Mitral annular disjunction in idiopathic ventricular fibrillation patients: just a bystander or a potential cause?

AIMS: Previously, we demonstrated that inferolateral mitral annular disjunction (MAD) is more prevalent in patients with idiopathic ventricular fibrillation (IVF) than in healthy controls. In the present study, we advanced the insights into the prevalence and ventricular arrhythmogenicity by inferolateral MAD in an even larger IVF cohort. METHODS AND RESULTS: This retrospective multi-centre study included 185 IVF patients [median age 39 (27, 52) years, 40% female]. Cardiac magnetic resonance images were analyzed for mitral valve and annular abnormalities and late gadolinium enhancement. Clinical characteristics were compared between patients with and without MAD. MAD in any of the 4 locations was present in 112 (61%) IVF patients and inferolateral MAD was identified in 24 (13%) IVF patients. Mitral valve prolapse (MVP) was found in 13 (7%) IVF patients. MVP was more prevalent in patients with inferolateral MAD compared with patients without inferolateral MAD (42 vs. 2%, P < 0.001). Pro-arrhythmic characteristics in terms of a high burden of premature ventricular complexes (PVCs) and non-sustained ventricular tachycardia (VT) were more prevalent in patients with inferolateral MAD compared to patients without inferolateral MAD (67 vs. 23%, P < 0.001 and 63 vs. 41%, P = 0.046, respectively). Appropriate implantable cardioverter defibrillator therapy during follow-up was comparable for IVF patients with or without inferolateral MAD (13 vs. 18%, P = 0.579). CONCLUSION: A high prevalence of inferolateral MAD and MVP is a consistent finding in this large IVF cohort. The presence of inferolateral MAD is associated with a higher PVC burden and non-sustained VTs. Further research is needed to explain this potential interplay.

Characterisation of hypertensive heart disease: pathological insights from a sudden cardiac death cohort to inform clinical practice.

Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.

Getting to the heart of the matter: investigating the idiopathic sudden cardiac death of a previous well soldier.

A 25-year-old infantry soldier, who was previously fit and well, had a cardiac arrest while undertaking an advanced fitness test. Despite early cardiopulmonary resuscitation by colleagues and the emergency services, he was later pronounced dead. A postmortem performed by an expert pathologist and a toxicology screen were normal and the death was attributed to sudden arrhythmic death syndrome (SADS). Screening of his family in our Inherited Cardiac Conditions clinic identified Brugada syndrome (BrS) in two first-degree relatives. This case generates discussion on sudden cardiac death, family screening in SADS, BrS and the limitations of recruit screening with an ECG.

Sudden cardiac arrest in sports - need for uniform registration: A Position Paper from the Sport Cardiology Section of the European Association for Cardiovascular Prevention and Rehabilitation.

There are large variations in the incidence, registration methods and reported causes of sudden cardiac arrest/sudden cardiac death (SCA/SCD) in competitive and recreational athletes. A crucial question is to which degree these variations are genuine or partly due to methodological incongruities. This paper discusses the uncertainties about available data and provides comprehensive suggestions for standard definitions and a guide for uniform registration parameters of SCA/SCD. The parameters include a definition of what constitutes an 'athlete', incidence calculations, enrolment of cases, the importance of gender, ethnicity and age of the athlete, as well as the type and level of sporting activity. A precise instruction for autopsy practice in the case of a SCD of athletes is given, including the role of molecular samples and evaluation of possible doping. Rational decisions about cardiac preparticipation screening and cardiac safety at sport facilities requires increased data quality concerning incidence, aetiology and management of SCA/SCD in sports. Uniform standard registration of SCA/SCD in athletes and leisure sportsmen would be a first step towards this goal.

Drug-associated arrhythmia in the military patient.

Members of the Armed Forces may be exposed to drugs, or combinations of drugs, with the potential to prolong the QRS or QT intervals. The effect of this is to increase the likelihood of developing dangerous ventricular tachyarrhythmias, including ventricular tachycardia, torsades de pointes or ventricular fibrillation. Common examples of the pharmacological agents associated include antibiotics, antiemetics and antimalarials. Genetic predisposition, electrolyte disturbance, anaesthesia and trauma may exacerbate the proarrhythmic effect of these medications. Screening of recruits does not detect all those with a genetic predisposition to drug-associated arrhythmias, so vigilance in preventing this iatrogenic disorder and recognising and appropriately managing it when present is important. This article explains the physiological basis of arrhythmogenesis, outlines the clinical features and provides guidance on investigation and management, with particular reference to military patients.

The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions.

The ability to predict the risk for serious drug-induced adverse reactions first requires a large patient database for characterization and validation of genetic markers. The Phenotype Standardization Project (PSP) was initiated to standardize phenotypic definitions, thereby facilitating much-needed recruitment without sacrificing the reliability of patient classification. Three phenotypes have been considered in this initial phase: drug-induced liver injury, drug-induced skin injury, and drug-induced torsade de pointes.

Feeding ecology of Pachyurus bonariensis Steindachner, 1879 (Sciaenidae: Perciformes) in the Ibicuí River, Southern Brazil: ontogenetic, seasonal and spatial variations.

Knowledge of the feeding ecology of fish is essential for understanding the functioning of freshwater communities. Here we report on an analysis of the diet of Pachyurus bonariensis Steindachner, 1879, a freshwater sciaenid. Fish were collected bimonthly from December 1999 to January 2002 at three locations along the Ibicuí River in the Rio Grande do Sul State, Brazil. At each location, the specimens were collected in both lentic and lotic environments. The stomachs of 324 fish were analysed for contents and fullness. The main items were Ephemeroptera, Diptera (larvae), Trichoptera and Odonata. Annelida, plant matter, Decapoda, Diptera (pupae), Coleoptera and Mollusca were present in small amounts. The fish consumed smaller amounts of food in winter than in other seasons. The most important source of dietary variation for P. bonariensis was the ontogenetic, related to intrinsic biological characters. However, spatial variation was also found, suggesting that this species can adapt its diet to environmental changes. Although P. bonariensis showed ontogenetic and spatial variations in the main items consumed, the main items were always insects, characterising P. bonariensis as a fish with an insectivorous feeding habit in the Ibicuí River.

Feeding ecology of Pachyurus bonariensis Steindachner, 1879 (Sciaenidae: Perciformes) in the Ibicuí River, Southern Brazil: ontogenetic, seasonal and spatial variations / Ecologia trófica de Pachyurus bonariensis Steindachner, 1879 (Sciaenidae: Perciformes) no Rio Ibicuí, sul do Brasil: variações ontogenéticas, sazonais e espaciais

Knowledge of the feeding ecology of fish is essential for understanding the functioning of freshwater communities. Here we report on an analysis of the diet of Pachyurus bonariensis Steindachner, 1879, a freshwater sciaenid. Fish were collected bimonthly from December 1999 to January 2002 at three locations along the Ibicuí River in the Rio Grande do Sul State, Brazil. At each location, the specimens were collected in both lentic and lotic environments. The stomachs of 324 fish were analysed for contents and fullness. The main items were Ephemeroptera, Diptera (larvae), Trichoptera and Odonata. Annelida, plant matter, Decapoda, Diptera (pupae), Coleoptera and Mollusca were present in small amounts. The fish consumed smaller amounts of food in winter than in other seasons. The most important source of dietary variation for P. bonariensis was the ontogenetic, related to intrinsic biological characters. However, spatial variation was also found, suggesting that this species can adapt its diet to environmental changes. Although P. bonariensis showed ontogenetic and spatial variations in the main items consumed, the main items were always insects, characterising P. bonariensis as a fish with an insectivorous feeding habit in the Ibicuí River.

A ecologia alimentar de uma espécie é muito importante para o entendimento do funcionamento das comunidades de água doce. Neste trabalho analisamos a dieta de Pachyurus bonariensis, um sciaenídeo restrito a ambientes dulceaquícolas. Os peixes foram coletados bimestralmente de dezembro de 1999 a janeiro de 2002 em três locais do rio Ibicuí no Estado do Rio Grande do Sul, Brasil. Em cada local os espécimes foram coletados em ambiente lótico e lêntico. Estômagos de 324 indivíduos foram analisados quanto ao seu conteúdo e grau de repleção. Os principais itens foram Ephemeroptera, Diptera (larva), Trichoptera e Odonata. Os itens Anellida, matéria vegetal, Decapoda, Diptera (pupas), Coleoptera e Mollusca estiveram presentes em menor quantidade. No inverno os peixes consumiram menor quantidade de alimento, quando comparado com as demais estações. A principal fonte de variação na dieta desse sciaenídeo foi proveniente de mudanças ontogenéticas, relacionadas a fatores biológicos intrínsecos. Entretanto também foi observada variação espacial na dieta de P. bonariensis, sugerindo que essa espécie pode adaptar sua dieta a mudanças ambientais. Apesar de P. bonariensis apresentar mudanças ontogenéticas e espaciais na sua dieta, os principais itens foram sempre insetos, caracterizando essa espécie como um peixe com hábitos insetívoros no rio Ibicuí.

Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair.

OBJECTIVES: The phenotypic triad of arrhythmogenic right ventricular cardiomyopathy (ARVC) associated with palmoplantar keratoderma and woolly hair has been previously associated with homozygous mutations in both plakoglobin and desmoplakin, which are both critical components of the desmosome. We present here a clinical and genetic study of a consanguineous pedigree in which 2 siblings present with ARVC with left ventricular involvement and associated mild palmoplantar keratoderma and woolly hair. METHODS: Clinical evaluation of the 2 patients and their family members was undertaken along with a homozygosity-mapping approach to identify the relevant gene and sequencing analysis to identify the causative mutation. RESULTS: The homozygosity-mapping approach excluded the involvement of both plakoglobin and desmoplakin in this pedigree. However, an extended region of homozygosity in both affected cases was revealed at the chromosome 18 desmocollin/desmoglein cluster, genes which encode components of the desmosome. Sequence analysis of the democollin-2 gene, located within this cluster, revealed a homozygous single-base deletion in exon 12 (1841delG). This mutation is predicted to lead to a frame shift and a premature termination codon at position 625 (S614fsX625). CONCLUSIONS: This is the first reported case of a mutation in desmocollin-2 associated with autosomal recessive ARVC.

Sudden arrhythmic death syndrome: a national survey of sudden unexplained cardiac death.

OBJECTIVE: To describe the characteristics of sudden arrhythmic death syndrome (SADS) and compare its incidence with official national mortality statistics for unascertained deaths. DESIGN AND SETTING: Sudden unexplained deaths were prospectively surveyed through 117 coroners' jurisdictions in England. Consecutive cases meeting the following criteria were included: white Caucasian, aged 4-64 years, no history of cardiac disease, last seen alive within 12 h of death, normal coroner's autopsy, cardiac pathologist's confirmation of a normal heart and negative toxicology. MAIN OUTCOME MEASURES: The estimated mortality from SADS was calculated and the official mortality statistics for unascertained causes of deaths in 4-64-year-olds was identified for the same time period. RESULTS: 115 coroner's cases were reported and 56 (49%) SADS victims were identified: mean age 32 years, range 7-64 years and 35 (63%) male. 7 of 39 cases (18%) had a family history of other premature sudden deaths (<45). The estimated mortality from SADS was 0.16/100 000 per annum (95% CI 0.12 to 0.21), compared with an official mortality of 0.10/100 000 per annum for International Classification of Diseases 798.1 (sudden death, cause unknown-instantaneous death) or 1.34/100 000 per annum for unascertained causes of death. CONCLUSIONS: Deaths from SADS occur predominantly in young males. When compared with official mortality, the incidence of SADS may be up to eight times higher than estimated: more than 500 potential SADS cases per annum in England. Families with SADS carry genetic cardiac disease, placing them at risk of further sudden deaths. SADS should therefore be a certifiable cause of death prompting specialised cardiological evaluation of families.

High-efficiency multiplex capillary electrophoresis single strand conformation polymorphism (multi-CE-SSCP) mutation screening of SCN5A: a rapid genetic approach to cardiac arrhythmia.

Mutations in the SCN5A gene coding for the alpha-subunit of the cardiac Na(+) ion channel cause long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, sick sinus node syndrome, progressive conduction disease, dilated cardiomyopathy and atrial standstill. These diseases exhibit variable expressivity, and identification of gene carriers is clinically important, particularly in sudden infant and adult death syndromes. The SCN5A gene comprises 28 exons distributed over 100 kbp of genomic sequence at chromosome 3p21. Disease-causing mutations are private and scattered over the DNA sequence, making it difficult to screen for specific mutations. We developed a multiplex capillary-electrophoresis single-strand conformation polymorphism (Multi-CE-SSCP) mutation screening protocol on the ABI 3100 platform and applied it to 10 previously slab-gel SSCP identified mutations and SNPs and used it to identify one novel deletion. The method is highly efficient, with a turnover of 23 patients per 24 h and a false positive rate of 0.5% of the analyzed amplicons. Each variant has a particular elution pattern, and all 20 carriers of the H558R polymorphism out of 57 persons were correctly identified. We suggest that the method could become part of routine work-up of patients with suspicious syncope and of members of families with sudden unexplained death.

The negative effect of red tape on research.

