8±51.2 mL; P<0.001; LVEF 31.8±7.4 vs. 37.6±12.3 %; P<0.001). LV reverse remodeling was also observed in 54 patients who could not undergo quadruple medical therapy for several reasons. Moreover, the incidence of cardiovascular events was also similar for patients who received or did not receive quadruple medical therapy (log-rank P=0.555). Significant LV reverse remodeling was observed in HF patients with reduced LVEF following administration of vericiguat. LV reverse remodeling was also observed in patients who could not receive quadruple medical therapy, thus making administration of vericiguat a potential new approach for treatment of these patients.

Takotsubo cardiomyopathy following liver transplantation: A multicenter cohort study.

Takotsubo cardiomyopathy (TCM) is an acute, stress-mediated, reversible cardiomyopathy that occurs in the absence of hemodynamically significant coronary artery disease. We aimed to investigate the characteristics and outcomes of patients who developed TCM following liver transplantation (LT) in a multicenter study. Adult patients from 6 centers across the United States who developed TCM according to Mayo Clinic criteria following LT between 2008 and 2023 were included. Demographics, perioperative and long-term outcomes, and treatment modalities were assessed. Fifty-five patients were included. The center incidence of TCM ranged from 0.1% to 0.5%. The majority were female (54.5%) and Caucasian (87.2%), and the median age at transplant was 59 years. The primary etiologies for LT were alcohol-associated cirrhosis (49.1%) and metabolic dysfunction-associated steatotic liver disease cirrhosis (21.8%). The median time from LT to TCM diagnosis was 4 days. TCM was associated with a 60.9% reduction in left ventricular ejection fraction (LVEF) from a pretransplant median LVEF of 64.0%-25.0%. The most common treatment for TCM was diuretics (67.3%) and afterload reduction (54.5%), with only 27.3% of patients requiring vasopressor support. At a median follow-up of 31.5 months, 1-year and 3-year overall survivals (OSs) were 86.3% and 69.4%, respectively. A repeat echocardiogram performed at a median of 84 days demonstrated that 45/55 patients (81.8%) had recovered LVEF ≥50%. Patients with LVEF recovery to ≥50% had significantly improved OS compared to those without LVEF recovery >50% (106.4 vs. 12.2mo, p = 0.001). TCM following LT is associated with a significant reduction in LVEF; however, the majority of patients recover LVEF to >50% with minimal perioperative mortality. Importantly, follow-up assessment of LVEF has significant implications as lack of recovery is associated with worse OS.

Alteration of cardiac structure and function and its prognostic value in patients with Takayasu arteritis: a cardiac magnetic resonance study.

To investigate the prevalence and characteristics of late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) and its prognostic value in patients with Takayasu arteritis (TA). Sixty TA patients with a CMR examination were retrospectively included. All TA patients were divided into with LGE-positive and LGE-negative groups. Bi-ventricular function and location, distribution, and pattern of left ventricular (LV) LGE were evaluated in both LGE-positive and LGE-negative groups. Primary outcome was defined as a composite of cardiovascular death, hospitalization for heart failure, coronary artery revascularization, and stroke. Univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the association between variables and primary outcomes. Sixty consecutive TA patients were enrolled in this study. The mean age was 38.2 ± 13.8 years and 54 patients (54/60, 90.0%) were female. LGE-positive was observed in twenty-one (21/60, 35%) patients in the total patients with TA. LGE was predominantly distributed in the middle wall and subendocardial. The patchy and infarcted LGE patterns were the most common. Compared with the LGE-negative group, the LGE-positive group had reduced LV ejection fraction (P = 0.033), elevated LV end-diastolic volume index (P = 0.008), LV end-systolic volume index (P = 0.012), and LV mass (P = 0.008). During a median follow-up period of 1,892 days (interquartile range: 1,764-1,988 days), the primary outcomes occurred in thirteen patients. In the univariate analysis, LGE-positive (hazard ratio [HR] = 4.478, 95% confidence interval [CI]: 1.376-14.570; P = 0.013) were independently associated with the primary outcomes. However, LGE-positive did not retain its value as an independent predictor of primary outcomes in the multivariate analysis. Instead, LVMI (HR = 1.030, 95%CI: 1.013-1.048; P = 0.001) was the strongest independent predictor of primary outcomes in patients with TA. The Kaplan-Meier plot revealed that patients with LVMI ≥ 57.5 g/m2 have a worse prognosis. LGE-positive detected by CMR was observed in 35% of total TA patients with different distributions and patterns. LGE is associated with adverse LV remodeling and worsen cardiac function. However, LVMI rather than LGE can provide independent prognostic information in patients with TA.

