Diagnostic performance of dobutamine stress echocardiography: A South African experience.

BACKGROUND: Dobutamine stress echocardiography (DSE) is a well-established modality for the diagnosis of coronary artery disease, but there are no reported diagnostic data in southern Africa. Objectives. To compare the safety, sensitivity and specificity of a South African (SA) DSE programme with larger, international series. Methods. All patients undergoing DSE from 2019 to 2021 at a single SA centre were included. A new wall motion abnormality (≥2 segments) signified inducible ischaemia. Results. A total of 106 patients (mean (standard deviation) age 61 (11) years, 68% male) were analysed. Six patients (6%) experienced chest pain during DSE and 4 (4%) developed an atrial arrhythmia. The sensitivity and specificity for epicardial coronary stenosis were 77% and 74%, respectively, changing to 82% and 72% when excluding those who had previous coronary artery bypass surgery. Conclusion. The sensitivity, specificity and safety of an SA DSE programme were comparable to international series. A DSE programme is feasible in a resource-constrained environment.

Percutaneous left atrial appendage occlusion: A South African experience.

BACKGROUND: Atrial fibrillation (AF) is associated with all-cause mortality, heart failure and non-fatal stroke, and thromboprophylaxis is traditionally provided with oral anticoagulants (OACs). Percutaneous left atrial appendage occlusion (LAAO) with a dedicated device is an alternative approach to thromboprophylaxis in patients with AF who are: (i) intolerant to OACs (e.g. life-threatening haemorrhage); (ii) non-adherent to OACs; or (iii) at a high bleeding risk with OACs. Non-inferiority of LAAO compared with OACs was demonstrated in e.g. the WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF) trial. Only very limited data are available on percutaneous LAAO in South Africa (SA), and no local outcome data have been reported. OBJECTIVES: To compare the safety and efficacy outcomes of an SA percutaneous LAAO programme with larger international series. METHODS: All patients undergoing percutaneous LAAO from 2013 to 2020 at a single centre (SAEndovascular, Kuils River Netcare Hospital, SA) were included from an ongoing registry. Survival analysis was performed with the Kaplan-Meier method. RESULTS: Of 101 LAAO recipients (mean (standard deviation) age 77 (10) years, 64% male) analysed, 90 (90%) had permanent AF, 1 (1%) persistent AF and 9 (9%) paroxysmal AF. The most common indication for LAAO was previous severe bleeding (n=23; 23%). The mean device size was 23 (3) mm and the procedural success rate was 98%. After a median (interquartile range) follow-up of 21 (5 - 41) months, 6 patients (6%) experienced stroke or all-cause mortality. Four patients (4%) had a life-threatening procedural complication (tamponade n=2 (2%) and device embolisation n=2 (2%)). These outcomes are comparable to large international series, e.g. PROTECT AF. CONCLUSIONS: The safety and efficacy outcomes of an SA percutaneous LAAO programme were comparable to large international series. A successful percutaneous LAAO programme is feasible in a southern African context.

First reported cases: renal denervation with second-generation multi-electrode catheter via brachial and radial access.

Renal denervation is a minimally invasive procedure that aims to reduce brain-kidney sympathetic cross-talk. Despite the negative results of the recent SYMPLICITY HTN-3 trial, the procedure is considered safe and has been associated with many beneficial effects, including the reversal of hypertensive heart disease substrate and the prevention of cardiac arrhythmia. The first-generation radiofrequency catheter system featured a monopolar catheter that required sequential singlepoint energy application, followed by rotation, partial withdrawal of the catheter and re-application of energy. The latest generation device features four electrodes configured in a helical arrangement that can simultaneously ablate in four quadrants of the vessel circumference. Renal denervation via brachial or radial arterial access with the second-generation system has not been described before.

MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients.

Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophic cardiomyopathy (HCM) is considered a model disease to study causal molecular factors underlying isolated cardiac hypertrophy. However, HCM manifests with various clinical symptoms, even in families bearing the same genetic defects, suggesting that additional factors contribute to hypertrophy. The gene encoding the cardiac myosin binding protein C (cMYBPC) is one of the most frequently implicated genes in HCM. Recently another myosin binding protein, myosin binding protein H (MYBPH) was shown to function in concert with cMYBPC in regulating cardiomyocyte contraction. Given the similarity in sequence, structure and the critical role MYBPH plays in sarcomere contraction, we proposed that MYBPH may be involved in HCM pathogenesis. Family-based genetic association analysis was employed to investigate the contribution of MYBPH in modifying hypertrophy. Seven single nucleotide polymorphisms and haplotypes in MYBPH were investigated for hypertrophy modifying effects in 388 individuals (27 families), in which three unique South African HCM-causing founder mutations (p.R403W and pA797T in ß-myosin heavy chain gene (MYH7) and p.R92W in the cardiac troponin T gene (TNNT2)) segregate. We observed a significant association between rs2250509 and hypertrophy traits in the p.A797T MYH7 mutation group. Additionally, haplotype GGTACTT significantly affected hypertrophy within the same mutation group. MYBPH was for the first time assessed as a candidate hypertrophy modifying gene. We identified a novel association between MYBPH and hypertrophy traits in HCM patients carrying the p.A797T MYH7 mutation, suggesting that variation in MYBPH can modulate the severity of hypertrophy in HCM.

Mendelian-inherited heart disease: a gateway to understanding mechanisms in heart disease Update on work done at the University of Stellenbosch.

The presence of founder effects in South Africa for many single-gene diseases, which include heart diseases such as progressive familial heart block types I and II, hypertrophic cardiomyopathy and the long QT syndromes, afforded us the opportunity to identify causal genes and associated mutations through genetic mapping and positional cloning. From finding the genes, the emphasis has shifted to elucidating how primary defects cause disease and recognising factors that could explain the often pronounced phenotypic variability seen in persons carrying the same inherited defect. In some of these diseases, sudden unexpected death has been a frequent occurrence in young, apparently healthy individuals who had not been aware that they had inherited an underlying risk. Herein, we review progress in identifying genes, mutations and risk factors associated with the diseases mentioned.

Striving towards the ideal cardiac functional assessment strategy: the contribution of tissue Doppler, strain and strain rate imaging.

In cardiac research, a major goal of prevention of catastrophic events by risk-factor management and earlier detection has, in recent years, led to a proliferation of imaging modalities, moving us from old-fashioned chest X-ray through increasingly sophisticated approaches such as magnetic resonance imaging (MRI) and multi-slice fast computer-aided tomography (CT) scanning. Today, we have the option of using a vast array of invasive and non-invasive approaches, with diverse technical underpinnings, to assess various, and often overlapping aspects of cardiac function. Tissue Doppler imaging (TDI) and the related applications of strain and strain rate imaging are new technologies that are now being evaluated in the realm of practical patient care, and the underlying principles remind us that cardiac contractility is a reflection of the integration of muscle fibre architecture, mechanics and metabolism. TDI is the first technology that allowed imaging of motion within the myocardial wall rather than that of the blood pool, and permits analysis of velocities and accelerations from ultrasonic scatterers in muscle. Since its inception, it has been used to evaluate both new cardiac functional parameters as well as conventional function; for some of these, TDI has proven the superior imaging modality, while for others it offers only incremental information over conventional approaches.

Race and gender representation of hypertrophic cardiomyopathy or long QT syndrome cases in a South African research setting.

We researched hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) as models for studying the pathophysiology of arrhythmias and hypertrophy, and in the process we have had the opportunity to compare local disease profiles with global patterns. We trawled our database entries over the past 20 years to identify all cases of heart muscle and arrhythmic disease. Among these, we separated the index cases from the rest of their family members, segregating for the relevant heart disease, so that numbers were not biased by family size, and analysed the race and gender composition of the HCM and LQTS sectors. The majority of HCM index cases (n = 90, 51.1% of HCM index cases) were of mixed ancestry (MA), with white Caucasian ancestry following closely behind with 74 cases (42.0%); only a few black African (n = 9, 5.1%) or Indian/Asian (n = 3, 1.7%) cases were seen or referred. The LQTS index cases were almost exclusively white Caucasian (n = 36, 88% of LQTS index cases), with four cases (9.8%) of MA, one (2.4%) of Indian/Asian and none of black African descent. These race demographics did not fit the national demographics for South Africa as a whole. In contrast, in both groups, gender biases (slightly more male than female HCM cases, and a 0.4 ratio of males to females in LQTS) previously reported elsewhere appeared to be replicated in our database. Genetic bias is an unlikely explanation for the skewed demographics in our database; a more likely explanation relates to various missed opportunities to diagnose, missed diagnoses and misdiagnoses, as well as the real population drainage of our main referral centre in the context of a differentiated healthcare system.

Progressive familial heart block type II (PFHBII): a clinical profile from 1977 to 2003.

