Tracking Treatment Response in Cardiac Light-Chain Amyloidosis With Native T1 Mapping.

Importance: Cardiac magnetic resonance (CMR) imaging-derived extracellular volume (ECV) mapping, generated from precontrast and postcontrast T1, accurately determines treatment response in cardiac light-chain amyloidosis. Native T1 mapping, which can be derived without the need for contrast, has demonstrated accuracy in diagnosis and prognostication, but it is unclear whether serial native T1 measurements could also track the cardiac treatment response. Objective: To assess whether native T1 mapping can measure the cardiac treatment response and the association between changes in native T1 and prognosis. Design, Setting, and Participants: This single-center cohort study evaluated patients diagnosed with cardiac light-chain amyloidosis (January 2016 to December 2020) who underwent CMR scans at diagnosis and a repeat scan following chemotherapy. Analysis took place between January 2016 and October 2022. Main Outcomes and Measures: Comparison of biomarkers and cardiac imaging parameters between patients with a reduced, stable, or increased native T1 and association between changes in native T1 and mortality. Results: The study comprised 221 patients (mean [SD] age, 64.7 [10.6] years; 130 male [59%]). At 6 months, 183 patients (mean [SD] age, 64.8 [10.5] years; 110 male [60%]) underwent repeat CMR imaging. Reduced native T1 of 50 milliseconds or more occurred in 8 patients (4%), all of whom had a good hematological response; by contrast, an increased native T1 of 50 milliseconds or more occurred in 42 patients (23%), most of whom had a poor hematological response (27 [68%]). At 12 months, 160 patients (mean [SD] age, 63.8 [11.1] years; 94 male [59%]) had a repeat CMR scan. A reduced native T1 occurred in 24 patients (15%), all of whom had a good hematological response, and was associated with a reduction in N-terminal pro-brain natriuretic peptide (median [IQR], 2638 [913-5767] vs 423 [128-1777] ng/L; P < .001), maximal wall thickness (mean [SD], 14.8 [3.6] vs 13.6 [3.9] mm; P = .009), and E/e' (mean [SD], 14.9 [6.8] vs 12.0 [4.0]; P = .007), improved longitudinal strain (mean [SD], -14.8% [4.0%] vs -16.7% [4.0%]; P = .004), and reduction in both myocardial T2 (mean [SD], 52.3 [2.9] vs 49.4 [2.0] milliseconds; P < .001) and ECV (mean [SD], 0.47 [0.07] vs 0.42 [0.08]; P < .001). At 12 months, an increased native T1 occurred in 24 patients (15%), most of whom had a poor hematological response (17 [71%]), and was associated with an increased N-terminal pro-brain natriuretic peptide (median [IQR], 1622 [554-5487] vs 3150 [1161-8745] ng/L; P = .007), reduced left ventricular ejection fraction (mean [SD], 65.8% [11.4%] vs 61.5% [12.4%]; P = .009), and an increase in both myocardial T2 (mean [SD], 52.5 [2.7] vs 55.3 [4.2] milliseconds; P < .001) and ECV (mean [SD], 0.48 [0.09] vs 0.56 [0.09]; P < .001). Change in myocardial native T1 at 6 months was independently associated with mortality (hazard ratio, 2.41 [95% CI, 1.36-4.27]; P = .003). Conclusions and Relevance: Changes in native T1 in response to treatment, reflecting a composite of changes in T2 and ECV, are associated with in changes in traditional markers of cardiac response and associated with mortality. However, as a single-center study, these results require external validation in a larger cohort.

Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). METHODS: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. RESULTS: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06). CONCLUSIONS: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.

Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival.

Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.

Impact of autoantibodies against the M2-muscarinic acetylcholine receptor on clinical outcomes in peripartum cardiomyopathy patients with standard treatment.

