Validation of existing risk scores for mortality prediction after a heart transplant in a Chinese population.

OBJECTIVES:The objectives of this study were to validate 3 existing heart transplant risk scores with a single-centre cohort in China and evaluate the efficacy of the 3 systems in predicting mortality.METHODS:We retrospectively studied 428 patients from a single centre who underwent heart transplants from January 2015 to December 2019. All patients were scored using the Index for Mortality Prediction After Cardiac Transplantation (IMPACT) and the United Network for Organ Sharing (UNOS) and risk stratification scores (RSSs). We assessed the efficacy of the risk scores by comparing the observed and the predicted 1-year mortality. Binary logistic regression was used to evaluate the predictive accuracy of the 3 risk scores. Model discrimination was assessed by measuring the area under the receiver operating curves. Kaplan-Meier survival analyses were performed after the patients were divided into different risk groups.RESULTS:Based on our cohort, the observed mortality was 6.54%, whereas the predicted mortality of the IMPACT and UNOS scores and the RSSs was 10.59%, 10.74% and 12.89%, respectively. Logistic regression analysis showed that the IMPACT [odds ratio (OR), 1.25; 95% confidence interval (CI), 1.15-1.36; P < 0.001], UNOS (OR, 1.68; 95% CI, 1.37-2.07; P < 0.001) and risk stratification (OR, 1.61; 95% CI, 1.30-2.00; P < 0.001) scores were predictive of 1-year mortality. The discriminative power was numerically higher for the IMPACT score [area under the curve (AUC) of 0.691)] than for the UNOS score (AUC 0.685) and the RSS (AUC 0.648).CONCLUSIONS:We validated the IMPACT and UNOS scores and the RSSs as predictors of 1-year mortality after a heart transplant, but all 3 risk scores had unsatisfactory discriminative powers that overestimated the observed mortality for the Chinese cohort.

Higher Serum Lysophosphatidic Acids Predict Left Ventricular Reverse Remodeling in Pediatric Dilated Cardiomyopathy.

Background: The prognosis of pediatric dilated cardiomyopathy (PDCM) is highly variable, ranging from death to cardiac function recovery. Left ventricular reverse remodeling (LVRR) represents a favorable prognosis in PDCM. Disturbance of lipid metabolism is associated with the change of cardiac function, but no studies have examined lipidomics data and LVRR. Methods: Discovery analyses were based on 540 targeted lipids in an observational, prospective China-AOCC (An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China) study. The OPLS-DA and random forest (RF) analysis were used to screen the candidate lipids. Associations of the candidate lipids were examined in Cox proportional hazards regression models. Furthermore, we developed a risk score comprising the significant lipids, with each attributed a score of 1 when the concentration was above the median. All significant findings were replicated in a validation set of the China-AOCC study. Results: There were 59 patients in the discovery set and 24 patients in the validation set. LVRR was observed in 27 patients (32.5%). After adjusting for age, left ventricular ejection fraction (LVEF), and left ventricular end-diastolic dimension (LVEDD) z-score, lysophosphatidic acids (LysoPA) 16:0, LysoPA 18:2, LysoPA 18:1, and LysoPA 18:0 were significantly associated with LVRR in the discovery set, and hazard ratios (HRs) were 2.793 (95% CI, 1.545-5.048), 2.812 (95% CI, 1.542-5.128), 2.831 (95% CI, 1.555-5.154), and 2.782 (95% CI, 1.548-5.002), respectively. We developed a LysoPA score comprising the four LysoPA. When the LysoPA score reached 4, LVRR was more likely to be observed in both sets. The AUC increased with the addition of the LysoPA score to the LVEDD z-score (from 0.693 to 0.875 in the discovery set, from 0.708 to 0.854 in the validation set) for prediction of LVRR. Conclusions: Serum LysoPA can predict LVRR in PDCM patients. When the LysoPA score was combined with the LVEDD z-score, it may help in ascertaining the prognosis and monitoring effects of anti-heart failure pharmacotherapy.

