Friedrich, Matthias G.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Abstract Background Myocardial feature-tracking (FT) strain from cardiovascular magnetic resonance (CMR) has incremental prognostic value beyond traditional imaging biomarkers. Clinical use is limited by the absence of population-specific healthy reference ranges. This study provides age-, sex-, and ethnicity-specific reference ranges for CMR-derived FT strain from the Healthy Hearts Consortium (HHC). Methods The HHC is an international collaboration comprising CMR scans from 9,088 verified healthy adults across six centres, covering the entire adult age spectrum and with diverse ethnic background. Standardised CMR acquisition protocols were used. Image analysis was performed by two experienced readers following pre-specified standard operating procedures and using two commercially available software platforms (cvi42®, Circle Cardiovascular Imaging Inc.; suiteHEART®, Neosoft LLC). The following metrics were extracted: i) global FT strain metrics from both ventricles (longitudinal, circumferential, and radial) and both atria (longitudinal); ii) strain rate; iii) Mitral/Tricuspid annular plane systolic excursion (MAPSE, TAPSE); iv) rapid strain (long-axis, junctional strain) from the left ventricle and both atria. Quality control included visual inspection of all images and the removal of biologically non-sensical values and extreme statistical outliers. Reference ranges were calculated by age group (deciles: 20-80 years), sex (male/female), and ethnicity (White, Black, Chinese, South Asian, Mixed/Other) using the 95% prediction interval method. Technical variations due to scanner vendor, software platform, and field strength (1.5T vs. 3.0T), were analysed. Results The study included 4,452 men (49%) and 4,636 women (51%). Ages ranged from 18 to 83 (mean 61±13) years. The sample included diverse ethnic backgrounds [White (81.7%), South Asian (5.6%), Mixed/Other (5.3%), Black (3.7%), and Chinese (3.7%)]. Women demonstrated significantly higher absolute strain values than men across. Absolute myocardial strain values were higher in younger age groups and lower in older age groups, most notably in left global circumferential and longitudinal strain. Ethnic differences in strain were most pronounced between White and Black as well as between White and Chinese individuals regarding left and right ventricular strain values, while left and right atrial strain values as well as rapid strain values, were similar across ethnic groups. Conclusion This study provides comprehensive, population-specific reference ranges for FT-CMR-derived myocardial strain, addressing a clinical knowledge gap. These findings inform clinical interpretation, improving diagnostic accuracy and risk stratification in different populations. This work represents a significant step towards a broader clinical implementation of myocardial strain analysis in routine cardiovascular care, ensuring more accurate classification of findings across varying demographic groups.

Abstract Introduction Cardiovascular magnetic resonance (CMR) imaging enables precise, non-invasive assessment of cardiac structure and function, yet the clinical utility of CMR metrics is limited by the lack of comprehensive, population-specific reference values. By directly reanalyzing data from a large, multi-ethnic cohort rather than relying solely on pooled literature, could enable the establishment of standardized reference ranges and severity grading thresholds. Aim To provide comprehensive, age-, sex-, and ethnicity-stratified CMR reference ranges and severity grading thresholds for key ventricular and atrial parameters. Methods We analyzed over 9,000 CMR scans from the Healthy Hearts Consortium (HHC), comprising six international cohorts. All individuals were free from overt cardiovascular disease and major comorbidities, ensuring a verified healthy sample. Two automated segmentation software solutions—cvi42 (Circle Cardiovascular Imaging) and suiteHEART (Neosoft)—were used to quantify left and right ventricular volumes, myocardial mass, and atrial volumes in standard cine stacks. All endorsed segmentation modes were applied. Quality control protocol combined expert visual review and statistical outlier analysis. We derived 95% prediction intervals (PI) to define the normal range, with additional severity thresholds for mild (95–99.73% PI), moderate (99.73–99.99% PI), and severe (>99.99% PI) deviation from the reference range. Results The final dataset comprised of 9,059 verified healthy adults aged 18–83 years (mean 61 ± 13 years), with a near-equal sex distribution (51% women). Demographics included White (81.6%), South Asian (5.6%), Mixed/Other (5.3%), Black (3.8%), and Chinese (3.7%) participants. Results demonstrated that sex, age, and ethnicity strongly influenced cardiac indices. Men had higher indexed LV and RV volumes and greater myocardial mass than women. Black participants presented the highest indexed LV myocardial mass across age groups, whereas Chinese participants had comparatively lower myocardial mass values (Figure 1). In contrast, atrial volumes remained relatively stable across age categories. Comparative analysis showed minor differences between the two software tools, particularly for atrial parameters; however, derived ejection fractions remained consistent. We established age-, sex-, and ethnicity-stratified reference ranges for key CMR parameters. To facilitate clinical interpretation, we defined severity thresholds corresponding to mild, moderate, and severe abnormalities. Conclusion This large-scale, international effort addresses prior limitations in CMR interpretation by offering robust, contemporary reference ranges and severity grading applicable to diverse populations and imaging protocols. Our severity grading thresholds support consistency in clinical reporting and decision-making, enabling clearer identification of early subclinical changes and more accurate monitoring of disease progression.Subset of CMR value ranges in females