OBJECTIVES: To evaluate the impact of autoantibodies against the M2-muscarinic receptor (anti-M2-R) on the clinical outcomes of patients receiving the standard treatment for peripartum cardiomyopathy (PPCM). METHODS: A total of 107 PPCM patients who received standard heart failure (HF) treatment between January 1998 and June 2020 were enrolled in this study. According to anti-M2-R reactivity, they were classified into negative (n = 59) and positive (n = 48) groups, denoted as the anti-M2-R (-) and anti-M2-R (+) groups. Echocardiography, 6-min walk distance, serum digoxin concentration (SDC), and routine laboratory tests were performed regularly for 2 years. The all-cause mortality, cardiovascular mortality, and rehospitalisation rate for HF were compared between the two groups. RESULTS: A total of 103 patients were included in the final data analysis, with 46 in the anti-M2-R (+) group and 57 in the anti-M2-R (-) group. Heart rate was lower in the anti-M2-R (+) group than in the anti-M2-R (-) group at the baseline (102.7 ± 6.1 bpm vs. 96.0 ± 6.4 bpm, p < 0.001). The initial SDC was higher in the anti-M2-R (+) group than in the anti-M2-R (-) group with the same dosage of digoxin (1.25 ± 0.45 vs. 0.78 ± 0.24 ng/mL, p < 0.001). The dosages of metoprolol and digoxin were higher in the anti-M2-R (-) patients than in the anti-M2-R (+) patients (38.8 ± 4.6 mg b.i.d. vs. 27.8 ± 5.3 mg b.i.d., p < 0.0001, respectively, for metoprolol; 0.12 ± 0.02 mg/day vs. 0.08 ± 0.04 mg/day, p < 0.0001, respectively, for digoxin). Furthermore, there was a greater improvement in cardiac function in the anti-M2-R (-) patients than in the anti-M2-R (+) patients. Multivariate analysis identified negativity for anti-M2-R as the independent predictor for the improvement of cardiac function. Rehospitalisation for HF was lower in the anti-M2-R (-) group, but all-cause mortality and cardiovascular mortality were the same. CONCLUSIONS: There were no differences in all-cause mortality or cardiovascular mortality between the two groups. Rehospitalisation rate for HF decreased in the anti-M2-R (-) group. This difference may be related to the regulation of the autonomic nervous system by anti-M2-R.

Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome.

Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient's DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient's fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant.

The Waiting List Mortality of Pediatric Heart Transplantation Candidates in Korea before the Pediatric Ventricular Assist Device Era.

BACKGROUND: Despite advancements in heart transplantation for pediatric patients in Korea, the waiting list mortality has not been reported. Therefore, we investigated the waiting list mortality rate and factors associated with patient mortality. METHODS: We reviewed the medical records of pediatric patients who were registered for heart transplantation at three major hospitals in Korea from January 2000 to January 2020. All patients who died while waiting for heart transplantation were investigated, and we identified the waiting list mortality rate, causes of mortality and median survival periods depending on the variable risk factors. RESULTS: A total of 145 patients received heart transplantations at the three institutions we surveyed, and the waiting list mortality rate was 26%. The most common underlying diseases were cardiomyopathy (66.7%) and congenital heart disease (30.3%). The leading causes that contributed to death were heart failure (36.3%), multi-organ failure (27.2%), and complications associated with extracorporeal membrane oxygenation (ECMO) (25.7%). The median survival period was 63 days. ECMO was applied in 30 patients. The different waiting list mortality percentages according to age, cardiac diagnosis, use of ECMO, and initial Korean Network of Organ Sharing (KONOS) level were determined using univariate analysis, but age was the only significant factor associated with waiting list mortality based on a multivariate analysis. CONCLUSION: The waiting list mortality of pediatric heart transplantation candidates was confirmed to be considerably high, and age, underlying disease, the application of ECMO, and the initial KONOS level were the factors that influenced the survival period.

A real-world study on diagnosis and prognosis of light-chain cardiac amyloidosis in Southern China.

BACKGROUND: Light-chain cardiac amyloidosis (AL-CA) has been highly valued in developed countries, but in developing countries, the recognition and diagnosis of this condition is still limited. There are currently few reports on a large number of Chinese patients with AL-CA. The present study aimed to report real-world clinical characteristics and prognosis of AL-CA in China. METHODS AND RESULTS: Consecutive patients with AL-CA diagnosed at the Second Xiangya Hospital of Central South University between June 2012 and September 2020 were reviewed. A total of 170 patients with AL-CA have been recruited, whose mean ages were 60.81 ± 10.46. 70.59% of the patients were male. They were from eight provinces in southern China, 55.7% were referred patients, and 37.3% had been misdiagnosed previously. 64 (37.6%) patients received chemotherapy. The median survival time for patients with AL-CA was 8.00 months, and survival time for patients who received chemotherapy was 13.00 months, which was significantly longer than that of patients with palliative treatment (13.00 vs 6.00, p = 0.004). CONCLUSIONS: Although clinicians have improved their understanding of AL-CA in recent years, the prognosis of AL-CA is still poor, and the misdiagnosis rate and missed diagnosis rate are still very high in China. It is imperative to improve the recognition and early diagnosis of this condition, which may require multidisciplinary collaboration among cardiologists, hematologists and nephrologists.