Meta-analysis of cardiac magnetic resonance in prognosticating left ventricular function in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) may result in a number of detrimental adverse cardiovascular events, notably persistent left ventricular ejection fraction (LVEF) reduction or even mortality. Imaging parameters on cardiac magnetic resonance (CMR) and their prognostic implications have rarely been perused in PPCM. We aimed to describe CMR's prognostic value in predicting poor left ventricular (LV) function recovery using late gadolinium enhancement (LGE) and T2-weighted or T2 mapping. PubMed, Europe PMC, and ScienceDirect were screened for studies on late gadolinium enhancement (LGE) and myocardial oedema using CMR and PPCM. The outcome of interest was poor LV function recovery, with a follow-up period of at least 6months. Comparisons between groups with the presence of LGE, myocardial oedema, and recovered against non-recovered patients were pooled. A random-effects model was employed to calculate the effect size. All pooled results were expressed as risk ratios (RRs) and 95% confidence intervals (CI). The area under the curve (AUC) was generated to test overall prognostic accuracy. Six cohort studies with 162 patients were included. The mean age of participants in this study was 30.6years, and the majority of patients were diagnosed with PPCM after delivery. LGE was associated with a higher risk of poor LV function recovery, particularly when conducted at a later stage of disease (≥2.8months) [RR=2.83 (95% CI=1.25-6.40); P=0.001]. On the contrary, CMR conducted early (<2.8months) exhibited a greater predictive value for myocardial oedema perceived by T2 mapping [RR=3.44 (95% CI=1.04-11.34); P=0.043]. Diagnostic-test accuracy meta-analysis revealed that LGE had a sensitivity of 73% (95% CI, 56-85%), specificity of 79% (95% CI, 45-95%), and AUC of 0.78 (95% CI, 0.75-0.82) in predicting poor LV recovery when performed in the later phase, whereas significant myocardial oedema in those with non-recovered LV function had a sensitivity of 12% (95% CI, 2-52%), specificity of 68% (95% CI, 39-88%), and AUC of 0.40 (95% CI, 0.36-0.44) while undertaken in the latter phase. Our findings support the notion that inflammation plays a significant role in PPCM and that alterations to tissue composition occur in a time-dependent manner. Contrast-enhanced CMR can be utilized as an adjunct examination in post-partum PPCM patients to stratify the risk of poor LV function recovery while conducted at a suitable point in time.

Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.

Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. At the latest data cut-off, 211 (91.3%) of 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the week 156 and 180 visits, respectively. Sustained reductions from baseline to week 180 occurred in left ventricular outflow tract gradients (mean [standard deviation]: resting, -40.3 [32.7] mmHg; Valsalva, -55.3 [33.7] mmHg), NT-proBNP (median [interquartile range]: -562 [-1162.5, -209] ng/L), and EQ-5D-5L score (mean [standard deviation]: 0.09 [0.17]). Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (week 24) and 63.9% (week 180). At week 180, 74 (77.9%) of 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.

Serial Changes in Ventricular Strain in Symptomatic Obstructive Hypertrophic Cardiomyopathy Treated With Mavacamten: Insights From the VALOR-HCM Trial.

In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were -14.7%, -22.2%, and -16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 (P=0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (-11.4%), with no significant worsening from baseline through week 56 (P=0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 (P=0.62 and P=0.56, respectively). In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04349072.

Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: A 36-week analysis from FOREST-HCM.

The aim of this study was to report safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST-HCM trial. Patients were started on aficamten 5 mg daily, with doses adjusted in 5-mg increments (5-20 mg) at ≥2-week intervals according to site-read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50-54%, decreased if LVEF 40-<50%, and temporarily interrupted if LVEF <40%. Safety and efficacy were assessed over 36 weeks. Overall, 34 patients were enrolled (mean age 57.2 ± 15.3 years, 62% female, 41% in New York Heart Association [NYHA] class III). Over 36 weeks, 82.3% achieved 15-20 mg daily dose and there was a modest reduction in LVEF by -4.3% ± 5.2 from 70% ± 6.1 (p < 0.0001). At Week 36, NYHA class improved by ≥1 class in 27 (79.4%) patients. Mean Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 13.8 ± 12.5 points relative to baseline. Median (interquartile range) levels of N-terminal pro-B-type natriuretic peptide were significantly improved from baseline (-665.5 pg/ml [-1244.0, -232.0]; p < 0.0001), while high-sensitivity cardiac troponin I was unchanged (-2.7 ng/L [-11.3, 1.6]; p = 0.25). There were no drug discontinuations due to adverse events. LVEF <50% occurred in 2 (5.9%) patients, one following pulmonary vein isolation and one associated with atrial fibrillation. Over 36 weeks, aficamten appeared safe and effective in the studied patients with nHCM.