Effects of CMYA1 overexpression on cardiac structure and function in mice.

CMYA1 (cardiomyopathy-associated protein 1, also termed Xin) localizes to the intercalated disks (ICDs) of the myocardium and functions to maintain ICD structural integrity and support signal transduction among cardiomyocytes. Our previous study showed that CMYA1 overexpression impairs the function of gap junction intercellular communication processes. Successful model generation was verified based on PCR, western blot analysis, immunohistochemistry, and immunofluorescence analysis. Myocardial CMYA1 expression was confirmed at both the mRNA and the protein levels in the CMYA1-OE transgenic mice. Masson's trichrome staining and electron microscopy revealed myocardial fibrosis and uneven bead width or the interruption of ICDs in the hearts of the CMYA1-OE transgenic mice. Furthermore, the Cx43 protein level was reduced in the CMYA1-OE mice, and co-immunoprecipitation assays of heart tissue protein extracts revealed a physical interaction between CMYA1 and Cx43. Electrocardiogram analysis enabled the detection of an obvious ventricular bigeminy for the CMYA1-OE mice. In summary, analysis of our mouse model indicates that elevated CMYA1 levels may induce myocardial fibrosis, impair ICDs, and downregulate the expression of Cx43. The observed ventricular bigeminy in the CMYA1-OE mice may be mediated by the reduced Cx43 protein level.

Author Correction: Donor-derived exosomes induce specific regulatory T cells to suppress immune inflammation in the allograft heart.

Fulminant Giant Cell Myocarditis vs. Lymphocytic Myocarditis: A Comparison of Their Clinical Characteristics, Treatments, and Outcomes.

Objectives: Fulminant myocarditis (FM) is a rapidly progressive and frequently fatal form of myocarditis that has been difficult to classify. This study aims to compare the clinical characteristics, treatments and outcomes in patients with fulminant giant cell myocarditis (FGCM) and fulminant lymphocytic myocarditis (FLM). Methods and Results: In our retrospective study, nine patients with FGCM (mean age 47.9 ± 7.5 years, six female) and 7 FLM (mean age 42.1 ± 12.3 years, four female) patients confirmed by histology in the last 11 years were included. Most patients with FGCM and FLM were NYHA functional class IV (56 vs. 100%, p = 0.132). Patients with FGCM had significantly lower levels of high-sensitivity C-reactive protein [hs-CRP, 4.4 (2.0-10.2) mg/L vs. 13.6 (12.6-14.6) mg/L, P = 0.004, data shown as the median with IQR], creatine kinase-myoglobin [CK-MB, 1.4 (1.0-3.2) ng/ml vs. 14.6 (3.0-64.9) ng/ml, P = 0.025, median with IQR], and alanine aminotransferase [ALT, 38.0 (25.0-61.5) IU/L vs. 997.0 (50.0-3,080.0) IU/L, P = 0.030, median with IQR] and greater right ventricular end-diastolic diameter (RVEDD) [2.9 ± 0.3 cm vs. 2.4 ± 0.6 cm, P = 0.034, mean ± SD] than those with FLM. No differences were observed in the use of intra-aortic balloon pump (44 vs. 43%, p = 1.000) and extracorporeal membrane oxygenation (11 vs. 43%, p = 0.262) between the two groups. The long-term survival rate was significantly lower in FGCM group compared with FLM group (0 vs. 71.4%, p = 0.022). A multivariate cox regression analysis showed the level of hs-CRP (hazard ratio = 0.871, 95% confidence interval: 0.761-0.996, P = 0.043) was an independent prognostic factor for FM patients. Furthermore, the level of hs-CRP had a good ability to discriminate between patients with FGCM and FLM (AUC = 0.94, 95% confidence interval: 0.4213-0.9964). Conclusions: The inflammatory response and myocardial damage in the patients with FGCM were milder than those with FLM. Patients with FGCM had distinctly poorer prognoses compared with those with FLM. Our results suggest that hs-CRP could be a promising prognostic biomarker and a hs-CRP level of 11.71 mg/L is an appropriate cutoff point for the differentiating diagnosis between patients with FGCM and FLM.