Differences in the characteristics and contemporary cardiac outcomes of patients with light-chain versus transthyretin cardiac amyloidosis.

AIMS: To compare the baseline cardiovascular characteristics of immunoglobulin light-chain (AL) and amyloid transthyretin (ATTR) cardiac amyloidosis (CA) and to investigate patients' contemporary cardiac outcomes. METHODS: Single-center analysis of clinical, laboratory, echocardiographic and cardiac magnetic resonance imaging (CMRi) characteristics of AL and ATTR-CA patients' cohort (years 2013-2020). RESULTS: Included were 67 CA patients of whom 31 (46%) had AL-CA and 36 (54%) had ATTR-CA. Patients with ATTR-CA versus AL-CA were older (80 (IQR 70, 85) years versus 65 (IQR 60, 71) years, respectively, p<0.001) with male predominance (p = 0.038). Co-morbidities in ATTR-CA patients more frequently included diabetes mellitus (19% versus 3.0%, respectively, p = 0.060) and coronary artery disease (39% versus 10%, respectively, p = 0.010). By echocardiography, patients with ATTR-CA versus AL-CA had a trend to worse left ventricular (LV) ejection function (50 (IQR 40, 55)% versus 60 (IQR 45, 60)%, respectively, p = 0.051), yet comparable LV diastolic function. By CMRi, left atrial area (31 (IQR 27, 36)cm2 vs. 27 (IQR 23, 30)cm2, respectively, p = 0.015) and LV mass index (109 (IQR 96, 130)grams/m2 vs. 82 (IQR 72, 98)grams/m2, respectively, p = 0.011) were increased in patients with ATTR-CA versus AL-CA. Nevertheless, during follow-up (median 20 (IQR 10, 38) months), patients with AL-CA were more frequently admitted with heart failure exacerbations (HR 2.87 (95% CI 1.42, 5.81), p = 0.003) and demonstrated increased mortality (HR 2.51 (95%CI 1.19, 5.28), p = 0.015). CONCLUSION: Despite the various similarities of AL-CA and ATTR-CA, these diseases have distinct baseline cardiovascular profiles and different heart failure course, thus merit tailored-cardiac management.

The prognostic role of cardiac positron emission tomography imaging in patients with sarcoidosis: A systematic review.

PURPOSE: Sarcoidosis is a multi-systemic inflammatory disease of unknown etiology. Cardiac sarcoidosis (CS) has been reported in as much as 25% of patients with systemic involvement. 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) has a high diagnostic sensitivity/specificity in the diagnosis of CS. The aim of this review is to summarize evidence on the prognostic role of FDG PET. METHODS: Studies were identified by searching MEDLINE from inception to October 2020. Medical subject headings (MeSH) terms for sarcoidosis; cardiac and FDG PET imaging were used. Studies of any design assessing the prognostic role of FDG PET in patients with either suspected or confirmed cardiac sarcoidosis imaging done at baseline were included. Abnormal PET was defined as abnormal metabolism (presence of focal or focal-on-diffuse uptake of FDG) OR abnormal metabolism and a perfusion defect. Studies reporting any outcome measure were included. Pooled risk ratio for the composite outcome of MACE was done. RESULTS: A total of 6 studies were selected for final inclusion (515 patients, 53.4% women, 19.8% racial minorities.) Studies were institution based, retrospective in design and enrolled consecutive patients. All were observational in nature and published in English. All studies used a qualitative assessment of PET scans (abnormal FDG uptake with or without abnormal perfusion). Two studies assessed quantitative metrics (summed stress score in segments with abnormal FDG uptake, standardized uptake value and cardiac metabolic activity.) All studies reported major adverse cardiovascular events (MACE) as a composite outcome. After a mean follow up ranging from 1.4 to 4.1 years, there were a total of 105 MACE. All studies included death (either all-cause death or sudden cardiac death) and ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation) as a component of MACE. Four of the six studies adjusted for several characteristics in their analysis. All four studies used left ventricular ejection fraction (LVEF). However, other adjustment variables were not consistent across studies. Five studies found a positive prognostic association with the primary outcome, two of which assessing right ventricular uptake. CONCLUSION: Although available evidence indicates FDG PET can be used in the risk stratification of patients with CS, our findings show further studies are needed to quantify the effect in this patient group.

