Prediction of cardiac death in patients with hypertrophic cardiomyopathy using plasma adipokine levels.

BACKGROUNDS AND AIMS: Hypertrophic cardiomyopathy (HCM) causes cardiac death through both sudden cardiac death (SCD) and death due to heart failure (HF). Although adipokines lead to adverse cardiac remodeling in HCM, the prognostic value of plasma adipokines in HCM remains unknown. We aimed to predict cardiac death in patients with HCM using plasma adipokines. METHODS AND RESULTS: We performed a multicenter prospective cohort study of patients with HCM. The outcome was cardiac death including heart transplant, death due to HF, and SCD. With data from 1 institution (training set), a prediction model was developed using random forest classification algorithm based on 10 plasma adipokines. The performance of the prediction model adjusted for 8 clinical parameters was examined in samples from another institution (test set). Time-to-event analysis was performed in the test set to compare the rate of outcome events between the low-risk and high-risk groups determined by the prediction model. In total, 389 (267 in the training set; 122 in the test set) patients with HCM were included. During the median follow-up of 2.7 years, 21 patients experienced the outcome event. The area under the covariates-adjusted receiver-operating characteristics curve was 0.89 (95 % confidence interval [CI] 0.71-0.99) in the test set. revealed the high-risk group had a significantly higher risk of cardiac death (hazard ratio 17.8, 95 % CI 2.1-148.3, P = 0.008). CONCLUSION: The present multicenter prospective study demonstrated that a panel of plasma adipokines predicts cardiac death in patients with HCM.

Neutrophil extracellular traps in feline cardiogenic arterial thrombi: a pilot study.

OBJECTIVES: The aim of this study was to investigate the spatial distribution of neutrophil extracellular traps (NETs) in cardiogenic arterial thromboembolism (CATE). Specifically, we aimed to examine the related structural features of NETs in feline arterial thrombi in relation to their arterial locations. METHODS: Paraffin-embedded aortic bifurcations from nine cats with hypertrophic cardiomyopathy (four with CATE and five without) were deparaffinized, and NETs were identified by immunodetection based on colocalization of cell-free DNA, citrullinated histone H3 and neutrophil elastase. The distribution of NETs in thrombi within the aortic bifurcations and common iliac arteries (CIAs) was compared based on their proximity to the descending aorta (proximal, mid, distal). Ten random fields per section were captured at × 10 and × 20 magnification for each section of the clot and analyzed. RESULTS: The distributions of NETs in thrombi within the aortic bifurcation and CIAs were found to differ in relation to their assigned zones (proximal, mid, distal; P = 0.04); NETs were concentrated mostly in the proximal region in the aortic bifurcations (47.56%, interquartile range [IQR] 14.07-77.95) and CIAs (44.69%, IQR 24.65-85.28), compared with the distal regions (2.69%, IQR 0.10-50.04 [P = 0.027]; 7.08%, IQR 1.27-59.33 [P = 0.02]). CONCLUSIONS AND RELEVANCE: The variation in NET distribution within arterial thrombi may shed light on the pathogenesis of thrombus growth. This may be due to possible neutrophil entrapment or variations in shear stress.

N-terminal pro-brain natriuretic peptide and adverse outcomes in Chinese patients with hypertrophic cardiomyopathy.

BACKGROUND: Although numerous studies have suggested that elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) is positively correlated with cardiovascular events, especially the heart failure and heart failure-related death (HFRD), evidence of the association between NT-proBNP and the adverse outcomes of hypertrophic cardiomyopathy (HCM) is still relatively limited. The present study was performed to evaluate the relationship between NT-proBNP and outcomes in patients with HCM. METHODS: Observational cohort methodology was used in the present study, and a total of 227 patients were included. And the patients were followed for 44.97 ± 16.37 months. Patients were categorized into three groups according to these NT-proBNP tertiles: first tertile (≤910 pg/ml, n=68), second tertile (913-2141 pg/ml, n=68), and third tertile (≥2151 pg/ml, n=69). The adverse outcomes of the present study were all-cause death (ACD) and cardiac death (CD). RESULTS: According to the risk category of NT-proBNP, the incidence of ACD (P=0.005) and CD (P=0.032) among the three groups showed significant differences. Multivariate Cox regression analysis suggested that the ACD and CD in the third tertile have 7.022 folds (hazard risk [HR] = 7.022 [95% confidence interval [CI]: 1.397-35.282], P=0.018) and 7.129 folds (HR = 7.129 [95% CI: 1.329-38.237], P=0.022) increased risks as compared with those in the first tertile. Kaplan-Meier survival analyses showed that the cumulative risks of ACD and CD in patients with HCM tended to increase. CONCLUSION: The present study indicated NT-proBNP was a novel biomarker suitable for predicting adverse prognosis in patients with HCM, which may be used for early recognition and risk stratification.

Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). OBJECTIVES: The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures. METHODS: Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory. RESULTS: More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m2 vs 41 ± 14 mL/m2; mean change from baseline of -7.5 mL/m2 [95% CI: -9.0 to -6.1 mL/m2] vs -0.09 mL/m2 [95% CI: -1.6 to 1.5 mL/m2]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04). CONCLUSIONS: Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).

Plasma metabolomic profiling of hypertrophic cardiomyopathy patients before and after surgical myectomy suggests postoperative improvement in metabolic function.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common inherited heart disorder complicated by left ventricle outflow tract (LVOT) obstruction, which can be treated with surgical myectomy. To date, no reliable biomarkers for LVOT obstruction exist. We hypothesized that metabolomic biomarkers for LVOT obstruction may be detectable in plasma from HCM patients. METHODS: We conducted metabolomic profiling on plasma samples of 18 HCM patients before and after surgical myectomy, using a commercially available metabolomics platform. RESULTS: We found that 215 metabolites were altered in the postoperative state (p-value < 0.05). 12 of these metabolites were notably significant after adjusting for multiple comparisons (q-value < 0.05), including bilirubin, PFOS, PFOA, 3,5-dichloro-2,6-dihydroxybenzoic acid, 2-hydroxylaurate, trigonelline and 6 unidentified compounds, which support improved organ metabolic function and increased lean soft tissue mass. CONCLUSIONS: These findings suggest improved organ metabolic function after surgical relief of LVOT obstruction in HCM and further underscore the beneficial systemic effects of surgical myectomy.

Prognostic value of red blood cell distribution width for mortality in patients with hypertrophic cardiomyopathy.

BACKGROUND: Red blood cell distribution width (RDW) has emerged as a useful indicator for adverse outcomes in several cardiovascular diseases. The relation between RDW and the prognosis of hypertrophic cardiomyopathy (HCM) remains to be evaluated. We examined the relation between RDW and all-cause mortality and HCM-related death in a population of adult HCM patients. METHODS: We performed clinical evaluation in 414 consecutive adult HCM patients (median age, 57.5 years; male, 54.8%). RESULTS: During a median follow-up of 3.7 years, all-cause mortality and HCM-related death occurred in 75 (18.1%) and 50 (12.1%) patients, respectively. Based on the tertiles of baseline RDW, mortality increased with higher tertile. With the tertile 1 as reference, adjusted all-cause mortality hazard ratios (HRs) were 3.9 for the tertile 2 (95% confidence interval [CI]: 1.5-10.3) and 3.1 for the tertile 3 (95% CI: 1.1-8.2). Adjusted HCM-related death HRs were higher in the tertile 2 (HR: 5.5; 95% CI: 1.2-24.4) and tertile 3 (HR: 6.6; 95% CI: 1.5-29.0) compared with the tertile 1. Further smooth curve fitting exhibited a saturation effect after adjusting for confounders, and there were a two-stage change and an inflection point. Two-piecewise Cox model suggested mortality significantly increased with RDW level up to the inflection point (about 14.0% for both all-cause mortality and HCM-related death), and RDW was not associated with mortality after the point. CONCLUSION: In adult HCM patients, we found increased RDW was a significant risk predictor for all-cause mortality and HCM-related death, and a saturation effect was observed.

Combined evaluation of coronary artery disease and high-sensitivity cardiac troponin T for prediction of adverse events in patients with hypertrophic cardiomyopathy.