Multiple genetic variants in adolescent patients with left ventricular noncompaction cardiomyopathy.

BACKGROUND:Left ventricular noncompaction cardiomyopathy (LVNC) is a primary cardiomyopathy with an unclear aetiology. The clinical symptoms range from asymptomatic to heart failure, arrhythmias and sudden cardiac death. This study aimed to characterize the genetic features and clinical outcomes of LVNC who underwent heart transplantation (HTx) to reveal the potential genetic pathogenesis.METHODS AND RESULTS:We recruited 16 cases who underwent HTx in our hospital. Exome-sequencing was performed to reveal genetic background. Clinical information and histopathology features of patients were investigated. Gene expression profiling of tissue fibrosis were evaluated by quantitative PCR. The median age of patients was 21 years. Of the 16 patients, 14 harboured multiple gene variants involved in LVNC. Ten of the patients harboured biallelic variants and/or truncating variants. Young patients (<18) with biallelic variants and/or truncating variants and lower LVEF (<45%) at initial symptom deteriorated quickly. Except for noncompaction myocardium, myocardial fibrosis was a remarkable pathological feature, and gene profiles related to immune inflammation and extracellular matrix remodelling were upregulated.CONCLUSIONS:This study showed that multiple pathologic variants were underlie genetic mechanism of LVNC who in high risks, suggesting that genetic screening should be applied to the diagnosis of LVNC. LVNC patient with multiple variants should be considered carefully follow-up. Genetics involved in the phenotype and cardiac fibrosis, and is the major causing for LVNC.

Association of Soluble ST2 Serum Levels With Outcomes in Pediatric Dilated Cardiomyopathy.

BACKGROUND:Prognosis in patients with pediatric dilated cardiomyopathy (PDCM) is urgently required to identify high-risk patients. Elevated soluble ST2 (sST2) is associated with prognosis in adult patients with heart failure. This study aimed to assess the prognostic value of sST2 in PDCM.METHODS:Ninety-four patients with PDCM were enrolled after admission from 2 centres in China and followed up for adverse events (death, cardiac transplantation, and heart-failure-related rehospitalization). B-type natriuretic peptide (BNP) and sST2 levels were measured.RESULTS:Over a median of 678 (interquartile range [IQR]: 533-785) days, 28 (29.8%) adverse events occurred. Patients in the highest tertile of sST2 levels had increased risk of short-term (< 6 months) (adjusted hazard ratio [HR]: 8.36, 95% confidence interval [CI], 1.02-73.52; P < 0.05) and long-term adverse events (2 years) (adjusted HR: 4.23; 95% CI, 1.32-13.60; P < 0.01) than those in lower tertiles. The C-statistic was increased with addition of sST2 to BNP from 0.697 (95% CI, 0.541-0.852) to 0.812 (95% CI, 0.697-0.939) for short-term and from 0.712 (95% CI, 0.604-0.819) to 0.798 (95% CI, 0.697-0.899) for prediction of long-term adverse events. An intermediate-risk subgroup was identified, and 24% had adverse events. When serial measurements were taken in a nested case-control subgroup, sST2 levels were constantly high in patients with late adverse events (> 6 months) but gradually decreased in nonadverse-event controls compared with 3-month and 6-month baseline levels.CONCLUSIONS:In patients with PDCM, serum sST2 levels are associated with adverse events and have robust prognostic value. Serial measurements of sST2 could help in managing patients for monitoring outcomes of treatment.

6-year change in resting heart rate is associated with incident type 2 diabetes mellitus.