PURPOSES: To describe the kind of the difficulties encountered when seeking research governance approval for a nationwide public health and genetic study-the Drug-Induced Arrhythmia Risk Evaluation study-in England. METHODS: Description of the processes followed when seeking research governance approval for the Drug-Induced Arrhythmia Risk Evaluation study-a case control study with annual follow-up of cases and controls over 5 years, set in the English National Health Service (NHS). RESULTS: The authors describe wide variations in NHS research governance approval procedures in England. CONCLUSION: NHS research governance procedures in England are impeding the process of epidemiological studies; there is the need for a centralised NHS R&D approval of studies, which is analogous to MREC for ethical approval.

Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome.

4.1% of sudden cardiac deaths in the 16-64 age-group are unexplained. In this group, cardiac pathological findings are normal and toxicological tests are negative; termed sudden arrhythmic death syndrome (SADS). We searched for evidence of inherited cardiac disease in cases of SADS. Of 147 first-degree relatives of 32 people who died of SADS, 109 (74%) underwent cardiological assessment. Seven (22%) of the 32 families were diagnosed with inherited cardiac disease: four with long QT syndrome; one with non-structural cardiac electrophysiological disease; one with myotonic dystrophy; and one with hypertrophic cardiomyopathy. Families of people who die of SADS should be offered assessment in centres with experience of inherited cardiac disease.

PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.

BACKGROUND: Mutations in KCNJ2, the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen-Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified. METHODS: Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2. The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS. RESULTS: Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations (D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP(2)-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2 -based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males. CONCLUSIONS: The novel mutations corresponding to residues involved in Kir2.1 channel-PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.

Cloning and expression of the complete SIVagm pol region in E. coli. Purification and partial characterization of the reverse transcriptase.

The complete pol region of the simian immunodeficiency virus from African green monkeys was cloned and expressed in E. coli. The reverse transcriptase was purified to high specific activity and could be shown to contain both reverse transcriptase activity as well as an associated RNase H activity. As is observed with other reverse transcriptases the enzyme is composed of two subunits which cannot be separated by conventional techniques. When comparing the recombinant enzyme with the authentic enzyme isolated from virus no differences were found by biochemical, enzymological, or immunological criteria. Moreover, the action of inhibitors against this enzyme did not show significant differences when compared to reverse transcriptases from HIV-1 and HIV-2.

Simian immunodeficiency virus reverse transcriptase. Purification and partial characterization.

Native reverse transcriptase from simian immunodeficiency virus was purified from virus with good recovery to near homogeneity. The optimum reaction conditions of the enzyme were determined with respect to divalent cations, pH and ionic strength. The enzyme was shown to possess both RNA-dependent and DNA-dependent DNA synthesis activity. In addition, we could demonstrate an associated RNase H activity. Employing novel assay conditions, activated DNA as a heteropolymeric substrate was used more efficiently than the homopolymeric substrate poly(rA).oligo(dT) which in turn was used twofold more effectively as the template primer than poly(dC).oligo(dG). Other homopolymeric substrates, including poly(rC).oligo(dG), were also tested but were found to be poorly used by the reverse transcriptase. The Miachaelis-Menten constants were determined for each of the four nucleotides needed to elongate a natural template primer. Simultaneously, using dideoxyadenosine triphosphate as nucleotide analogue, we could show that this compound acts as a competitive inhibitor with respect to dATP, whereas it acts as a non-competitive inhibitor with respect to the other nucleotides. Gel electrophoretic analysis showed the enzyme to consist of two polypeptides with apparent molecular masses of 64 and 48 kDa. Using activity gel electrophoresis, we were able to demonstrate that both subunits exhibit DNA synthesis activity.

Azidothymidine triphosphate is an inhibitor of both human immunodeficiency virus type 1 reverse transcriptase and DNA polymerase gamma.

The reverse transcriptase from human immunodeficiency virus type 1 was purified from the virus to near homogeneity. The enzyme was shown to possess both RNA-dependent and DNA-dependent DNA-synthesizing activity. Activated DNA as a heteropolymeric substrate was used as efficiently as was the homopolymeric substrate poly(rA)-oligo(dT). The Michaelis-Menten constants were determined for each of the four nucleotides needed to elongate a natural template primer. Azidothymidine triphosphate, a well-known inhibitor of the enzyme, inhibited the enzyme competitively with respect to dTTP and noncompetitively with respect to the other nucleotides. Azidothymidine triphosphate acted as an efficient inhibitor of cellular DNA polymerase gamma, whereas other enzymes of eucaryotic DNA metabolism, namely, DNA polymerase alpha-primase and DNA polymerase beta, were not inhibited. This finding may explain why some acquired immunodeficiency syndrome patients suffer side effects during azidothymidine therapy.