BACKGROUND: This study was performed to investigate the clinical significance of combined evaluation of both coronary artery disease (CAD) and high-sensitivity cardiac troponin T (hs-cTnT) for prediction of major adverse cardiovascular events (MACEs) in patients with hypertrophic cardiomyopathy (HCM). METHODS: We performed clinical evaluations, including coronary artery imaging and hs-cTnT measurement, in 162 patients with HCM. RESULTS: The patients were followed up for a median period of 3.7 years (interquartile range 2.4-5.6 years; total of 632.3 person-years [PYs]), during which time MACEs occurred in 24 (14.8%) patients. The incidence of MACEs was 6.4 and 2.7 per 100 PYs for patients with CAD and normal coronary arteries, respectively; similarly, the incidence was 5.8 and 2.1 per 100 PYs in patients with an elevated hs-cTnT concentration (> 14.0 ng/L) and a normal hs-cTnT concentration, respectively. The multivariate analysis suggested that CAD and an elevated hs-cTnT concentration tended to be positively associated with MACEs. When the groups were allocated according to these two markers, the patients were divided into four groups, which further improved the predictive values. The incidence of MACEs was 10.4 per 100 PYs in the CAD and elevated hs-cTnT group, which was much higher than the incidence in all other groups (range, 2.0-3.5 per 100 PYs). With the normal coronary arteries and normal hs-cTnT group serving as a reference, the adjusted hazard ratio was 5.0 (95% confidence interval 1.0-23.8; P = 0.046) for the CAD and elevated hs-cTnT group. In addition, the subgroup analysis showed similar findings among the patients without severe CAD. CONCLUSIONS: In patients with HCM, combined evaluation of both CAD and hs-cTnT might facilitate more reliable prediction of MACEs than evaluation of a single marker. These may serve as clinically useful markers to guide risk management.

Usefulness of High-Sensitivity Cardiac Troponin T to Predict Long-Term Outcome in Patients with Hypertrophic Cardiomyopathy.

Since the first report of an association between cardiac troponin (cTn) and adverse outcome in hypertrophic cardiomyopathy (HD), there is a paucity in confirmative data. We performed a prospective, prespecified 5-year follow-up cohort study of 135 HC patients who participated in a national multicenter project and underwent clinical evaluation, MRI (cine, LGE and T2-weighted imaging) and biomarker assessment (high-sensitivity cTnT (hs-cTnT), N-terminal pro-B-type natriuretic peptide, soluble tumorgenicity suppressor-2, Galectin-3, Growth differentiation factor-15, C-terminal Propeptide of Type I Collagen (CICP)). An elevated hs-cTnT concentration was defined as ≥14ng/L. Follow-up was systematically performed for the primary endpoint: a composite of sudden cardiac death, heart failure related death, stroke-related death, heart failure hospitalization, hospitalization for stroke, spontaneous sustained ventricular tachycardia (VT) or appropriate ICD discharge, and progression to NYHA class III-IV. Elevated hs-cTnT was present in 33 of 135 (24%) HC patients. During a median follow-up of 5.0 years (IQR: 4.9-5.1) 18 patients reached the primary endpoint. Using Cox regression analysis, elevated hs-cTnT was univariately associated with the primary endpoint (HR: 3.4 (95%CI: 1.4-8.7, p=0.009). Also female sex, previous syncope, previous non-sustained VT, reduced LV ejection fraction (<50%) and CICP were associated with the primary endpoint. In multivariable analysis, elevated hs-cTnT remained independently associated with outcome (aHR: 4.7 (95%CI: 1.8-12.6, p = 0.002). In conclusion, this 5-year follow-up study is the first to prospectively confirm the association of elevated hs-cTnT and adverse outcomes. In addition to established clinical variables, cTn seems the biomarker of interest to further improve risk prediction in HC, which should be evaluated in larger prospective registries.

Clinical value of 2D speckle tracking imaging in evaluating the effect of percutaneous intramyocardial septal radiofrequency ablation in patients with hypertrophic obstructive cardiomyopathy.

