In biology, classification systems are used to promote understanding and systematic discussion through the use of logical groups and hierarchies. In clinical medicine, similar principles are used to standardise the nomenclature of disease. For more than three decades, heart muscle diseases have been classified into primary or idiopathic myocardial diseases (cardiomyopathies) and secondary disorders that have similar morphological appearances, but which are caused by an identifiable pathology such as coronary artery disease or myocardial infiltration (specific heart muscle diseases). In this document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme. The aim is to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses.

In patients with hypertrophic cardiomyopathy, left ventricular outflow tract obstruction at rest is a strong, independent predictor of progression to severe symptoms of heart failure and of death.

Background-Nonobstructive hypertrophic cardiomyopathy (HCM) has been regarded as the predominant hemodynamic form of the disease on the basis of assessment of outflow gradient under resting conditions. We sought to prospectively define the prevalence, clinical profile, and significance of left ventricular (LV) outflow tract obstruction under resting conditions and with physiological exercise in a large HCM cohort. Methods and Results-We prospectively analyzed 320 consecutive HCM patients (age, 47Ϯ17 years), measuring LV outflow gradient at rest, with Valsalva maneuver, and with exercise echocardiography. LV outflow obstruction was present at rest and/or with exercise in 225 patients (70%); 119 had rest gradients Ն50 mm Hg and were not exercised.Of the other 201 patients with gradients Ͻ50 mm Hg at rest (average, 4Ϯ9 mm Hg), 106 developed mechanical obstruction to LV outflow resulting from mitral valve-septal contact after exercise (80Ϯ43 mm Hg), including 76 with marked gradients Ն50 mm Hg and 46 with heart failure symptoms. The remaining 95 patients (30%) had no or small gradients (Ͻ30 mm Hg) both at rest and with exercise. Valsalva maneuver underestimated the presence and magnitude of exercise-induced obstruction. Conclusions-Among those patients who come to clinical evaluation, HCM is a predominantly obstructive disease in which LV outflow gradients, frequently associated with heart failure symptoms and often identified only with exercise, are evident in most patients (ie, 70%

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2)1. Here we characterize a third class of BRAF mutants—those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS–GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

In patients with hypertrophic cardiomyopathy, the degree of microvascular dysfunction is a strong, independent predictor of clinical deterioration and death. Severe microvascular dysfunction is often present in patients with mild or no symptoms and may precede clinical deterioration by years.

Surgical myectomy performed to relieve outflow obstruction and severe symptoms in HCM was associated with long-term survival equivalent to that of the general population, and superior to obstructive HCM without operation. In this retrospective study, septal myectomy seems to reduce mortality risk in severely symptomatic patients with obstructive HCM.

Background-Clinical impact of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is largely unresolved.Thus, we analyzed the prognostic implications of AF in a large, community-based HCM population assembled from Italian and US cohorts. Methods and Results-Occurrence of AF and outcome were assessed in 480 consecutive HCM patients (age at diagnosis, 45Ϯ20 years; 61% male) who were followed up for 9.1Ϯ6.4 years. AF occurred in 107 patients (22%; incidence, 2%/y) and was independently predicted by advancing age, congestive symptoms, and increased LA size at diagnosis. Patients with AF had increased risk for HCM-related death (OR, 3.7; PϽ0.002) because of excess heart failure-related mortality but not sudden, unexpected death. This risk associated with AF was substantially greater in patients with outflow obstruction or with earlier development of AF (Յ50 years of age). AF patients were also at increased risk for stroke (OR, 17.7; Pϭ0.0001) and severe functional limitation (OR for NYHA class III or IV, 2.8; PϽ0.0001). Compared with those with exclusively paroxysmal AF, patients developing chronic AF showed higher combined probability of HCM-related death, functional impairment, and stroke (PϽ0.0001). In a subgroup of 37 patients with AF (35%), the clinical course was largely benign in the absence of stroke and severe symptoms. Conclusions-In a community-based HCM population, AF (1) was common, with 22% prevalence over 9 years; (2) was associated with substantial risk for heart failure-related mortality, stroke, and severe functional disability, particularly in patients with outflow obstruction, those Յ50 years of age, or those developing chronic AF; and (3) was nevertheless compatible with benign outcome in 35% of patients.

Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry. Results We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months (95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study. Conclusion Ado-trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted.