Risk stratification for sudden cardiac death

Recent advances in pharmacological and device-based therapies have provided a range of management options for patients at risk of sudden cardiac death (SCD). Since all such interventions come with their attendant risks, however, stratification procedures aimed at identifying those who stand to benefit overall have gained a new degree of importance. This review assesses the value of risk stratification measures currently available in clinical practice, as well as of others that may soon enter the market. Parameters that may be obtained only by performing invasive cardiac catheterisation procedures are considered separately from those that may be derived using more readily available non-invasive techniques. It is concluded that effective stratification is likely to require the use of composite parameters and that invasive procedures might only be justified in specific sub-groups of patients.     

Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: Dutch cardiologists and the care of mutation carriers

Background. Patients with hypertrophic cardiomyopathy (HCM) and HCM mutation carriers are at risk of sudden cardiac death (SCD). Both groups should therefore be subject to regular cardiological testing – including risk stratification for SCD – according to international guidelines. We evaluated Dutch cardiologists' knowledge of and adherence to international guidelines on risk stratification and prevention of SCD in mutation carriers with and without manifest HCM. Methods. A questionnaire was sent to 1109 Dutch cardiologists (in training) containing case-based questions. Results. The response rate was 21%. Own general knowledge on HCM care was rated as insufficient by 63% of cardiologists. The percentage of correct answers (i.e. in agreement with international guidelines), on the case-based questions ranged from 37 to 96%, being lowest in cases with an unknown number of risk factors for SCD. A substantial portion of correct answers was based on the correct answer ‘ask an expert opinion’. Significantly more correct answers were provided in cases with manifest HCM. There was little difference between the answers of cardiologists with different self-reported levels of knowledge, with different numbers of HCM patients in their practice or with different numbers of carriers without manifest HCM. Conclusion. Knowledge on risk stratification and preventive therapy was mediocre, and knowledge gaps exist, especially on HCM mutation carriers without manifest disease. Fortunately, experts are frequently asked for their opinion which might bring patient care to an adequate level. Hopefully, our results will stimulate cardiologists to follow developments in this field, thereby increasing quality of care for HCM patients and mutation carriers. (Neth Heart J 2009:17:464–9.).     

Towards a better risk stratification for sudden cardiac death in patients with structural heart disease

With the introduction of the implantable cardioverter defibrillator (ICD), patients can be protected against sudden cardiac death (SCD) due to ventricular arrhythmia (VA). Guidelines have been drawn up for selecting patients for primary and secondary prophylaxis. However, most ICD recipients today who receive an ICD for primary prevention will not experience a life-threatening VA requiring antitachypacing or shock therapy. Better risk stratification is desirable with efficacy, costs and complication rate in mind. An overview is presented of widely accepted and potentially valuable risk markers and the role they may play in better identifying candidates for ICD therapy. (Neth Heart J 2009;17:101–6.)     

Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy

Pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy are at high risk of sudden cardiac death (SCD). We sought to identify the arrhythmic mechanism of SCD, the relation to changes in left ventricular (LV) function, and inducibility of malignant arrhythmias before SCD. Juvenile pigs (n = 72) were instrumented with chronic stenoses on proximal left anterior descending and circumflex arteries. Survival was only 29% 3 mo after instrumentation, and all deaths were sudden and without prodromal symptoms of heart failure. Triphenyltetrazolium chloride staining demonstrated necrosis in only nine animals averaging 2.3 +/- 0.9% of the LV, with no difference between SCD animals and survivors. Implantable loop recorders (n = 13) documented both ventricular fibrillation (n = 6) and bradyasystole (n = 2) as the arrhythmic mechanism of death. Although regional and global function were depressed [anteroseptal wall thickening 1.8 +/- 0.2 vs. 4.2 +/- 0.2 mm in Sham animals (P < 0.001); fractional shortening 21 +/- 2 vs. 31 +/- 1% in Sham animals (P < 0.01)], there were no differences between SCD animals and survivors. LV mass increased in animals with ischemic cardiomyopathy and was greater in animals with SCD (4.0 +/- 0.2 vs. 3.1 +/- 0.1 g/kg in survivors; P < 0.001). Serial programmed ventricular stimulation failed to induce any sustained arrhythmias. We conclude that pigs with viable dysfunctional myocardium and globally reduced LV function have a high rate of SCD with a spectrum of arrhythmias similar to patients with ischemic cardiomyopathy. The risk is independent of necrosis but appears to increase with LV hypertrophy. Like patients with ischemic cardiomyopathy, programmed stimulation is insensitive to predict SCD when viable dysfunctional myocardium is the pathological substrate.     

Preliminary clinical study of left ventricular myocardial strain in patients with non-ischemic dilated cardiomyopathy by three-dimensional speckle tracking imaging

Background

Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence.

Methods

We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years).

Results

In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively.

Conclusions

The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%.     

Variants of Toll-like receptor 4 predict cardiac recovery in patients with dilated cardiomyopathy

The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.     

A novel mutation of the LMNA gene in a family with dilated cardiomyopathy, conduction system disease, and sudden cardiac death of young females

The LMNA gene, which encodes the nuclear envelope protein lamin A/C, is considered to be the most common autosomal disease gene associated with familial dilated cardiomyopathy. To date, each mutation of the LMNA gene has been associated with a specific disease phenotype. Clinical data, family histories, and blood samples were collected from 27 biological members of a family with dilated cardiomyopathy, prominently occurring as heart failure and conduction system disease with a high incidence of sudden cardiac death in young females. Twelve exons of the LMNA gene were screened for nucleotide alterations. A novel insertion mutation (nucleotide 1526insA, amino acid T510Y) in exon nine of the LMNA gene was identified in seven subjects (7/27, 25.9 %). This reveals that the LMNA gene insertion mutation (T510Y frameshift mutation) can cause dilated cardiomyopathy, conduction system disease, and sudden cardiac death without skeletal myopathy, clinically manifested with early onset, severe symptoms, and poor prognosis.     

Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy

Vinculin is a ubiquitously expressed multiliganded protein that links the actin cytoskeleton to the cell membrane. In myocytes, it is localized in protein complexes which anchor the contractile apparatus to the sarcolemma. Its function in the myocardium remains poorly understood. Therefore, we developed a mouse model with cardiac-myocyte-specific inactivation of the vinculin (Vcl) gene by using Cre-loxP technology. Sudden death was found in 49% of the knockout (cVclKO) mice younger than 3 months of age despite preservation of contractile function. Conscious telemetry documented ventricular tachycardia as the cause of sudden death, while defective myocardial conduction was detected by optical mapping. cVclKO mice that survived through the vulnerable period of sudden death developed dilated cardiomyopathy and died before 6 months of age. Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart tissue showed abnormal adherens junctions with dissolution of the intercalated disc structure, expression of the junctional proteins cadherin and beta1D integrin were reduced, and the gap junction protein connexin 43 was mislocalized to the lateral myocyte border. This is the first report of tissue-specific inactivation of the Vcl gene and shows that it is required for preservation of normal cell-cell and cell-matrix adhesive structures.     

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas’ disease and idiopathic dilated cardiomyopathy

Chagas’ disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.     

Ventricular tachycardia prediction in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death

Clinical data analysis of 83 patients with implantable cardioverter-defibrillators (ICDs) for sudden cardiac death (SCD) primary prevention has been done. We revealed 5 parameters associated with the detection of life-threatening ventricular arrhythmias. These parameters formed the basis for constructing a logistic regression model. The model makes it possible to obtain the probability of occurrence of a specific event depending on the severity of the predictive parameters and the degree of its influence (risk of true ventricular arrhythmias detection). Estimating the potential risk of the life-threatening arrhythmias, individual programming options are required in implantable cardioverter-defibrillators (ICDs) to reduce the amount of unnecessary electrotherapy, as well as more accurate monitoring of the patient's drug therapy.     

Pathogenic roles of cardiac autoantibodies in dilated cardiomyopathy

Whether autoimmunity could cause dilated cardiomyopathy (DCM) was disputed for more than half a century. Autoantibodies against various cardiac antigens have been found in the sera of patients with DCM but none of these autoantibodies has been shown to have a substantial role in the development of DCM. It was recently reported that the injection of autoantibodies against cardiac troponin I (cTnI) can induce DCM in normal mice. This observation showed that autoantibodies can cause DCM and put an end to the controversy. Clinical trials of immunoglobulin-adsorption therapy for DCM have already started in Germany and the results seem promising. Here, we discuss the recent findings and possibilities of immunoglobulin-adsorption therapy for this deadly disease.     