PURPOSE: To explore the short-term changes after percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) in patients with hypertrophic obstructive cardiomyopathy (HOCM), using quantitative analysis of two-dimensional speckle tracking imaging (2D-STI). METHODS: This prospective self-controlled study included 30 HOCM patients treated with PIMSRA. The study for each patient spanned over at least 1 year. Interventricular septal thickness and the left ventricular outflow tract peak pressure gradient (LVOT-PG) were measured through echocardiography, and 2D-STI was used to evaluate the left ventricular (LV) systolic function and synchrony. Cardiac function was assessed using the New York Heart Association's (NYHA) functional classification for cardiac disease, and through the serum levels of cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Biomarkers procollagen type I carboxy-terminal propeptide (PICP) and matrix metalloproteinases-2 (MMP-2) were detected for noninvasive assessment of myocardial fibrosis. RESULTS: The patients' interventricular septal thickness, LVOT-PG, NYHA class, and plasma PICP and MMP-2 levels at the first month postoperatively were significantly lower than before operation (all P < .05). The 2D-STI quantitative variables of LV systolic function and synchrony improved significantly (all P < .05). They improved further 1 year postoperatively (P < .01 or P < .001). Serum cTnI and NT-proBNP levels increased 1 month postoperatively, but significantly decreased 1 year postoperatively (both P < .05). Pearson or Spearman correlation analysis showed that the improvement of interventricular septal thickness, LVOT-PG, NYHA class, and the levels of cTnI, NT-proBNP, PICP and MMP-2, were in positive correlation with the restoration of LV systolic function and synchrony (P < .01 or P < .001). CONCLUSION: The changes in 2D-STI quantitative variables related to LV systolic function and synchrony are closely correlated with the improvement of cardiac function in HOCM patients after PIMSRA. These 2D-STI variables can serve for objective, accurate, and noninvasive evaluation of the HOCM treatment.

CMR feature tracking strain patterns and their association with circulating cardiac biomarkers in patients with hypertrophic cardiomyopathy.

AIMS: CMR feature tracking strain (CMR-FT) provides prognostic information. However, there is a paucity of data in hypertrophic cardiomyopathy (HCM). We sought to analyze global CMR-FT parameters in all four cardiac chambers and to assess associations with NT-proBNP and cardiac troponin T (hsTnT) in patients with HCM. METHODS: This retrospective study included 144 HCM patients and 16 healthy controls with CMR at 1.5 T. Analyses were performed on standard steady-state free precession cine (SSFP) CMR data using a commercially available software. Global left ventricular (LV) strain was assessed as longitudinal (LVLAX-GLS), circumferential (LVLAX-GCS) and radial strain (LVLAX-GRS) on long -axis (LAX) and as LVSAX-GCS and LVSAX-GRS on short- axis (SAX). Right ventricular (RV-GLS), left atrial (LA-GLS) and right atrial (RA-GLS) strain were assessed on LAX. RESULTS: We found LVLAX-GLS [- 18.9 (- 22.0, - 16.0), - 23.5 (- 25.5, - 22.0) %, p = 0.0001), LVSAX-GRS [86.8 (65.9-115.5), 119.6 (91.3-143.7) %, p = 0.001] and LALAX-GLS [LA2CH-GLS 29.2 (19.1-37.7), LA2CH-GLS 38.2 (34.3-47.1) %, p = 0.0036; LA4CH-GLS 22.4 (14.6-30.7) vs. LA4CH-GLS 33.4 (28.4-37.3) %, p = 0.0033] to be impaired in HCM compared to healthy controls despite normal LVEF. Furthermore, LV and LA strain parameters were impaired in HCM with elevated NT-proBNP and/or hsTnT, despite preserved LVEF compared to HCM with normal biomarker levels. There was a moderate correlation of LV and LA CMR-FT with levels of NT-proBNP and hsTnT. CONCLUSION: CMR-FT reveals LV and LA dysfunction in HCM despite normal LVEF. The association between impaired LV strain and elevated NT-proBNP and hsTnT indicates a link between unapparent functional abnormalities and disease severity in HCM. Typical CMR-FT findings in patients with hypertrophic cardiomyopathy.