BACKGROUND AND AIMS:Elevated resting heart rate (RHR) is associated with risk of type 2 diabetes mellitus (T2DM). However, the association of change in RHR (ΔRHR) and incident T2DM is not fully elucidated. We aimed to assess the dose-response association between 6-year ΔRHR and T2DM.METHODS AND RESULTS:A total of 12155 non-T2DM participants ≥18 years old were enrolled during 2007-2008 and followed up during 2013-2014. ΔRHR was calculated by subtracting the baseline RHR from the RHR value at 6-year follow-up. Age-, sex-, and RHR-specific relative risks (RRs) and 95% confidence intervals (CIs) for the effect of ΔRHR on incident T2DM were calculated by using modified Poisson regression models. As compared with ΔRHR of 0 beats/min, the adjusted risk of T2DM was significantly increased with RHR increment and reduced with RHR reduction. ΔRHR was positively associated with future risk of T2DM [RR per unit increase: 1.03 (1.03-1.04)]. As compared with stable change in RHR group (-5<ΔRHR<5 beats/min), for ΔRHR ≤ -10 beats/min, -10<ΔRHR ≤ -5 beats/min, 5≤ΔRHR<10 beats/min, and ΔRHR ≥10 beats/min groups, the pooled adjusted RR (95% CI) of T2DM was 0.69 (0.55-0.86), 0.90 (0.73-1.11), 1.31 (1.07-1.61), and 1.90 (1.59-2.26), respectively. This significant association still existed on subgroup analyses based on age, sex, and baseline RHR and sensitivity analyses.CONCLUSIONS:Dynamic RHR change was significantly associated with incident T2DM. Our study suggests that RHR may be a non-invasive clinical indicator for interventions aiming to reduce incident T2DM in the general population.

The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients.

BACKGROUND AND OBJECTIVES:Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients.METHODS:We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality.RESULTS:In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314).CONCLUSIONS:CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

Letter by Ma et al Regarding Article, "Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy".

Validation of existing risk scores for mortality prediction after a heart transplant in a Chinese population.

OBJECTIVES:The objectives of this study were to validate 3 existing heart transplant risk scores with a single-centre cohort in China and evaluate the efficacy of the 3 systems in predicting mortality.METHODS:We retrospectively studied 428 patients from a single centre who underwent heart transplants from January 2015 to December 2019. All patients were scored using the Index for Mortality Prediction After Cardiac Transplantation (IMPACT) and the United Network for Organ Sharing (UNOS) and risk stratification scores (RSSs). We assessed the efficacy of the risk scores by comparing the observed and the predicted 1-year mortality. Binary logistic regression was used to evaluate the predictive accuracy of the 3 risk scores. Model discrimination was assessed by measuring the area under the receiver operating curves. Kaplan-Meier survival analyses were performed after the patients were divided into different risk groups.RESULTS:Based on our cohort, the observed mortality was 6.54%, whereas the predicted mortality of the IMPACT and UNOS scores and the RSSs was 10.59%, 10.74% and 12.89%, respectively. Logistic regression analysis showed that the IMPACT [odds ratio (OR), 1.25; 95% confidence interval (CI), 1.15-1.36; P < 0.001], UNOS (OR, 1.68; 95% CI, 1.37-2.07; P < 0.001) and risk stratification (OR, 1.61; 95% CI, 1.30-2.00; P < 0.001) scores were predictive of 1-year mortality. The discriminative power was numerically higher for the IMPACT score [area under the curve (AUC) of 0.691)] than for the UNOS score (AUC 0.685) and the RSS (AUC 0.648).CONCLUSIONS:We validated the IMPACT and UNOS scores and the RSSs as predictors of 1-year mortality after a heart transplant, but all 3 risk scores had unsatisfactory discriminative powers that overestimated the observed mortality for the Chinese cohort.

Higher Serum Lysophosphatidic Acids Predict Left Ventricular Reverse Remodeling in Pediatric Dilated Cardiomyopathy.

Background: The prognosis of pediatric dilated cardiomyopathy (PDCM) is highly variable, ranging from death to cardiac function recovery. Left ventricular reverse remodeling (LVRR) represents a favorable prognosis in PDCM. Disturbance of lipid metabolism is associated with the change of cardiac function, but no studies have examined lipidomics data and LVRR. Methods: Discovery analyses were based on 540 targeted lipids in an observational, prospective China-AOCC (An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China) study. The OPLS-DA and random forest (RF) analysis were used to screen the candidate lipids. Associations of the candidate lipids were examined in Cox proportional hazards regression models. Furthermore, we developed a risk score comprising the significant lipids, with each attributed a score of 1 when the concentration was above the median. All significant findings were replicated in a validation set of the China-AOCC study. Results: There were 59 patients in the discovery set and 24 patients in the validation set. LVRR was observed in 27 patients (32.5%). After adjusting for age, left ventricular ejection fraction (LVEF), and left ventricular end-diastolic dimension (LVEDD) z-score, lysophosphatidic acids (LysoPA) 16:0, LysoPA 18:2, LysoPA 18:1, and LysoPA 18:0 were significantly associated with LVRR in the discovery set, and hazard ratios (HRs) were 2.793 (95% CI, 1.545-5.048), 2.812 (95% CI, 1.542-5.128), 2.831 (95% CI, 1.555-5.154), and 2.782 (95% CI, 1.548-5.002), respectively. We developed a LysoPA score comprising the four LysoPA. When the LysoPA score reached 4, LVRR was more likely to be observed in both sets. The AUC increased with the addition of the LysoPA score to the LVEDD z-score (from 0.693 to 0.875 in the discovery set, from 0.708 to 0.854 in the validation set) for prediction of LVRR. Conclusions: Serum LysoPA can predict LVRR in PDCM patients. When the LysoPA score was combined with the LVEDD z-score, it may help in ascertaining the prognosis and monitoring effects of anti-heart failure pharmacotherapy.

Effects of CMYA1 overexpression on cardiac structure and function in mice.

CMYA1 (cardiomyopathy-associated protein 1, also termed Xin) localizes to the intercalated disks (ICDs) of the myocardium and functions to maintain ICD structural integrity and support signal transduction among cardiomyocytes. Our previous study showed that CMYA1 overexpression impairs the function of gap junction intercellular communication processes. Successful model generation was verified based on PCR, western blot analysis, immunohistochemistry, and immunofluorescence analysis. Myocardial CMYA1 expression was confirmed at both the mRNA and the protein levels in the CMYA1-OE transgenic mice. Masson's trichrome staining and electron microscopy revealed myocardial fibrosis and uneven bead width or the interruption of ICDs in the hearts of the CMYA1-OE transgenic mice. Furthermore, the Cx43 protein level was reduced in the CMYA1-OE mice, and co-immunoprecipitation assays of heart tissue protein extracts revealed a physical interaction between CMYA1 and Cx43. Electrocardiogram analysis enabled the detection of an obvious ventricular bigeminy for the CMYA1-OE mice. In summary, analysis of our mouse model indicates that elevated CMYA1 levels may induce myocardial fibrosis, impair ICDs, and downregulate the expression of Cx43. The observed ventricular bigeminy in the CMYA1-OE mice may be mediated by the reduced Cx43 protein level.

Author Correction: Donor-derived exosomes induce specific regulatory T cells to suppress immune inflammation in the allograft heart.

Fulminant Giant Cell Myocarditis vs. Lymphocytic Myocarditis: A Comparison of Their Clinical Characteristics, Treatments, and Outcomes.