Non-invasive evaluation of function in both cardiac ventricles and arrhythmias in patients with dilated cardiomyopathy]

Resting echocardiography with M-mode technique under the control of bidimensional picture and pulsating Doppler ultra sound and a 24-hour ECG with Holter technique were performed in 19 patients with dilated cardiomyopathy (6 females and 13 males; mean age 46 years, mean duration of the disease 23 months). A group of 7 patients with electrocardiographic features of the left ventricle hypertrophy, according to Sokolov index, was distinguished and compared with a group of patients without ventricular hypertrophy. The symptoms of pulmonary hypertension with progressing dilatation and failure of the right cardiac ventricle were found in patients with dilated cardiomyopathy without coexisting hypertrophy, despite of significant deterioration of the contractive function. Cardiac arrhythmias and thrombotic disorders which are hazardous for life were significantly more frequent (78% and 22%, respectively) in this group. Percentage of sudden deaths in these patients was high (56%).     

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.     

Exon skipping in cardiac troponin T of turkeys with inherited dilated cardiomyopathy

Troponin T is a central component of the thin filament-associated troponin-tropomyosin system and plays an essential role in the Ca(2+) regulation of striated muscle contraction. The importance of the structure and function of troponin T is evident in the regulated isoform expression during development and the point mutations resulting in familial hypertrophic and dilated cardiomyopathies. We report here that turkeys with inherited dilated cardiomyopathy and heart failure express an unusual low molecular weight cardiac troponin T missing 11 amino acids due to the splice out of the normally conserved exon 8-encoded segment. The deletion of a 9-bp segment from intron 7 of the turkey cardiac troponin T gene may be responsible for the weakened splicing of the downstream exon 8 during mRNA processing. The exclusion of the exon 8-encoded segment results in conformational changes in cardiac troponin T, an altered binding affinity for troponin I and tropomyosin, and an increased calcium sensitivity of the actomyosin ATPase. Expression of the exon 8-deleted cardiac troponin T prior to the development of cardiomyopathy in turkeys indicates a novel RNA splicing disease and provides evidence for the role of troponin T structure-function variation in myocardial pathogenesis and heart failure.     

Myotonic dystrophy presenting as severely dilated cardiomyopathy with out-of-hospital cardiac arrest

Netherlands Heart Journal -     

Hypertrophic cardiomyopathy and sudden cardiac death due to physical exercise in Croatia in a 27-year period

The paper deals with the sudden cardiac death during physical exercise in males in Croatia. The data are a part of a retrospective study dealing with 69 sudden death due to physical activity in men in Croatia during 27 years: from January 1, 1984 to December 31, 2010. Three of them suddenly died during training and two of them died during recreational physical exercise, probably because of malignant ventricular arrhythmia due to hyperthrophic cardiomyopathy. One had an obstructive form of hypertrophic cardiomyopathy with i.v. septum of 40 mm and four had a non-obstructive forms of hyperthrophic cardiomyopathy with left ventricular wall of 18-20-22-25 mm. First athlete was a short trails runner, aged 24, with no any previous physical discomforts, who suddenly collapsed and died during training. The second athlete was a soccer player aged 18, with no any previous physical discomfort, who suddenly collapsed and died during training. The third aged 15, was a school boy, basketball player, with no any previous physical discomfort, who collapsed and died during training. Two aged 25 and 34, were with no physical discomfort during exercise and died suddenly during recreational soccer games. A sudden cardiac death due to physical exercise in young athletes in Croatia suffered of hyperthropic cardiomyopathy reached 0.06/100 000 yearly (p = 0.00000) in 27 years, in teenagers 0.26/100 000 (p = 0.00226), in teenagers suffered of hypertrophic cardiomyopathy reached 0.10/100 000 (p = 0.00000), in all young athletes suffered of other heart diseases reached 0.19/100 000 (p = 0.00005), and in the total male population aged 15 or more, engaged in sports and recreational physical exercise: 0.71/100.0000 (p = 0.00001).