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and can be classified into an obstructive (HOCM) and non-obstructive (HNCM) form. Major characteristics for HCM are the hypertrophy of cardiomyocytes and development of cardiac fibrosis. Patients with HCM have a higher risk for sudden cardiac death compared to a healthy population. In the present study, we investigated the abundancy of selected proteins as potential biomarkers in patients with HCM. We included 60 patients with HCM and 28 healthy controls and quantitatively measured the rate of a set of 92 proteins already known to be associated with cardiometabolic processes via protein screening using the proximity extension assay technology in a subgroup of these patients (20 HCM and 10 healthy controls). After validation of four hits in the whole cohort of patients consisting of 88 individuals (60 HCM patients, 28 healthy controls) we found only one candidate, c-KIT, which was regulated significantly different between HCM patients and healthy controls and thus was chosen for further analyses. c-KIT is a tyrosine-protein kinase acting as receptor for the stem cell factor and activating several pathways essential for cell proliferation and survival, hematopoiesis, gametogenesis and melanogenesis. Serum protein levels of c-KIT were significantly lower in patients with HCM than in healthy controls, even after adjusting for confounding factors age and sex. In addition, c-KIT levels in human cardiac tissue of patients with HOCM were significant higher compared to controls indicating high levels of c-KIT in fibrotic myocardium. Furthermore, c-KIT concentration in serum significantly correlated with left ventricular end-diastolic diameter in HOCM, but not HCM patients. The present data suggest c-KIT as a novel biomarker differentiating between patients with HCM and healthy population and might provide further functional insights into fibrosis-related processes of HOCM.

Difference in Metabolomic Response to Exercise between Patients with and without Hypertrophic Cardiomyopathy.

It is unclear how hypertrophic cardiomyopathy (HCM) affects cardiac metabolic pathways at rest and with exercise. This case-control study compared 15 cases with HCM to 2 control groups without HCM. Metabolomic profiling of 210 metabolites was carried out at rest and at peak exercise. The 50 most discriminant metabolites differentially regulated during exercise were selected using partial least squares discriminant analysis. Pathway enrichment analysis was also performed. At rest, no significant difference was observed in metabolomic profiling of HCM cases as compared to controls. By contrast, there were significant differences in metabolomic profiling in response to exercise (p < 0.05) in the following metabolic pathways: the aminoacyl-tRNA biosynthesis pathway; the nitrogen metabolism pathway; the glycine, serine, and threonine metabolism pathway; and the arginine and proline metabolism pathway. The present study demonstrates differential regulation of several metabolic pathways in patients with HCM in the setting of exercise stress.

N-terminal pro-brain natriuretic peptide and sudden cardiac death in hypertrophic cardiomyopathy.

OBJECTIVE: Elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with heart failure-related death in hypertrophic cardiomyopathy (HCM), but the relationship between NT-proBNP level and sudden cardiac death (SCD) in HCM remains undefined. METHODS: The study prospectively enrolled 977 unrelated patients with HCM with available NT-proBNP results who were prospectively enrolled and followed for 3.0±2.1 years. The Harrell's C-statistic under the receiver operating characteristic curve was calculated to evaluate discrimination performance. A combination model was constructed by adding NT-proBNP tertiles to the HCM Risk-SCD model. The correlation between log NT-proBNP level and cardiac fibrosis as measured by late gadolinium enhancement (LGE) or Masson's staining was analysed. RESULTS: During follow-up, 29 patients had SCD. Increased log NT-proBNP levels were associated with an increased risk of SCD events (adjusted HR 22.27, 95% CI 10.93 to 65.63, p<0.001). The C-statistic of NT-proBNP in predicting SCD events was 0.80 (p<0.001). The combined model significantly improved the predictive efficiency of the HCM Risk-SCD model from 0.72 to 0.81 (p<0.05), with a relative integrated discrimination improvement of 0.002 (p<0.001) and net reclassification improvement of 0.67 (p<0.001). Furthermore, log NT-proBNP levels were significantly correlated with cardiac fibrosis as detected either by LGE (r=0.257, p<0.001) or by Masson's trichrome staining in the myocardium (r=0.198, p<0.05). CONCLUSION: NT-proBNP is an independent predictor of SCD in patients with HCM and may help with risk stratification of this disease.

Reversed Septal Curvature Is Associated with Elevated Troponin Level in Hypertrophic Cardiomyopathy.

The aim of study was to compare patients with hypertrophic cardiomyopathy divided according to septal configuration assessed in a 4-chamber apical window. The study group consisted of 56 consecutive patients. Reversed septal curvature (RSC) and non-RSC were diagnosed in 17 (30.4%) and 39 (69.6%) patients, respectively. Both RSC and non-RSC groups were compared in terms of the level of high-sensitivity troponin I (hs-TnI), NT-proBNP (absolute value), NT-proBNP/ULN (value normalized for sex and age), and echocardiographic parameters, including left ventricular outflow tract gradient (LVOTG). A higher level of hs-TnI was observed in RSC patients as compared to the non-RSC group (102 (29.2-214.7) vs. 8.7 (5.3-18) (ng/l), p = 0.001). A trend toward increased NT-proBNP value was reported in RSC patients (1279 (367.3-1186) vs. 551.7 (273-969) (pg/ml), p = 0.056). However, no difference in the NT-proBNP/ULN level between both groups was observed. Provocable LVOTG was higher in RSC as compared to non-RSC patients (51 (9.5-105) vs. 13.6 (7.5-31) (mmHg), p = 0.04). Furthermore, more patients with RSC had prognostically unfavourable increased septal thickness to left LV diameter at the end diastole ratio. Patients with RSC were associated with an increased level of hs-TnI, and the only trend observed in this group was for the higher NT-proBNP levels. RSC seems to be an alerting factor for the risk of ischemic events. Not resting but only provocable LVOTG was higher in RSC as compared to non-RSC patients.

Shear Stress-Induced Activation of von Willebrand Factor and Cardiovascular Pathology.

The von Willebrand factor (vWF) is a plasma protein that mediates platelet adhesion and leukocyte recruitment to vascular injury sites and carries coagulation factor VIII, a building block of the intrinsic pathway of coagulation. The presence of ultra-large multimers of vWF in the bloodstream is associated with spontaneous thrombosis, whereas its deficiency leads to bleeding. In cardiovascular pathology, the progression of the heart valve disease results in vWF deficiency and cryptogenic gastrointestinal bleeding. The association between higher plasma levels of vWF and thrombotic complications of coronary artery disease was described. Of note, it is not the plasma levels that are crucial for vWF hemostatic activity, but vWF activation, triggered by a rise in shear rates. vWF becomes highly reactive with platelets upon unfolding into a stretched conformation, at shear rates above the critical value (more than 5000 s-1), which might occur at sites of arterial stenosis and injury. The activation of vWF and its counterbalance by ADAMTS-13, the vWF-cleaving protease, might contribute to complications of cardiovascular diseases. In this review, we discuss vWF involvement in complications of cardiovascular diseases and possible diagnostic and treatment approaches.

Diffusion-weighted imaging in hypertrophic cardiomyopathy: association with high T2-weighted signal intensity in addition to late gadolinium enhancement.

Diffusion-weighted imaging (DWI) has been confirmed to be associated with late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM). In this context, we aimed to study whether DWI could reflect the active tissue injury and edema information of HCM which were usually indicated by T2 weighted images. Forty HCM patients were examined using a 3.0 T magnetic resonance scanner. Cine, T2-weighted short tau inversion recovery (T2-STIR), DWI and LGE sequences were acquired. T1 mapping was also included to quantify the focal and diffuse fibrosis. Cardiac troponin I (cTnI) was tested to assess the recently myocardial injury. Student's t-test, Mann-Whitney U test, One-way analysis, Kruskal-Wallis analysis, the Spearman correlation analysis, and multivariable regression were used in this study. The apparent diffusion coefficient (ADC) was significantly elevated in the cTnI positive group (P = 0.01) and correlated with LGE (ρ = 0.312, P = 0.049) and HighT2 extent (ρ = 0.443, P = 0.004) in the global level. In the segmental analysis, the ADC significantly differentiated the segments with and without HighT2/LGE presence (P = 0.00). The average ADC values were higher in segments with HighT2 and LGE coexistence than in those with only LGE presence (P < 0.05). Multivariable regression indicated that segmental HighT2 and LGE were both contributing factors to the ADC values. In this study of HCM, we confirmed that ADC as a molecular diffusion parameter reflects the replacement fibrosis of myocardium. Moreover, it also reveals edema extent and its association with serum cTnI.

B-type natriuretic peptide and outcome in patients with apical hypertrophic cardiomyopathy.

BACKGROUND: Although elevated B-type natriuretic peptide (BNP) levels predict outcome in patients with hypertrophic cardiomyopathy (HCM), the association between BNP levels and outcome in patients with the apical phenotype of HCM remains unclear. We evaluated the impact of elevated BNP levels on outcome in a cohort of apical HCM patients. METHODS: Among 432 HCM patients, 144 with an apical phenotype were examined. Plasma BNP levels were measured at the time of the initial evaluation. RESULTS: The median (interquartile range) BNP level at initial evaluation in these patients was 188.5 (72.0-334.4) pg/mL. During a median follow-up period of 9.5 years, 34 patients experienced HCM-related adverse outcomes, including 2 patients with sudden death, 5 with appropriate implantable defibrillator shocks, 3 with stroke-related death, 8 with non-fatal stroke, and 16 with heart failure hospitalization. Receiver operating characteristic (ROC) curve analysis of the prognostic value of BNP for the combined endpoint gave an area under the ROC curve of 0.756, and optimal BNP cut-off point of 226.0pg/mL. Patients with high BNP levels (≥226.0pg/mL) were at significantly greater risk of the combined endpoint (log-rank p<0.001) than patients with low BNP levels. Multivariable analysis that included BNP levels and potential confounders showed that high BNP levels were an independent determinant of the combined endpoint (adjusted hazard ratio: 3.71; p=0.002). CONCLUSIONS: Measuring BNP may help stratify the risk of HCM-related adverse outcome in apical HCM patients.

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

Association between severity of obstructive sleep apnea and high-sensitivity C-reactive protein in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in patients with hypertrophic obstructive cardiomyopathy (HOCM). Inflammatory responses are increased in patients with OSA, meanwhile, inflammation is also associated with adverse outcomes in HOCM. HYPOTHESIS: To investigate the association between severity of OSA and high-sensitivity C-reactive protein (hs-CRP) in patients with HOCM. METHODS: Three hundred and ninteen patients with HOCM who underwent sleep evaluations at Fuwai Hospital were retrospectively included between February 2010 and December 2018. Data from baseline clinical characteristics and polysomnography studies were collected. RESULTS: OSA was present in 168 (52.7%). Patients with OSA were older, more likely to be male, had a higher body mass index and more clinical comorbidities. Patients with OSA had enlarged left ventricular diameter and similar left ventricular outflow tract obstruction compared with those without. In multivariate logistic analysis, apnea-hypopnea index (OR, 1.024; 95% CI, 1.005-1.044; P = .014), oxygen desaturation index (OR, 1.025; 95% CI, 1.004-1.046; P = .018) and lowest oxygen saturation (OR, 0.951; 95% CI, 0.915-0.989; P = .011) were independently associated with high risk hs-CRP (>3 mg/L) after adjusting for confounders. In addition, decreasing lowest oxygen saturation (ß = -.159, P = .004) was also independently correlated with increasing hs-CRP concentrations in multivariate linear analysis after adjusting for confounders. CONCLUSIONS: Severity of OSA was independently associated with elevated hs-CRP levels in patients with HOCM. Further studies are needed to evaluate the effects of treating OSA on hs-CRP as well as clinical outcomes in these patients.

Cardiovascular magnetic resonance T2* mapping for the assessment of cardiovascular events in hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of adverse cardiac events. Beyond classic risk factors, relative myocardial ischaemia and succeeding myocardial alterations, which can be detected using either contrast agents or parametric mapping in cardiovascular magnetic resonance (CMR) imaging, have shown an impact on outcome in HCM. CMR may help to risk stratify using parametric T2* mapping. Therefore, the aim of the present study was to evaluate the association of T2* values or fibrosis with cardiovascular events in HCM. Methods: The relationship between T2* with supraventricular, ventricular arrhythmia or heart failure was retrospectively assessed in 91 patients with HCM referred for CMR on a 1.5T MR imaging system. Fibrosis as a reference was added to the model. Patients were subdivided into groups according to T2* value quartiles. Results: 47 patients experienced an event of ventricular arrhythmia, 25 of atrial fibrillation/flutter and 17 of heart failure. T2*≤28.7 ms yielded no association with ventricular events in the whole HCM cohort. T2* of non-obstructive HCM showed a significant association with ventricular events in univariate analysis, but not in multivariate analysis. For the combined endpoint of arrhythmic events, there was already an association for the whole HCM cohort, but again only in univariate analyses. Fibrosis stayed the strongest predictor in all analyses. There was no association for T2* and fibrosis with heart failure. Conclusions: Decreased T2* values by CMR only provide a small association with arrhythmic events in HCM, especially in non-obstructive HCM. No information is added for heart failure.