Lamin A/C mutations in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplant. Mutations in 60 genes have been associated with DCM. Approximately 6% of all DCM cases are caused by mutations in the lamin A/C gene (LMNA). LMNA codes for type-V intermediate filaments that support the structure of the nuclear membrane and are involved in chromatin structure and gene expression. Most LMNA mutations result in striated muscle diseases while the rest affects the adipose tissue, peripheral nervous system, multiple tissues or lead to progeroid syndromes/overlapping syndromes. Patients with LMNA mutations exhibit a variety of cellular and physiological phenotypes. This paper explores the current phenotypes observed in LMNA-caused DCM, the results and implications of the cellular and animal models of DCM and the prevailing theories on the pathogenesis of laminopathies.

Superior early diagnostic performance of a sensitive cardiac troponin assay as compared to a standard troponin test in the diagnosis of acute myocardial infarction

Background: New generation cardiac troponin assays have sufficient precision to detect and quantify plasma troponin concentrations below the lower threshold of detection of the currently employed troponin tests. However, diagnostic performance of the newer generation assays in daily clinical practice is not well established. Aim: To evaluate the diagnostic performance of a sensitive assay as compared to a standard assay in a single reading at admission in the diagnosis of acute myocardial infarction (AMI) in patients presenting to the Emergency Department with chest pain. Methods: The study comprised 187 consecutive patients admitted to the Institute of Cardiology in Warsaw in June and July 2010 with chest pain in whom the attending physician ordered troponin assay to rule AMI in or out. In all of these patients, in addition to the standard Dimension Flex Troponin I (Siemens Healthcare Diagnostics, Inc.) the sensitive Architect Stat Troponin I (Abbott Diagnostics) test was assayed. The triage of patients as well as all diagnostic and treatment decisions were left to the discretion of the attending physician who was blinded to the sensitive troponin test readings. The final diagnosis was adjudicated by a team of two cardiologists on the basis of all the available medical records except for sensitive troponin test results. Results: Mean age of the study cohort (n = 187) was 64.3 ± 13.9 years and 119 (63.6%) were males. The final diagnosis of AMI was adjudicated in 84 (44.9%) patients (mean age 67.5 ± 12.9 years; 119 [63.6%] males). Receiver operating characteristic (ROC) analysis showed greater area under the curve (AUC) for the sensitive cardiac troponin assay compared to the standard assay (AUC = 0.916, 95% CI = 0.866–0.951 vs AUC = 0.863, 95% CI = 0.806–0.909, respectively; p = 0.02) in a single reading at admission. Sensitive assay was characterised by higher sensitivity (87%), specificity (88%), positive (86%) and negative (89%) predictive values in the detection of AMI compared to the standard troponin test (82%, 81%, 78%, and 85% respectively). Conclusions: The newer generation sensitive cardiac troponin assay presented superior diagnostic accuracy in the diagnosis of AMI compared to the standard troponin test in a single reading at admission with improved sensitivity and specificity. The sensitive troponin assay has the potential to improve early detection and/or exclusion of AMI.Background: New generation cardiac troponin assays have sufficient precision to detect and quantify plasma troponin concentrations below the lower threshold of detection of the currently employed troponin tests. However, diagnostic performance of the newer generation assays in daily clinical practice is not well established. Aim: To evaluate the diagnostic performance of a sensitive assay as compared to a standard assay in a single reading at admission in the diagnosis of acute myocardial infarction (AMI) in patients presenting to the Emergency Department with chest pain. Methods: The study comprised 187 consecutive patients admitted to the Institute of Cardiology in Warsaw in June and July 2010 with chest pain in whom the attending physician ordered troponin assay to rule AMI in or out. In all of these patients, in addition to the standard Dimension Flex Troponin I (Siemens Healthcare Diagnostics, Inc.) the sensitive Architect Stat Troponin I (Abbott Diagnostics) test was assayed. The triage of patients as well as all diagnostic and treatment decisions were left to the discretion of the attending physician who was blinded to the sensitive troponin test readings. The final diagnosis was adjudicated by a team of two cardiologists on the basis of all the available medical records except for sensitive troponin test results. Results: Mean age of the study cohort (n = 187) was 64.3 +- 13.9 years and 119 (63.6%) were males. The final diagnosis of AMI was adjudicated in 84 (44.9%) patients (mean age 67.5 +- 12.9 years; 119 [63.6%] males). Receiver operating characteristic (ROC) analysis showed greater area under the curve (AUC) for the sensitive cardiac troponin assay compared to the standard assay (AUC = 0.916, 95% CI = 0.866–0.951 vs AUC = 0.863, 95% CI = 0.806–0.909, respectively; p = 0.02) in a single reading at admission. Sensitive assay was characterised by higher sensitivity (87%), specificity (88%), positive (86%) and negative (89%) predictive values in the detection of AMI compared to the standard troponin test (82%, 81%, 78%, and 85% respectively). Conclusions: The newer generation sensitive cardiac troponin assay presented superior diagnostic accuracy in the diagnosis of AMI compared to the standard troponin test in a single reading at admission with improved sensitivity and specificity. The sensitive troponin assay has the potential to improve early detection and/or exclusion of AMI

Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis

Background: Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland.Methods: Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed.Results: In 2017–2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased left ventricular ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke.Conclusions: According to available data, this is the first time that the types of TTR mutations and the clinical characteristics of Polish patients with cardiac hereditary ATTR have been described. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population

Cardiovascular involvement and prognosis in Loeys-Dietz syndrome

Background: Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis.Aims: The study aimed at analysis of clinical data on cardiovascular involvement and management of LDS patients.Methods: The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery, or otherwise unexplained sudden death.Results: Thirty-four patients from 15 families were included, and five identified variants were novel. Probands’ mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity, and tortuosity of cervical arteries were present in 79%, 71%, 68%, and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at a median age of 35 years. The youngest age at AD was 16 years, and 7 years for elective aneurysm repair. Second and third aortic events occurred in 9 and 4 patients, respectively. Eight patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in the presence of skin striae (P = 0.03), tended to be shorter in the presence of Marfanoid features (P = 0.06), and longer with TGFB2 variants (P = 0.06).Conclusions: LDS is associated with high burden of cardiovascular complications at a young age

Clinical features, etiology, and survival in patients with restrictive cardiomyopathy: A single-center experience

Background: Numerous prognostic factors have been proposed for cardiac amyloidosis (CA). The knowledge about other subtypes of restrictive cardiomyopathy (RCM) is scant.Aims: This study aimed to elucidate the etiology and prognostic factors of RCM as well as assess cardiac biomarkers: high-sensitive troponin T (hs-TnT), growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and soluble suppression of tumorigenicity 2, as mortality predictors in RCM.Methods: We enrolled 36 RCM patients in our tertiary cardiac department. All patients were screened for CA. Genetic testing was performed in 17 patients without CA.Results: Pathogenic or likely pathogenic gene variants were found in 86% of patients, including 5 novel variants. Twenty patients died, and 4 had a heart transplantation during the study. Median overall survival was 29 months (8–55). The univariate Cox models analysis indicated that systolic and diastolic blood pressure, GDF-15, hs-TnT, NT-proBNP, left ventricular stroke volume, the ratio of the transmitral early peak velocity (E) estimated by pulsed wave Doppler over the early mitral annulus velocity (e’), tricuspid annulus plane systolic excursion, early tricuspid valve annular systolic velocity, the presence of pulmonary hypertension, and pericardial effusion influenced survival (P <0.05). A worse prognosis was observed in patients with GDF-15 >1316 pg/ml, hs-TnT >42 ng/l, NT-proBNP >3383 pg/ml, and pericardial effusion >3.5 mm (Kaplan-Meier analysis, log-rank test, P <0.001).Conclusions: Genetic testing should be considered in every RCM patient where light-chain amyloidosis has been excluded. Survival remains poor regardless of etiology. Increased concentrations of GDF-15, hs-TNT, NT-proBNP, and pericardial effusion are associated with worse prognosis. Further studies are warranted