Objectives: Fulminant myocarditis (FM) is a rapidly progressive and frequently fatal form of myocarditis that has been difficult to classify. This study aims to compare the clinical characteristics, treatments and outcomes in patients with fulminant giant cell myocarditis (FGCM) and fulminant lymphocytic myocarditis (FLM). Methods and Results: In our retrospective study, nine patients with FGCM (mean age 47.9 ± 7.5 years, six female) and 7 FLM (mean age 42.1 ± 12.3 years, four female) patients confirmed by histology in the last 11 years were included. Most patients with FGCM and FLM were NYHA functional class IV (56 vs. 100%, p = 0.132). Patients with FGCM had significantly lower levels of high-sensitivity C-reactive protein [hs-CRP, 4.4 (2.0-10.2) mg/L vs. 13.6 (12.6-14.6) mg/L, P = 0.004, data shown as the median with IQR], creatine kinase-myoglobin [CK-MB, 1.4 (1.0-3.2) ng/ml vs. 14.6 (3.0-64.9) ng/ml, P = 0.025, median with IQR], and alanine aminotransferase [ALT, 38.0 (25.0-61.5) IU/L vs. 997.0 (50.0-3,080.0) IU/L, P = 0.030, median with IQR] and greater right ventricular end-diastolic diameter (RVEDD) [2.9 ± 0.3 cm vs. 2.4 ± 0.6 cm, P = 0.034, mean ± SD] than those with FLM. No differences were observed in the use of intra-aortic balloon pump (44 vs. 43%, p = 1.000) and extracorporeal membrane oxygenation (11 vs. 43%, p = 0.262) between the two groups. The long-term survival rate was significantly lower in FGCM group compared with FLM group (0 vs. 71.4%, p = 0.022). A multivariate cox regression analysis showed the level of hs-CRP (hazard ratio = 0.871, 95% confidence interval: 0.761-0.996, P = 0.043) was an independent prognostic factor for FM patients. Furthermore, the level of hs-CRP had a good ability to discriminate between patients with FGCM and FLM (AUC = 0.94, 95% confidence interval: 0.4213-0.9964). Conclusions: The inflammatory response and myocardial damage in the patients with FGCM were milder than those with FLM. Patients with FGCM had distinctly poorer prognoses compared with those with FLM. Our results suggest that hs-CRP could be a promising prognostic biomarker and a hs-CRP level of 11.71 mg/L is an appropriate cutoff point for the differentiating diagnosis between patients with FGCM and FLM.

Multiple genetic variants in adolescent patients with left ventricular noncompaction cardiomyopathy.

BACKGROUND:Left ventricular noncompaction cardiomyopathy (LVNC) is a primary cardiomyopathy with an unclear aetiology. The clinical symptoms range from asymptomatic to heart failure, arrhythmias and sudden cardiac death. This study aimed to characterize the genetic features and clinical outcomes of LVNC who underwent heart transplantation (HTx) to reveal the potential genetic pathogenesis.METHODS AND RESULTS:We recruited 16 cases who underwent HTx in our hospital. Exome-sequencing was performed to reveal genetic background. Clinical information and histopathology features of patients were investigated. Gene expression profiling of tissue fibrosis were evaluated by quantitative PCR. The median age of patients was 21 years. Of the 16 patients, 14 harboured multiple gene variants involved in LVNC. Ten of the patients harboured biallelic variants and/or truncating variants. Young patients (<18) with biallelic variants and/or truncating variants and lower LVEF (<45%) at initial symptom deteriorated quickly. Except for noncompaction myocardium, myocardial fibrosis was a remarkable pathological feature, and gene profiles related to immune inflammation and extracellular matrix remodelling were upregulated.CONCLUSIONS:This study showed that multiple pathologic variants were underlie genetic mechanism of LVNC who in high risks, suggesting that genetic screening should be applied to the diagnosis of LVNC. LVNC patient with multiple variants should be considered carefully follow-up. Genetics involved in the phenotype and cardiac fibrosis, and is the major causing for LVNC.

Association of Soluble ST2 Serum Levels With Outcomes in Pediatric Dilated Cardiomyopathy.

BACKGROUND:Prognosis in patients with pediatric dilated cardiomyopathy (PDCM) is urgently required to identify high-risk patients. Elevated soluble ST2 (sST2) is associated with prognosis in adult patients with heart failure. This study aimed to assess the prognostic value of sST2 in PDCM.METHODS:Ninety-four patients with PDCM were enrolled after admission from 2 centres in China and followed up for adverse events (death, cardiac transplantation, and heart-failure-related rehospitalization). B-type natriuretic peptide (BNP) and sST2 levels were measured.RESULTS:Over a median of 678 (interquartile range [IQR]: 533-785) days, 28 (29.8%) adverse events occurred. Patients in the highest tertile of sST2 levels had increased risk of short-term (< 6 months) (adjusted hazard ratio [HR]: 8.36, 95% confidence interval [CI], 1.02-73.52; P < 0.05) and long-term adverse events (2 years) (adjusted HR: 4.23; 95% CI, 1.32-13.60; P < 0.01) than those in lower tertiles. The C-statistic was increased with addition of sST2 to BNP from 0.697 (95% CI, 0.541-0.852) to 0.812 (95% CI, 0.697-0.939) for short-term and from 0.712 (95% CI, 0.604-0.819) to 0.798 (95% CI, 0.697-0.899) for prediction of long-term adverse events. An intermediate-risk subgroup was identified, and 24% had adverse events. When serial measurements were taken in a nested case-control subgroup, sST2 levels were constantly high in patients with late adverse events (> 6 months) but gradually decreased in nonadverse-event controls compared with 3-month and 6-month baseline levels.CONCLUSIONS:In patients with PDCM, serum sST2 levels are associated with adverse events and have robust prognostic value. Serial measurements of sST2 could help in managing patients for monitoring outcomes of treatment.

6-year change in resting heart rate is associated with incident type 2 diabetes mellitus.

BACKGROUND AND AIMS:Elevated resting heart rate (RHR) is associated with risk of type 2 diabetes mellitus (T2DM). However, the association of change in RHR (ΔRHR) and incident T2DM is not fully elucidated. We aimed to assess the dose-response association between 6-year ΔRHR and T2DM.METHODS AND RESULTS:A total of 12155 non-T2DM participants ≥18 years old were enrolled during 2007-2008 and followed up during 2013-2014. ΔRHR was calculated by subtracting the baseline RHR from the RHR value at 6-year follow-up. Age-, sex-, and RHR-specific relative risks (RRs) and 95% confidence intervals (CIs) for the effect of ΔRHR on incident T2DM were calculated by using modified Poisson regression models. As compared with ΔRHR of 0 beats/min, the adjusted risk of T2DM was significantly increased with RHR increment and reduced with RHR reduction. ΔRHR was positively associated with future risk of T2DM [RR per unit increase: 1.03 (1.03-1.04)]. As compared with stable change in RHR group (-5<ΔRHR<5 beats/min), for ΔRHR ≤ -10 beats/min, -10<ΔRHR ≤ -5 beats/min, 5≤ΔRHR<10 beats/min, and ΔRHR ≥10 beats/min groups, the pooled adjusted RR (95% CI) of T2DM was 0.69 (0.55-0.86), 0.90 (0.73-1.11), 1.31 (1.07-1.61), and 1.90 (1.59-2.26), respectively. This significant association still existed on subgroup analyses based on age, sex, and baseline RHR and sensitivity analyses.CONCLUSIONS:Dynamic RHR change was significantly associated with incident T2DM. Our study suggests that RHR may be a non-invasive clinical indicator for interventions aiming to reduce incident T2DM in the general population.

The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients.

BACKGROUND AND OBJECTIVES:Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients.METHODS:We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality.RESULTS:In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314).CONCLUSIONS:CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

Letter by Ma et al Regarding Article, "Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy".