Stratified medicine for acute and chronic coronary syndromes: A patient-tailored approach.

The traditional approach to management of cardiovascular disease relies on grouping clinical presentations with common signs and symptoms into pre-specified disease pathways, all uniformly treated according to evidence-based guidelines ("one-size-fits-all"). The goal of precision medicine is to provide the right treatment to the right patients at the right time, combining data from time honoured sources (e.g., history, physical examination, imaging, laboratory) and those provided by multi-omics technologies. In patients with ischemic heart disease, biomarkers and intravascular assessment can be used to identify endotypes with different pathophysiology who may benefit from distinct treatments. This review discusses strategies for the application of stratified management to patients with acute and chronic coronary syndromes.

Utility and acceptability of remote 6-lead electrocardiographic monitoring in children with inherited cardiac conditions.

OBJECTIVE: This pilot study sought to investigate the utility and acceptability of the KardiaMobile 6-lead ECG (KM6LECG) as a tool for remote monitoring in children with inherited cardiac conditions. DESIGN: A single-centre prospective cohort study. Children underwent standard clinical evaluation including a 12-lead ECG and a KM6LECG in the clinic. Participants recorded KM6LECGs monthly at home for 3 months. Families completed a questionnaire on their experience. SETTING: Great Ormond Street Hospital Centre for Inherited Cardiovascular Diseases. PARTICIPANTS: 64 children: 22 with hypertrophic cardiomyopathy (HCM); 22 with long QT syndrome and 20 unaffected siblings (controls). MAIN OUTCOME MEASURES: Comparison of data extracted from the clinic 12-lead ECG and supervised KM6LECG, and the supervised and unsupervised KM6LECG recording. RESULTS: Of 64 children (35% female, mean age 12 years), 58 had a baseline 12-lead ECG and appropriate baseline KM6LECG. In children with HCM, abnormalities in ventricular depolarisation/repolarisation in the limb leads of the 12-lead ECG were reliably reproduced. From the whole cohort, there was a strong positive correlation between the corrected QT interval from the 12-lead ECG and baseline KM6LECG (intraclass correlation coefficient=0.839) and baseline KM6LECG with an unsupervised KM6LECG (intraclass correlation coefficient=0.736). Suspected 'lead' misplacement impacted 18% of unsupervised recordings. Overall, the acceptability of the KM6LECG to families was good. CONCLUSIONS: The KM6LECG provides an accurate tool for assessing some ECG abnormalities associated with paediatric inherited cardiovascular disease and may provide a useful at-home adjunct to face-to-face clinical care of children requiring ECG assessment.

Oral anticoagulation in patients with left ventricular thrombus - a systematic review and meta-analysis.

AIMS: Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analyzed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety. METHODS: We conducted a systematic search and meta-analysis of observational and randomized data comparing DOACs versus VKAs in patients with LVT. Endpoints of interest were stroke or systemic embolism, thrombus resolution, all-cause death, and a composite bleeding endpoint. Estimates were pooled using a random-effect model meta-analysis, and their robustness was investigated using sensitivity and influential analyses. RESULTS: We identified 22 articles (18 observational studies, 4 small randomized clinical trials) reporting on a total of 3,587 patients (2,489 VKA vs. 1,098 DOAC therapy). The pooled estimates for stroke or systemic embolism (OR 0.81; 95% CI [0.57, 1.15]) and thrombus resolution (OR 1.12; 95% CI [0.86; 1.46]) were comparable, and there was low heterogeneity overall across the included studies. DOAC use was associated with lower odds of all-cause death (OR 0.65; 95%CI [0.46; 0.92]) and a composite bleeding endpoint (OR 0.67; 95%CI [0.47; 0.97]). A risk of bias was evident particularly for observational reports, with some publication bias suggested in funnel plots. CONCLUSION: In this comprehensive analysis of mainly observational data, the use of DOACs was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution compared to VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Adequately sized randomized clinical trials are needed to confirm these findings, which could allow a wider adoption of DOACs in patients with LVT.

Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM. METHODS: Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels. RESULTS: Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044). CONCLUSIONS: In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.

Endomyocardial biopsy: safety and prognostic utility in paediatric and adult myocarditis in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry.

BACKGROUND AND AIMS: Contemporary multicentre data on clinical and diagnostic spectrum and outcome in myocarditis are limited. Study aims were to describe baseline features, 1-year follow-up, and baseline predictors of outcome in clinically suspected or biopsy-proven myocarditis (2013 European Society of Cardiology criteria) in adult and paediatric patients from the EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry. METHODS: Five hundred eighty-one (68.0% male) patients, 493 adults, median age 38 (27-52) years, and 88 children, aged 8 (3-13) years, were divided into 3 groups: Group 1 (n = 233), clinically suspected myocarditis with abnormal cardiac magnetic resonance; Group 2 (n = 222), biopsy-proven myocarditis; and Group 3 (n = 126) clinically suspected myocarditis with normal or inconclusive or no cardiac magnetic resonance. Baseline features were analysed overall, in adults vs. children, and among groups. One-year outcome events included death/heart transplantation, ventricular assist device (VAD) or implantable cardioverter defibrillator (ICD) implantation, and hospitalization for cardiac causes. RESULTS: Endomyocardial biopsy, mainly right ventricular, had a similarly low complication rate in children and adults (4.7% vs. 4.9%, P = NS), with no procedure-related death. A classical myocarditis pattern on cardiac magnetic resonance was found in 31.3% of children and in 57.9% of adults with biopsy-proven myocarditis (P < .001). At 1-year follow-up, 11/410 patients (2.7%) died, 7 (1.7%) received a heart transplant, 3 underwent VAD (0.7%), and 16 (3.9%) underwent ICD implantation. Independent predictors at diagnosis of death or heart transplantation or hospitalization or VAD implantation or ICD implantation at 1-year follow-up were lower left ventricular ejection fraction and the need for immunosuppressants for new myocarditis diagnosis refractory to non-aetiology-driven therapy. CONCLUSIONS: Endomyocardial biopsy was safe, and cardiac magnetic resonance using Lake Louise criteria was less sensitive, particularly in children. Virus-negative lymphocytic myocarditis was predominant both in children and adults, and use of immunosuppressive treatments was low. Lower left ventricular ejection fraction and the need for immunosuppressants at diagnosis were independent predictors of unfavourable outcome events at 1 year.

Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. OBJECTIVES: The aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis. METHODS: For this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children). CONCLUSIONS: Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.

Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry.

BACKGROUND AND AIMS: Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. METHODS: Prospective data were collected on individuals aged 1-<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014-December 2016). RESULTS: A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0-10] years, and there was a male predominance [n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P = .003]. Over a median follow-up of 12.5 months (IQR 11.3-15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). CONCLUSIONS: The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2023.

Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2 and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and treatment of CVDs.

Childhood-onset hypertrophic cardiomyopathy caused by thin-filament sarcomeric variants.

Up to 20% of children with sarcomeric hypertrophic cardiomyopathy (HCM) have disease-causing variants in genes coding for thin-filament proteins. However, data on genotype-phenotype correlations for thin-filament disease are limited. This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease.Longitudinal data were collected from 40 children under 18 years with a disease-causing variant in a thin-filament protein from a single quaternary referral centre. Twenty-one (female n=6, 35.5%) were diagnosed with HCM at a median age of 13.0 years (IQR 8.3-14.0). Over a median follow-up of 5.0 years (IQR 4.0-8.5), three (14.3%) experienced one or more major adverse cardiac events (MACE) (two patients had an out-of-hospital arrest and eight appropriate implantable cardiac defibrillator (ICD) therapies in three patients). One gene carrier died suddenly at age 9 years. Compared with those with thick-filament disease, children with thin-filament variants more commonly experienced non-sustained ventricular tachycardia [NSVT; n=6 (28.6%) vs n=14 (10.8%), p=0.024] or underwent ICD insertion (thin, n=13 (61.9%) vs thick, n=50 (38.5%), p=0.040). However, there was no difference in the incidence of MACE (thin 2.47/100 pt years (95% CI 0.80 to 7.66) vs thick 3.63/100 pt years (95% CI 2.25 to 5.84)) or an arrhythmic event (thin 1.65/100 pt years (95% CI 0.41 to 6.58) vs thick 2.55/100 pt years (95% CI 1.45 to 4.48), p value 0.43).This study suggests that adverse events in thin-filament disease are predominantly arrhythmic and may occur in the absence of hypertrophy, but overall short-term outcomes do not differ significantly from thick-filament disease.

Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

AIMS: This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. CONCLUSIONS: These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

Biallelic PKP2 loss of function variants are associated with a lethal perinatal-onset biventricular dilated cardiomyopathy with excessive trabeculations and ventricular septal defects.

Homozygous plakophilin-2 (PKP2) variants have been identified as a cause of a lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET) in three cases. We report three more cases from two families with homozygous pathogenic PKP2 variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function PKP2 variants cause a lethal, perinatal-onset cardiomyopathy.

Innate immune signaling in hearts and buccal mucosa cells of patients with arrhythmogenic cardiomyopathy.

Background: Nuclear factor κB (NF-κB) signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy (ACM) by mobilizing CCR2-expressing macrophages that promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with ACM. Objectives: We sought to determine if persistent innate immune signaling via NF-κB occurs in cardiac myocytes in patients with ACM and if this is associated with myocardial infiltration of proinflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF-κB signaling. Methods: We analyzed myocardium from ACM patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NF-κB signaling. We also counted myocardial CCR2-expressing cells. Results: RelA/p65 signal was seen in numerous cardiac myocyte nuclei in 34 of 36 cases of ACM but not in 19 age-matched control individuals. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF-κB signaling. NF-κB signaling was observed in buccal cells in young subjects with active disease. Conclusions: Patients with clinically active ACM exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells, reflecting a local and systemic inflammatory process. Such individuals may benefit from anti-inflammatory therapy.

Performance of the PRIMaCY sudden death risk prediction model for childhood hypertrophic cardiomyopathy: implications for implantable cardioverter-defibrillator decision-making.

AIMS: The validated HCM Risk-Kids model provides accurate individualized estimates of sudden cardiac death risk in children with hypertrophic cardiomyopathy (HCM). A second validated model, PRIMaCY, also provides individualized estimates of risk, but its performance and clinical impact has not been independently investigated. The aim of this study was to investigate the clinical impact of using the PRIMaCY sudden cardiac death (SCD) risk model in childhood HCM. METHODS AND RESULTS: The estimated 5-year SCD risk was calculated for children meeting diagnostic criteria for HCM in a large single-centre cohort using PRIMaCY (clinical and genetic) and HCM Risk-Kids model, and model performance was assessed. Three hundred one patients [median age 10 (interquartile range 4-14)] were followed up for an average of 4.9 (±3.8) years, during which 30 (10.0%) reached the SCD or equivalent event endpoint. Harrell's C-statistic for the clinical and genetic models was 0.66 [95% confidence interval (CI) 0.52-0.8] and 0.66 (95% CI 0.54-0.80) with a calibration slope of 0.19 (95% CI 0.04-0.54) and 0.26 (95% CI -0.03-0.62), respectively. The number needed to treat to potentially treat one life-threatening arrhythmia for the PRIMaCY clinical, PRIMaCY genetic, and HCM Risk-Kids models was 13.7, 14.5, and 9.4, respectively. CONCLUSION: Although PRIMaCY has a similar discriminatory ability to that reported for HCM Risk-Kids, estimated risk estimates did not correlate well with observed risk. A higher proportion of patients met implantable cardioverter-defibrillator thresholds using PRIMaCY model compared with HCM Risk-Kids. This has important clinical implications as these patients will be exposed to a lifetime risk of complications and inappropriate therapies.