An evaluation of a 38-year-old Caucasian woman, who was referred to Tygerberg Hospital (Western Cape Province, RSA) with Wenckebach second-degree or possibly complete atrioventricular (AV) block that had progressed from first-degree AV block, identified a family history of the cardiac conduction system disorder progressive familial heart block type II (PFHBII). This prompted a retrospective clinical review of the subjects described in the original study, as well as additional family members who had not been examined in the original study. Progression of clinical features was observed, but more importantly, PFHBII was clinically redefined as an AV nodal disorder, which may progress to dilated cardiomyopathy (DCM).

Association between a catechol-o-methyltransferase polymorphism and obsessive-compulsive disorder in the Afrikaner population.

BACKGROUND: It has been proposed that the catechol-o-methyl transferase gene (COMT) may play a role in the pathogenesis of obsessive-compulsive disorder (OCD). Whereas studies in a North American population showed that the low activity (L) allele of a functional polymorphism in COMT was associated with OCD in male patients, this result was not supported by studies in a Japanese population. The present association study assessed the risk for OCD conferred by this COMT polymorphism in a geographically different patient group, namely, the relatively genetically homogeneous Afrikaner population of South Africa. METHODS: Fifty-four unrelated OCD patients and fifty-four sex-matched controls were recruited from the same Afrikaner community. Patients and controls were phenotyped (DSM-IV) and genotyped for a NlaIII polymorphism with H (high activity) or L (low activity) alleles in the COMT gene. RESULTS: The H/L genotype was significantly more common than expected in the OCD patient group (P = 0.0017). LIMITATIONS: Replication studies with related individuals may be useful in discovering factors underpinning the H/L genotype abundance in the Afrikaner population. CONCLUSIONS: These results emphasise the need for further studies in genetically homogeneous populations to help define the complex etiology of this disease.

The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations-Ala797Thr in the beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.

Sudden death due to troponin T mutations.

OBJECTIVES: This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy caused by cardiac tropnin T gene mutations. BACKGROUND: The most common cause of sudden cardiac death in the young is hypertrophic cardiomyopathy, which is usually familial. Mutations causing familial hypertrophic cardiomyopathy have been identified in a number of contractile protein genes, raising the possibility of genetic screening for subjects at risk. A previous report suggested that mutations in the cardiac troponin T gene were notable because they were associated with a particularly poor prognosis but only mild hypertrophy. Given the variability of some genotype:phenotype correlations, further analysis of cardiac troponin T mutations has been a priority. METHODS: Deoxyribonucleic acid from subjects with hypertrophic cardiomyopathy was screened for cardiac troponin T mutations using a ribonuclease protection assay. Polymerase chain reaction-based detection of a novel mutation was used to genotype members of two affected pedigrees. Gene carriers were examined by echocardiography and electrocardiology, and a family history was obtained. RESULTS: A novel cardiac troponin T gene mutation, arginine 92 tryptophan, was identified in 19 of 48 members of two affected pedigrees. The clinical phenotype was characterized by minimal hypertrophy (mean [+/-SD] maximal ventricular wall thickness 11.3 +/- 5.4 mm) and low disease penetrance by clinical criteria (40% by echocardiography) but a high incidence of sudden cardiac death (mean age 17 +/- 9 years). CONCLUSIONS: These data support the observation that apparently diverse cardiac troponin T gene mutations produce a consistent disease phenotype. Because this is one of poor prognosis, despite deceptively mild or undetectable hypertrophy, genotyping at this locus may be particularly informative in patient management and counselling.

Evidence of a long QT founder gene with varying phenotypic expression in South African families.

We report five South African families of northern European descent (pedigrees 161, 162, 163, 164, and 166) in whom Romano-Ward long QT syndrome (LQT) segregates. The disease mapped to a group of linked markers on chromosome 11p15.5, with maximum combined two point lod scores, all generated at theta = 0, of 15.43 for the D11S922, 10.51 for the D11S1318, and 14.29 for the tyrosine hydroxylase (TH) loci. Recent studies have shown that LQT is caused by an Ala212Val mutation in a potassium channel gene (KVLQT1) in pedigrees 161 to 164. We report that the same mutation is responsible for the disease in pedigree 166. Haplotype construction showed that all the families shared a common haplotype, suggesting a founder gene effect. DNA based identification of gene carriers allowed assessment of the clinical spectrum of LQT. The QTc interval was significantly shorter in both carriers and non-carriers in pedigree 161 (0.48 s and 0.39 s, respectively) than the same two groups in pedigree 161 (0.52 s and 0.42 s, respectively). The spectrum of clinical symptoms appeared more severe in pedigree 162. The possible influence of modulating genetic factors, such as HLA status and sex of family members, on the expression of an LQT founder gene is discussed.

Clinical and prognostic evaluation of familial hypertrophic cardiomyopathy in two South African families with different cardiac beta myosin heavy chain gene mutations.

BACKGROUND: Familial hypertrophic cardiomyopathy is the most common inherited cardiac disorder, with sudden cardiac death at a young age the most frequent cause of death in affected individuals. Some cases of familial hypertrophic cardiomyopathy are caused by missense mutations of the beta myosin heavy chain (beta MHC) gene on chromosome 14 and at least 17 such mutations have been described. Recent reports suggest that a correlation exists between a specific beta MHC gene mutation and prognosis in familial hypertrophic cardiomyopathy. This premise is currently being used as a basis to provide counselling for affected families. This mutation/prognosis association, however, has not been widely assessed as yet. The clinical and prognostic features of two South African families of mixed racial descent, in which different beta MHC gene mutations were segregating, were studied to evaluate this correlation. The results were compared with those of previously published reports of European families carrying the same mutations. METHODS: The beta MHC gene missense mutations in two affected families were identified by single strand conformation polymorphism analysis and sequencing (pedigree 106: Arg403Trp; pedigree 108: Arg249Gln). All family members were subjected to genotypic analysis using polymerase chain reaction amplification and restriction enzyme based mutation detection techniques. Clinical, electrocardiographic, and echocardiographic studies were performed on genotypically affected individuals in these two kindreds. RESULTS: The number of individuals identified in pedigree 106 with the Arg403Trp mutation was 32.10 individuals bore the Arg249Gln mutation in pedigree 108. The penetrance rate in adults (equal to or greater than 16 years), using the strict echocardiographic criterion of maximum left ventricular wall thickness > or = 13 mm, was 25% for pedigree 106 and 33% for pedigree 108. Familial hypertrophic cardiomyopathy compatible electrocardiographic and echocardiographic abnormalities were seen in 60% of genotypically positive individuals aged > or = 16 years in pedigree 106 and 80% in pedigree 108. The prognosis was uniformly benign in the two families. For pedigree 106 this corresponded to a report of no early sudden cardiac deaths in a French family with the Arg403Trp mutation. For pedigree 108 the absence of such deaths was in apparent contrast to the four cases reported in 24 genotypically affected individuals in a study of a kindred of European ancestry bearing the Arg249Gln mutation. CONCLUSION: This study of a large South African kindred confirmed the benign nature of the Arg403Trp mutation suggested in a previous report. The number and the relatively young age of affected individuals in a second South African family must be considered when comparing the absence of familial hypertrophic cardiomyopathy associated deaths with the intermediate survival reported for the Arg249Gln mutation in a European family. This investigation lends support to current evidence relating specific beta MHC gene mutations to prognosis, which may be used as a basis to provide counselling for affected families.

Gene for progressive familial heart block type I maps to chromosome 19q13.

BACKGROUND: Progressive familial heart block type I (PF-HBI) is a dominantly inherited cardiac bundle-branch conduction disorder that has been traced through nine generations of a large South African kindred. Similar conduction disorders have been reported elsewhere; however, the cause of these diseases is unknown. The aim of the present study was to determine by linkage analysis the approximate chromosomal position of the gene causing PFHBI, thereby allowing family-based diagnosis and the development of positional cloning strategies to identify the causative gene. METHODS AND RESULTS: Eighty-six members of three pedigrees, 39 members of which were affected with PFHBI, were genotyped at four linked polymorphic marker loci mapped to chromosome 19, bands q13.2-q13.3 (chromosome 19q13.2-13.3). Maximum two-point logarithm of the odds scores (which represent the logarithm of the odds ratio of detecting linkage versus nonlinkage) generated were 6.49 (theta = 0) for the kallikrein locus, 5.72 (theta = 0.01) for the myotonic dystrophy locus, 3.44 (theta = 0) for the creatine kinase muscle-type locus and 4.51 (theta = 0.10) for the apolipoprotein C2 locus. The maximum multipoint logarithm of the odds score was 11.6, with the 90% support interval positioning the PFHBI locus within a 10 cM distance centering on the kallikrein 1 locus. CONCLUSIONS: The gene for PFHBI maps to an area of approximately 10 cM on chromosome 19q13.2-13.3. There are several candidate genes in this interval; although a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHBI, the proximity of these two loci may be relevant to the observed cardiac abnormalities of myotonic dystrophy. The results provide a means of DNA-based diagnosis in the families studied and a foundation for cloning studies to identify the causative gene.