Vitamin D supplementation prior to or during COVID-19 associated with better 3-month survival in geriatric patients: Extension phase of the GERIA-COVID study.

BACKGROUND: The objective of this extension phase of the quasi-experimental GERIA-COVID study was to determine whether vitamin D3 supplementation taken prior to or during COVID-19 was associated with better 3-month survival in geriatric patients hospitalized for COVID-19. METHODS: Intervention group was defined as all participants supplemented with vitamin D3 prior to or during COVID-19 (n = 67). Supplements were either bolus vitamin D3 (ie, 50,000 IU per month, or 80,000 IU or 100,000 IU or 200,000 IU every 2-3 months), or daily supplementation with 800 IU. Comparator group involved those without vitamin D supplements (n = 28). Outcome was 3-month mortality. Covariables were age, sex, functional abilities, history of malignancies, cardiomyopathy, undernutrition, number of acute health issues, antibiotics use, systemic corticosteroids use, and 25(OH)D concentration. RESULTS: 76.1 % (n = 51) of participants survived at 3 months in Intervention group, compared to only 53.6 % (n = 15) in Comparator group (P = 0.03). The fully-adjusted hazard ratio for 3-month mortality was HR = 0.23 [95 %CI: 0.09;0.58](P = 0.002) in Intervention group compared to Comparator group. Intervention group had also longer survival time (log-rank P = 0.008). CONCLUSIONS: Vitamin D3 supplementation was associated with better 3-month survival in older COVID-19 patients.

Lipocalin 10 as a New Prognostic Biomarker in Sepsis-Induced Myocardial Dysfunction and Mortality: A Pilot Study.

INTRODUCTION: Sepsis-induced myocardial dysfunction (SIMD) is the most common complications of sepsis and septic shock with extremely high incidence and mortality. Lipocalin 10 (Lcn10) has recently been identified as a potential biomarker for heart failure, yet its relation to sepsis has not been investigated. The purpose of this study was to explore whether circulating Lcn10 could be used as a prognostic tool in patients with SIMD. METHODS: In this single-center observational pilot study, seventy-five sepsis patients were enrolled after sepsis diagnosis or ICU admission (45.3% female, median age 60 years), and 35 patients (46.7%) developed myocardial dysfunction. Serum Lcn10 levels of septic patients were measured using the enzyme-linked immunosorbent assay (ELISA) at the time of admission. Other biomarkers of cardiac function and Lcn10 concentration were compared between SIMD and non-SIMD groups. RESULTS: We observed that the median Lcn10 levels were 2.780 ng/mL in patients with SIMD and 2.075 ng/mL in patients without SIMD (P < 0.05). The area under the receiver operating characteristic (ROC) curve for the diagnosis of SIMD was 0.797 (P < 0.05). In addition, elevated serum Lcn10 levels at the time of admission were positively associated with 28-day mortality in septic patients. CONCLUSIONS: Our study indicates that circulating Lcn10 levels may serve as a novel biomarker for the diagnosis and prognosis of myocardial dysfunction induced by sepsis. An additional large multicenter study may be warranted to confirm the findings of this study.

Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications.

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.

Implications of multiple late gadolinium enhancement lesions on the frequency of left ventricular reverse remodeling and prognosis in patients with non-ischemic cardiomyopathy.

