Daily Cardiology Research Analysis

Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.

BACKGROUND: Advances in rejection diagnostics are reshaping post-transplant surveillance. The Molecular Microscope Diagnostic System (MMDx), which analyzes biopsy-derived transcriptomic profiles, may address limitations of histology, particularly for antibody-mediated rejection (ABMR). We evaluated the impact of donor-specific antibodies (DSA) and donor-derived cell-free DNA (dd-cfDNA) on ABMR detection using MMDx. METHODS: We conducted a prospective, single-center study of 351 for-cause heart transplant (HT) biopsies. Biopsies were graded by ISHLT criteria and assessed with MMDx. DSA was categorized by antibody class and mean fluorescence intensity (MFI). Comparisons and regression analyses accounted for repeated biopsies using generalized estimating equations (GEE) and generalized linear models (GLM) with clustered robust errors. Diagnostic performance was assessed with receiver operating characteristics (ROC) analysis and compared using the DeLong test. RESULTS: Across 351 biopsies from 223 HT recipients, MMDx identified ABMR more frequently than histology (14.8% vs 6.0%; OR 3.26, 95% CI 1.65-6.45; p < 0.001), both in DSA-positive (21.5% vs 10.5%; p = 0.005) and DSA-negative biopsies (8.4% vs 1.7%; p = 0.034). When stratified by antibody strength, MMDx detected ABMR ten-fold more often than histology among low-MFI antibodies (<4000; 19.2% vs 2.6%; OR 10.8, 95% CI 2.18-53.4; p = 0.003), whereas detection rates were similar in high-MFI antibodies (≥4000; 23.9% vs 18.9%; OR 1.81, 95% CI 0.75-4.35; p = 0.19). In the DSA⁺ cohort, when MFI was modeled as a continuous variable, AUC for predicting ABMR was 0.52 (95% CI 0.44-0.65) for MMDx-defined ABMR vs 0.87 (95% CI 0.78-0.94) for histology-defined AMR. For MMDx-defined ABMR, dd-cfDNA outperformed DSA (AUC 0.80 [0.70-0.89] vs 0.52 [0.48-0.57]; p < 0.001) with minimal incremental gain when combined (AUC 0.80 [0.71-0.90]). For histology-defined AMR, both biomarkers showed modest discrimination (AUC 0.61 for dd-cfDNA vs 0.51 for DSA) without significant improvement when combined (AUC 0.61; p = 0.40). CONCLUSIONS: MMDx enhances ABMR assessment, independent of DSA characteristics, capturing early antibody-mediated changes not evident by histology. DSA alone provides limited diagnostic discrimination and should be interpreted alongside dd-cfDNA, which more accurately reflects active immune-mediated injury. These findings suggest that combining molecular and plasma-based diagnostics can enhance multimodal surveillance strategies.

BACKGROUND: Prognostication of recovery in patients who are unconscious following cardiac arrest can be guided by concentrations of brain injury biomarkers in the blood. The optimal biomarker and cutoff concentrations for the prediction of outcome remain unknown. In this study, we aimed to evaluate which biomarker of brain injury is most accurate for predicting functional outcome after cardiac arrest, and to evaluate cutoff levels for the prediction of good and poor outcome. METHODS: This study was a prospective, international, observational biomarker study within the international Targeted Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial including adults aged 18 years or older with a presumed cardiac cause or unknown cause of arrest. Patients were recruited from 24 European hospitals. Serum samples were collected at 0, 24, 48, and 72 h after admission to intensive care units. Concentrations of neuron-specific enolase, S100, neurofilament light, and glial fibrillary acidic protein were analysed with Elecsys electrochemiluminescence immunoassays. The primary outcome was 6-month good (modified Rankin Scale 0-3) or poor (modified Rankin Scale 4-6) functional outcome. Prognostic accuracy was evaluated by the area under the receiver operating characteristic curve (AUROC). The biomarker with the highest AUROC at each timepoint was compared with that of the second highest marker using DeLong's test. As pre-specified, to account for multiple comparisons using Bonferroni correction, a p value of less than 0·0125 was considered statistically significant. FINDINGS: Between April, 2018, and January, 2020, 113 (12%) of 932 eligible patients were excluded due to death, missed sampling, or missing outcome data. 661 (81%) of 819 included patients were male and 158 (19%) were female, the mean age was 64 years (SD 13), and 418 (51%) had a poor outcome. In patients who were unconscious, neurofilament light predicted functional outcome with AUROCs at 0, 24, 48, and 72 h of 0·77 (95% CI 0·73-0·80), 0·92 (0·90-0·94), 0·93 (0·91-0·95), and 0·93 (0·91-0·95), respectively. Glial fibrillary acidic protein achieved an AUROC of 0·74 (95% CI 0·70-0·77) at 0 h, 0·87 (0·84-0·90) at 24 h, 0·87 (0·84-0·90) at 48 h, and 0·87 (0·84-0·91) at 72 h. Neuron-specific enolase predicted functional outcome with an AUROC of 0·61 (95% CI 0·56-0·65) at 0 h, 0·78 (0·75-0·82) at 24 h, 0·85 (0·81-0·88) at 48 h, and 0·86 (0·82-0·89) at 72 h. S100 achieved an AUROC of 0·74 (95% CI 0·71-0·78) at 0 h, 0·84 (0·81-0·87) at 24 h, 0·79 (0·75-0·82) at 48 h, and 0·78 (0·74-0·82) at 72 h. Neurofilament light had a statistically significantly higher AUROC than the second highest marker, glial fibrillary acidic protein, at 24, 48, and 72 h (p<0·0001), but not at 0 h (p=0·27). INTERPRETATION: Neurofilament light is a highly accurate predictor of long-term outcome after cardiac arrest and superior to other relevant biomarkers evaluated in this study. FUNDING: The Swedish Research Council (Vetenskapsrådet), the Swedish Heart-Lung Foundation, the Stig and Ragna Gorthon Foundation, the Knutsson Foundation, the Laerdal Foundation, the Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, the Bundy Academy at Lund University, Regional Research Support in Skåne, the Swedish Government, and Roche Diagnostics International.