Abstract Background Myocardial strain derived from cardiovascular magnetic resonance (CMR) using feature tracking (FT) offers incremental prognostic value beyond traditional imaging markers. However, its broader clinical application is hindered by the lack of population-specific reference ranges. This study establishes age-, sex-, and ethnicity-specific normative data for FT-CMR-derived myocardial strain metrics from the Healthy Hearts Consortium (HHC). Methods The HHC is a large, international, multicohort initiative comprising CMR data from 9,088 rigorously screened healthy adults across six centers. The cohort spans the full adult age range and includes greater ethnic diversity than any comparable dataset. CMR scans were acquired using standardized protocols. Image analysis followed pre-specified standard operating procedures and was performed by two experienced readers using two commercial platforms (CVI42®, Circle Cardiovascular Imaging; suiteHEART®, Neosoft). Metrics extracted included: (i) global longitudinal, circumferential, and radial FT strain for both ventricles and atria; (ii) strain rate; (iii) annular plane systolic excursion (MAPSE, TAPSE); and (iv) rapid strain metrics (long-axis, junctional strain) for the left ventricle and atria. Comprehensive quality control involved visual review and exclusion of biologically implausible or extreme outlier values. Reference ranges were calculated using the 95% prediction interval method, stratified by age deciles (20–80 years), sex, and ethnicity (White, Black, Chinese, South Asian, Mixed/Other). The impact of technical factors—scanner vendor, field strength (1.5T vs 3.0T), and software platform—was also assessed. Results The study included 4,452 men (49%) and 4,636 women (51%), aged 18 to 83 years (mean 61 ± 13). The cohort was ethnically diverse: White (81.7%), South Asian (5.6%), Mixed/Other (5.3%), Black (3.7%), and Chinese (3.7%). Women consistently exhibited higher absolute strain values than men. A clear age-related decline in strain was observed, particularly in left ventricular global circumferential and longitudinal strain. Ethnic differences were most pronounced between White and Black, and White and Chinese individuals for RV and LV strain metrics; in contrast, RA, LA, and rapid strain metrics showed minimal ethnic variation. Conclusion This study delivers the most comprehensive age-, sex-, and ethnicity-specific reference ranges to date for FT-CMR-derived myocardial strain. These normative values support improved clinical interpretation, aiding diagnosis and risk stratification in diverse populations. The findings mark a pivotal advancement towards the routine integration of myocardial strain assessment in cardiovascular imaging practice.

Abstract Introduction Cannabidiol has been shown to exert significant anti-inflammatory effects and has demonstrated efficacy in murine models of autoimmune myocarditis, pericarditis, and heart failure. The ARCHER Study assessed whether a pharmaceutically produced cannabidiol formulation showed beneficial effects on cardiac magnetic resonance (CMR) endpoints known to predict prognosis in this patient population. Methods In a multicentre international double-blind placebo-controlled phase 2 study, we randomly assigned 109 patients within 10 days of CMR confirmed diagnosis of acute myocarditis to 12 weeks of pharmaceutically produced oral cannabidiol (active) or placebo. Dose was titrated up to 10 mg/kg of body weight twice daily. Primary endpoints were the difference in extracellular volume (ECV) and global longitudinal strain (GLS) measured by CMR at week 12. Other CMR endpoints included left-ventricular ejection fraction (LVEF), LV mass, intracellular volume (ICV), LV end-diastolic and end-systolic volumes (LVEDV, LVESV), and left-atrial end-systolic volume (LAESV). Results All randomized patients (56 active/53 placebo) completed the study with no loss to follow-up. Study drug appeared safe and well tolerated. Baseline mean ECV 38.9 ± 10.9 ml, GLS −15.3 ± 3.6%, and LVEF 60.6 ± 9.9% were consistent with mild to moderate myocarditis and predominantly intact LV function. Week 12 mean ECV was 33.6 ml in the active group and 37.3 ml in the placebo group, a difference of −3.7 ml, confidence interval (CI): −7.4 to 0.1; P = .0538; GLS was −16.0% in the active group and −15.9% in the placebo group, difference of −0.1, CI: −1.2 to 1.1; P = .90. Left ventricular mass was significantly reduced in the active group at 121.1 g compared to placebo 130.3 g, a difference of −9.2, CI: −16.4 to −2.1; P = .0117. In terms of remodelling, LAESV was significantly reduced in the active group (−8.1 ml; P = .0376) while the reduction in LVEDV failed to reach significance (−7.4 ml; P = .098). Conclusion In mild-to-moderate acute myocarditis, treatment with pharmaceutically manufactured cannabidiol was not associated with a statistically significant change in myocardial ECV or GLS, although a trend towards reduction in ECV was observed. In addition, improvement in other potential markers of myocardial recovery, including a significant reduction in LV mass, was seen in the active treatment group. Further investigation of the therapeutic potential of this therapy in inflammatory cardiac conditions is warranted.

Abstract Aims Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF). Methods and results We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper. Conclusions The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments.

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.