BACKGROUND: Non-ischemic cardiomyopathy (NICM) is a heterogeneous disease, and its prognosis varies. Although late gadolinium enhancement (LGE)-cardiovascular magnetic resonance (CMR) demonstrates a linear pattern in the mid-wall of the septum or multiple LGE lesions in patients with NICM, the therapeutic response and prognosis of multiple LGE lesions have not been elucidated. This study aimed to investigate the frequency of left ventricular (LV) reverse remodeling (LVRR) and prognosis in patients with NICM who have multiple LGE lesions. METHODS: This single-center retrospective study included 101 consecutive patients with NICM who were divided into 3 groups according to LGE-CMR results: patients without LGE (no LGE group = 48 patients), patients with a typical mid-wall LGE pattern (n = 29 patients), and patients with multiple LGE lesions (n = 24 patients). LVRR was defined as an increase in LV ejection fraction (LVEF) ≥ 10 % and a final value of LVEF > 35 %, which was accompanied by a decrease in LV end-systolic volume ≥ 15 % at 12-month follow-up using echocardiography. The frequency of composite cardiac events, defined as sudden cardiac death (SCD), aborted SCD (non-fatal ventricular fibrillation, sustained ventricular tachycardia, or adequate implantable cardioverter-defibrillator therapies), and heart failure death or hospitalization for worsening heart failure, were summarized and compared between the groups. RESULTS: Among the 3 groups, the frequency of LVRR was significantly lower in the multiple lesions group than in the no LGE and mid-wall groups (no LGE vs. mid-wall vs. multiple lesions: 49 % vs. 52 % vs. 19 %, p = 0.03). There were 24 composite cardiac events among the patients: 2 in patients without LGE (hospitalization for worsening heart failure; 2), 7 in patients of the mid-wall group (SCD; 1, aborted SCD; 1 and hospitalization for worsening heart failure; 5), and 15 in patients of the multiple lesions group (SCD; 1, aborted SCD; 8 and hospitalization for worsening heart failure; 6). The multiple LGE lesions was an independent predictor of composite cardiac events (hazard ratio: 11.40 [95 % confidence intervals: 1.49-92.01], p = 0.020). CONCLUSIONS: Patients with multiple LGE lesions have a higher risk of cardiac events and poorer LVRR. The LGE pattern may be useful for an improved risk stratification in patients with NICM.

Association of early versus delayed normalisation of left ventricular ejection fraction with mortality in ischemic cardiomyopathy.

OBJECTIVE: In patients with non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (LVEF), normalisation of LVEF is associated with improved outcomes. However, data on patients with ischaemic cardiomyopathy and recovered LVEF are lacking. The goal of this study was to assess the prognostic significance of normalisation of the LVEF in patients with ischaemic cardiomyopathy. METHODS/RESULTS: We performed a non-prespecified post hoc analysis of the Surgical Treatment for Ischaemic Heart Failure (STICH) trial to determine the association between normalisation of LVEF (>50%) and mortality during follow-up. Of the 1212 patients with LVEF <35% enroled in the STICH trial, 932 underwent assessment of LVEF at 4 months and/or 2 years after enrolment. Among them, 18 patients experienced normalisation in LVEF at 4-month follow-up and 35 patients experienced recovery in LVEF at 2 years. Recovery of LVEF at 4 months and recovery of LVEF at 2 years were not correlated. Recovery of LVEF at 4 months was not associated with reduced all-cause mortality in unadjusted analysis (log-rank test p=0.54) or in Cox proportional hazards analysis (HR: 0.93; 95% CI: 0.48 to 1.80; p=0.82). Ejection fraction recovery at 2 years was associated with a reduction in all-cause mortality, both in unadjusted analysis (log-rank test p=0.004) and in the Cox proportional hazard model (HR: 0.41; 95% CI: 0.21 to 0.80; p=0.009). CONCLUSIONS: In patients with ischaemic cardiomyopathy, delayed normalisation of LVEF is associated with reduced mortality, whereas early recovery of LVEF is not. Further studies are needed to confirm these findings.

