Clinical and genetic yield of familial screening after a sudden unexplained death at a young age.

BACKGROUND: In a population under 45 years of age, the predominant causes of sudden cardiac death (SCD) are inherited cardiac diseases. Determining the underlying cause may help identify relatives at risk and prevent further events but is more difficult if an autopsy has not been performed. AIMS: We aimed to assess the diagnostic value of clinical and genetic screening in relatives of young non-autopsied sudden unexplained death (SUD) victims. MATERIAL AND METHODS: Eighty-seven relatives of 65 young non-autopsied SUD victims from 39 families were evaluated from 2016 to 2019. The relatives underwent extensive noninvasive cardiac workup. Genetic examinations were performed in 39 families. RESULTS: The definite diagnoses were made in 17 of 39 (44%) families. Cardiomyopathies were identified in 10 families (5 hypertrophic, 4 dilated, and 1 arrhythmogenic), followed by long QT syndrome (5 families). In 3 families, probable diagnoses were made, whereas in 20 families no diagnosis was achieved. In total, definite and probable diagnoses were made in 18 and 5 patients, respectively. All affected relatives were offered medical management, one of them died of heart failure and one underwent transplantation during the median follow-up of 3 years. Disease-causing variants were found in 7 of 39 (18%) probands; all in families with a definite diagnosis. Variants of unknown significance were found in 2 probands. CONCLUSION: Screening of relatives of SUD victims is warranted and may save lives, even if it is not guided by autopsy results. Genetic testing in families without the disease phenotype has little effectiveness.

A novel risk model for predicting potentially life-threatening arrhythmias in non-ischemic dilated cardiomyopathy (DCM-SVA risk).

BACKGROUND: Non-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients. METHODS: 1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information. RESULTS: During a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90-1.03) and the C-index was 0.72 (95% CI 0.71-0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations. CONCLUSIONS: This DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.

A Recurrent Exertional Syncope and Sudden Cardiac Arrest in a Young Athlete with Known Pathogenic p.Arg420Gln Variant in the RYR2 Gene.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of causes of sudden cardiac death in the young, especially in athletes. Diagnosis of CPVT may be difficult since all cardiological examinations performed at rest are usually normal, and exercise stress test-induced ventricular tachycardia is not commonly present. The identification of a pathogenic mutation in RYR2 or CASQ2 is diagnostic in CPVT. We report on a 20-year-old athlete who survived two sudden cardiac arrests during swimming. Moreover, he suffered repeated syncopal spells on exercise. The diagnosis was made only following genetic testing using a multi-gene panel, and the p.Arg420Gln RYR2 variant was identified. We present diagnostic and therapeutic issues in this young athlete with CPVT.

Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?

Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.

Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations.

TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.

A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations.

BACKGROUND: In humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients. METHODS: We studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction. RESULTS: We detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied. CONCLUSIONS: In Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9(th) PLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.

A novel model of exercise walking training in patients after coronary artery bypass grafting.

BACKGROUND: Exercise training is an established, guideline-recommended treatment approach in cardiovascular disease. Designing novel methods of exercise training that would be accepted by the patients seems to be a way to increase patient attendance at cardiac rehabilitation (CR). The 6-min walking test (6-MWT) is a simple, safe and objective method to assess exercise capacity. In patients without heart failure, oxygen consumption after 6 min of walking reaches the ventilatory threshold (VT) level. Training up to the VT level is recommended in CR. Theoretical grounds exist for designing a novel model of CR based on diagnostic 6-MWT. AIM: Pilot implementation and evaluation of the effectiveness of a new form of walking training based on 6-MWT in low-risk patients after coronary artery bypass grafting (CABG). METHODS: The study included 119 men after CABG undergoing phase II CR. Depending on whether patients granted a consent to undergo home-based electrocardiography (ECG) telemonitored CR or not, they were divided into two groups: group A (60 patients) - standard CR combined with the new model (walking 6 times for 6 min with 3-min intervals) for 5 days a week; and group B (59 controls) - standard CR. At baseline and after 3 and 12 months, the patients underwent the following tests: 6-MWT, 24-h Holter ECG monitoring (including evaluation of heart rate variability), and biochemical laboratory tests. RESULTS: No significant differences in 6-MWT distance were found between the groups at baseline and at 3 and 12 months. At 3 months, 6-MWT distance increased significantly in both groups (group A: 419 ± 73 vs. 515 ± 70 m, p < 0.02; group B: 422 ± 86 vs. 519 ± 73 m, p < 0.02). At 3 and 12 months, body mass was higher in group B controls (p < 0.05). At 3 months, glycaemia and high-sensitivity C-reactive protein (hsCRP) levels were significantly lower in group A patients (p < 0.05). At 12 months, triglyceride levels were higher in group B (p < 0.05). At 3 months, SDNN was higher in group A. After 12 months, LF was lower in group A. At baseline, the LF/HF ratio was significantly higher in group A (p < 0.05) but during further follow-up, favourable changes in the LF/HF ratio were noted only in group A. CONCLUSIONS: The novel model of exercise walking training had a favourable effect on body mass, glycaemia and hsCRP level reduction, and induced favourable changes of the sympathovagal balance.

Effect of the dynamics of depression symptoms on outcomes after coronary artery bypass grafting.

BACKGROUND: As coronary artery bypass grafting (CABG) remains an important myocardial revascularisation strategy, more attention has been paid to the role of numerous factors affecting outcomes after CABG, including depression and depressive symptoms. However, previous studies on this issue gave inconsistent results, the dynamics of depression has been seldom investigated, and only few reports have specifically addressed this problem in Poland. AIM: Prospective evaluation of the effect of depressive symptoms and the dynamics of their occurrence on the incidence of cardiac events in patients after CABG during a 2-year follow-up. METHODS: We studied 170 patients aged 63 ± 10 years, including 17 women and 153 men, who underwent CABG. The Beck Depression Inventory (BDI) was used to evaluate the severity of depressive symptoms at 2 weeks (0M), 3 months (3M), and 24 months (24M) after CABG. Based on the BDI findings during subsequent follow-up visits, patients were divided into three groups depending on the dynamics of depressive symptoms: Group I without depression (67 patients), Group II with incidental depression (72 patients), and Group III with chronic depression (31 patients). During the 2-year follow-up, we evaluated the incidence of three combined endpoints that included death, myocardial infarction (MI), coronary angioplasty or redo CABG surgery; recurrent angina; and hospitalisations due to arrhythmia, heart failure or other cardiac causes. We analysed the effect of demographic, clinical, perioperative end psychological parameters to identify independent risk factors for cardiac events. RESULTS: Among patients with chronic depression, more cardiac events were noted compared to patients without depression or with incidental depression. All combined endpoints were significantly more common in patients with chronic depression compared to those without depression (death, MI, coronary angioplasty or redo CABG surgery: 19.3% in Group III vs. 5.9% in Group I, p = 0.0437; recurrent angina: 45% in Group III vs. 16.4% in Group I, p = 0.027; hospitalisations due to arrhythmia, heart failure or other cardiac causes: 54.8% in Group III vs. 31.3% in Group I, p = 0.0287). Hospitalisation rate was also higher among patients with chronic depression compared to those with incidental depression (54.8% in Group III vs. 31.9% in Group II, p = 0.031). In multivariate analysis using a linear regression model, independent risk factors for hospitalisation during the 2-year follow-up included the presence of depressive symptoms in the early postoperative period (p = 0.03) and the BDI score at 3 months after CABG (p = 0.0001). Use of antidepressants at baseline was an independent risk factor for recurrent angina (p = 0.004). Depressive symptoms, regardless of their dynamics, were not found to be a risk factor for the combined endpoint of death, MI, coronary angioplasty or redo CABG surgery. CONCLUSIONS: During a 2-year prospective follow-up of patients after CABG, cardiac events were significantly more common among patients with chronic depression (but not incidental depression) as compared to patients without depressive symptoms. Hospitalisation rate among patients with chronic depression was significantly higher compared to both patients without depression or with incidental depression. Both chronic and incidental depression was not shown to be to be a risk factor for the combined endpoint of death, MI, coronary angioplasty or redo CABG surgery. Severe depressive symptoms that required the use of antidepressants at baseline were an independent risk factor of recurrent angina. The presence of depressive symptoms at baseline and BDI score at 3 months were independent risk factors for rehospitalisation. This suggests that the dynamics of depressive symptoms may have an effect on rehospitalisations in patients after CABG.