Germline HAVCR2/TIM-3 Checkpoint Inhibitor Receptor Deficiency in Recurrent Autoinflammatory Myocarditis.

Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. To provide understanding on inflammatory myocarditis, we describe clinical, genetic, and immunological properties of a young male patient who suffered from recurrent myocarditis episodes since the age of four years. Electrocardiography, troponin I/T, echocardiography, myocardial magnetic resonance imaging and histological findings were consistent with recurrent myocarditis episodes. Homozygous c.245 A > G p.Tyr82Cys pathogenic variant in Hepatitis A Virus Cellular Receptor 2 (HAVCR2) gene encoding T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) receptor was found. Peripheral blood mononuclear cells were collected when the patient was asymptomatic; CD4+ and CD8+ T lymphoblasts, CD56+ natural killer cells and CD14+ monocytes were negative for surface TIM-3 expression. In vitro, TLR4 mediated interleukin-1ß (IL-1ß) response was high after LPS/ATP stimulation. Clinical symptoms responded to IL-1 receptor antagonist anakinra. TIM-3 p.Tyr82Cys CD4+ and CD8+ T cell proliferation in vitro was unrestrained. Findings on IL-2, interferon gamma, regulatory T cells, signal transducer and activator of transcription (STAT) 1, 3 and 4 phosphorylation, and PD-1 and LAG-3 checkpoint inhibitor receptor analyses were comparable to controls. We conclude that TIM-3 deficiency due to homozygous HAVCR2 c.245 A > G p.Tyr82Cys pathogenic variant in the patient described here is associated with autoinflammatory symptoms limited to early onset recurrent febrile myocarditis. Excessive IL-1ß production and defective regulation of T cell proliferation may contribute to this clinical condition responsive to anakinra treatment.

Risk factors for major adverse cardiovascular events after the first acute coronary syndrome.

AIMS: To evaluate risk factors for major adverse cardiac event (MACE) after the first acute coronary syndrome (ACS) and to examine the prevalence of risk factors in post-ACS patients. METHODS: We used Finnish population-based myocardial infarction register, FINAMI, data from years 1993-2011 to identify survivors of first ACS (n = 12686), who were then followed up for recurrent events and all-cause mortality for three years. Finnish FINRISK risk factor surveys were used to determine the prevalence of risk factors (smoking, hyperlipidaemia, diabetes and blood pressure) in post-ACS patients (n = 199). RESULTS: Of the first ACS survivors, 48.4% had MACE within three years of their primary event, 17.0% were fatal. Diabetes (p = 4.4 × 10-7), heart failure (HF) during the first ACS attack hospitalization (p = 6.8 × 10-15), higher Charlson index (p = 1.56 × 10-19) and older age (p = .026) were associated with elevated risk for MACE in the three-year follow-up, and revascularization (p = .0036) was associated with reduced risk. Risk factor analyses showed that 23% of ACS survivors continued smoking and cholesterol levels were still high (>5mmol/l) in 24% although 86% of the patients were taking lipid lowering medication. CONCLUSION: Diabetes, higher Charlson index and HF are the most important risk factors of MACE after the first ACS. Cardiovascular risk factor levels were still high among survivors of first ACS.

The validity of hospital discharge register data on non-ST-elevation and ST-elevation myocardial infarction in Finland.

Objectives. To examine the validity of ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) diagnoses in Finnish nation-wide hospital discharge register (HDR). Design. In the first stage of the study, we sampled 180 patients treated in 1996-2012 for MI in three different hospitals, Oulu university hospital, Turku university hospital and North Karelia Central hospital, 60 patients in each hospital. A cardiology resident classified the patients on the basis of ECG finding into following categories: NSTEMI, STEMI or not classifiable myocardial infarction (NCMI). In the second stage of the study, we sampled altogether 270 additional patients i.e. 90 patients per hospital. Patients were treated between 2012-2014 for STEMI (n = 3 × 30), NSTEMI (n = 3 × 30), and NCMI (n = 3 × 30). The ECGs of these patients were independently evaluated by the cardiology resident and a senior cardiologist and compared with the HDR diagnosis. Results. In the first stage of the study, the agreement between the ECG coding of the cardiology resident and the HDR diagnoses was poor (Cohen's kappa coefficient 0.38 (95% CI 0.10-0.32). In the second stage, the agreement remained at the same poor level (Cohen's kappa = 0.22 (95% CI 0.11-0.03)). The agreement between the cardiology resident and the senior cardiologist was, however, good (Cohen's kappa = 0.75 (95% CI 0.65-0.85)). Conclusions. Our results show that the division of MI diagnoses to STEMI and NSTEMI is not reliable in the Finnish HDR. These diagnoses should not be used as outcomes in scientific research without additional verification from the original ECGs.