Single-Cell RNA Sequencing Uncovers Paracrine Functions of the Epicardial-Derived Cells in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) manifests with sudden death, arrhythmias, heart failure, apoptosis, and myocardial fibro-adipogenesis. The phenotype typically starts at the epicardium and advances transmurally. Mutations in genes encoding desmosome proteins, including DSP (desmoplakin), are major causes of ACM. METHODS: To delineate contributions of the epicardium to the pathogenesis of ACM, the Dsp allele was conditionally deleted in the epicardial cells in mice upon expression of tamoxifen-inducible Cre from the Wt1 locus. Wild type (WT) and Wt1-CreERT2:DspW/F were crossed to Rosa26mT/mG (R26mT/mG) dual reporter mice to tag the epicardial-derived cells with the EGFP (enhanced green fluorescent protein) reporter protein. Tagged epicardial-derived cells from adult Wt1-CreERT2:R26mT/mG and Wt1-CreERT2: R26mT/mG:DspW/F mouse hearts were isolated by fluorescence-activated cell staining and sequenced by single-cell RNA sequencing. RESULTS: WT1 (Wilms tumor 1) expression was progressively restricted postnatally and was exclusive to the epicardium by postnatal day 21. Expression of Dsp was reduced in the epicardial cells but not in cardiac myocytes in the Wt1-CreERT2:DspW/F mice. The Wt1-CreERT2:DspW/F mice exhibited premature death, cardiac dysfunction, arrhythmias, myocardial fibro-adipogenesis, and apoptosis. Single-cell RNA sequencing of ≈18 000 EGFP-tagged epicardial-derived cells identified genotype-independent clusters of endothelial cells, fibroblasts, epithelial cells, and a very small cluster of cardiac myocytes, which were confirmed on coimmunofluorescence staining of the myocardial sections. Differentially expressed genes between the paired clusters in the 2 genotypes predicted activation of the inflammatory and mitotic pathways-including the TGFß1 (transforming growth factor ß1) and fibroblast growth factors-in the epicardial-derived fibroblast and epithelial clusters, but predicted their suppression in the endothelial cell cluster. The findings were corroborated by analysis of gene expression in the pooled RNA-sequencing data, which identified predominant dysregulation of genes involved in epithelial-mesenchymal transition, and dysregulation of 146 genes encoding the secreted proteins (secretome), including genes in the TGFß1 pathway. Activation of the TGFß1 and its colocalization with fibrosis in the Wt1-CreERT2:R26mT/mG:DspW/F mouse heart was validated by complementary methods. CONCLUSIONS: Epicardial-derived cardiac fibroblasts and epithelial cells express paracrine factors, including TGFß1 and fibroblast growth factors, which mediate epithelial-mesenchymal transition, and contribute to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of ACM. The findings uncover contributions of the epicardial-derived cells to the pathogenesis of ACM.

Outcomes of Blacks Versus Whites with Cardiomyopathy.

Racial disparities in health outcomes have been widely documented in medicine, including in cardiovascular care. While some progress has been made, these disparities have continued to plague our healthcare system. Patients with cardiomyopathy are at an increased risk of death and cardiovascular hospitalizations. In the present analysis, we examined the baseline characteristics and outcomes of black and white men and women with cardiomyopathy. All patients with cardiomyopathy (left ventricular ejection fraction (LVEF) < 50%) cared for at University of Pittsburgh Medical Center (UPMC) between 2011 and 2017 were included in this analysis. Patients were stratified by race, and outcomes were compared between Black and White patients using Cox proportional hazard models. Of a total of 18,003 cardiomyopathy patients, 15,804 were white (88%), 1,824 were black (10%) and 375 identified as other (2%). Over a median follow-up time of 3.4 years, 7,899 patients died. Black patients were on average a decade younger (p <0.001) and demonstrated lower unadjusted all-cause mortality (hazard ratio [HR]: 0.83%; 95% CI 0.77 to 0.90; p < 0.001). However, after adjusting for age and other comorbidities, black patients had higher all-cause mortality compared to white patients (HR: 1.15, 95% CI 1.07 to 1.25; p < 0.001). These differences were seen in both men (HR:1.19, 95% CI 1.08 to 1.33; p < 0.001) and women (HR:1.12, 95% CI 0.99 to 1.25; p = 0.065). In conclusion, our data demonstrate higher all-cause mortality in black compared to white men and women with cardiomyopathy. These findings are likely explained, at least in part, by significantly higher rates of comorbidities in black patients. Earlier interventions targeting these comorbidities may mitigate the risk of progression to heart failure and improve outcomes.

Using high sensitivity cardiac troponin values in patients with SARS-CoV-2 infection (COVID-19): The Padova experience.

BACKGROUND: The spectrum of Coronavirus Disease 2019 (COVID-19) is broad and thus early appropriate risk stratification can be helpful. Our objectives were to define the frequency of myocardial injury using high-sensitivity cardiac troponin I (hs-cTnI) and to understand how to use its prognostic abilities. METHODS: Retrospective study of patients with COVID-19 presenting to an Emergency Department (ED) in Italy in 2020. Hs-cTnI was sampled based on clinical judgment. Myocardial injury was defined as values above the sex-specific 99th percentile upper reference limits (URLs). Most data is from the initial hospital value. RESULTS: 426 unique patients were included. Hs-cTnI was measured in 313 (73.5%) patients; 85 (27.2%) had myocardial injury at baseline. Patients with myocardial injury had higher mortality during hospitalization (hazard ratio = 9 [95% confidence interval (CI) 4.55-17.79], p < 0.0001). Multivariable analysis including clinical and laboratory variables demonstrated an AUC of 0.942 with modest additional value of hs-cTnI. Myocardial injury was associated with mortality in patients with low APACHE II scores (<13) [OR (95% CI): 4.15 (1.40, 14.22), p = 0.014] but not in those with scores > 13 [OR (95% CI): 0.48 (0.08, 2.65), p = 0.40]. Initial hs-cTnI < 5 ng/L identified 33% of patients that were at low risk with 97.8% sensitivity (95% CI 88.7, 99.6) and 99.2% negative predictive value. Type 1 myocardial infarction (MI) and type 2 MI were infrequent. CONCLUSIONS: hs-cTnI at baseline is a significant predictor of mortality in COVID-19 patients. A value < 5 ng/L identified patients at low risk.

Comparison of Outcomes and Mortality in Patients Having Left Ventricular Assist Device Implanted Early -vs- Late After Diagnosis of Cardiomyopathy.

LVAD implantation in patients with a recently diagnosed cardiomyopathy has been poorly investigated. This work aims at describing the characteristics and outcomes of patients receiving a LVAD within 30 days following the diagnosis of cardiomyopathy. Patients from the ASSIST-ICD study was divided into recently and remotely diagnosed cardiomyopathy based on the time from initial diagnosis of cardiomyopathy to LVAD implantation using the cut point of 30 days. The primary end point of the study was all-cause mortality at 30-day and during follow-up. A total of 652 patients were included and followed during a median time of 9.1 (2.5 to 22.1) months. In this population, 117 (17.9%) had a recently diagnosed cardiomyopathy and had LVAD implantation after a median time of 15.0 (9.0 to 24.0) days following the diagnosis. This group of patients was significantly younger, with more ischemic cardiomyopathy, more sudden cardiac arrest (SCA) events at the time of the diagnosis and were more likely to receive temporary mechanical support before LVAD compared with the remotely diagnosed group. Postoperative in-hospital survival was similar in groups, but recently diagnosed patients had a better long-term survival after hospital discharge. SCA before LVAD and any cardiac surgery combined with LVAD implantation were identified as 2 independent predictors of postoperative mortality in recently diagnosed patients. In conclusion, rescue LVAD implantation for recently diagnosed severe cardiomyopathy is common in clinical practice. Such patients experience a relatively low postoperative mortality and have a better long-term survival compared with remotely diagnosed patients.

Maternal death analysis based on data from the nationwide registration system in Japan (2010-2018).

The maternal mortality rate in Japan was 3.5 per 100 000 live births in 2017, similar to that reported in other developed countries. To reduce the number of maternal deaths, a Japanese nationwide registration and analysis system was implemented in 2010. Between January 2010 and April 2018, 367 maternal deaths were reported. Among them, by reviewing 80 autopsy records, the direct obstetric causes of death were identified in 52 women. The major causes of deaths were amniotic fluid embolism and acute pulmonary thromboembolism. The other 26 maternal deaths were associated with indirect obstetric causes including invasive Group A Streptococcus infection, aortic dissection, cerebral stroke and cardiomyopathies. This review highlights the importance of autopsy in maternal deaths. On analyzing 42 autopsy specimens obtained from registered cases of maternal death during 2012-2015, the 36% of causes of death by autopsy were discordant with the clinical diagnosis. Moreover, of the 38% of non-autopsied maternal death, the cause of death could not be clarified from the clinical chart. We emphasized that detailed autopsies are necessary to clarify the precise pathologic evidence related to pregnancy and delivery, especially causes of unexpected death such as amniotic fluid embolism.