Clinical Characteristics and Burden of Risk Factors Among Patients With Early Onset Acute Coronary Syndromes: The ANZACS-QI New Zealand National Cohort (ANZACS-QI 17).

BACKGROUND: Cardiovascular (CV) risk factor profiles of people experiencing acute coronary syndromes (ACS) vary with age, and in New Zealand (NZ), Maori and people of Pacific Island descent typically present with ACS at a younger age. We aimed to explore age- and ethnicity-related differences in CV risk factors in a large NZ cohort with first-time ACS. METHODS: The All NZ Acute Coronary Syndrome Quality Improvement program (ANZACS-QI) registry collects comprehensive data for patients admitted with ACS at NZ hospitals. This analysis includes patients with no prior atherosclerotic CV disease enrolled from 1 July, 2012 to 30 June, 2015. RESULTS: 14,190 patients had confirmed ACS, 8493 (60%) patients with no prior CVD comprised the study cohort. The mean age was 64 years, 25% were aged <55years, and 66% were male. Those aged <55years were more likely than older patients to be current smokers (48% vs 19%), have higher body mass index (BMI) (48% vs 34% with BMI≥30kg/m2), and higher total cholesterol:HDL ratios (≥4.0, 70% vs 50%), all p<0.001. Sixteen per cent of those <55years had diabetes; these patients often had a BMI≥30kg/m2 (67%) and higher median HbA1c than older patients with diabetes (69mmol/mol vs 55mmol/mol). Maori and people of Pacific Island descent were overrepresented in the younger age group; these patients had a very high risk factor burden. CONCLUSIONS: A quarter of NZ patients admitted to hospital with a first-time CV disease event are aged <55years. Younger patients have a very high risk factor burden: half are current smokers, half have a BMI≥30kg/m2, and 16% have diabetes.

Differing prognostic value of pulse pressure in patients with heart failure with reduced or preserved ejection fraction: results from the MAGGIC individual patient meta-analysis.

AIMS: Low pulse pressure is a marker of adverse outcome in patients with heart failure (HF) and reduced ejection fraction (HF-REF) but the prognostic value of pulse pressure in patients with HF and preserved ejection fraction (HF-PEF) is unknown. We examined the prognostic value of pulse pressure in patients with HF-PEF [ejection fraction (EF) ≥ 50%] and HF-REF. METHODS AND RESULTS: Data from 22 HF studies were examined. Preserved left ventricular ejection fraction (LVEF) was defined as LVEF ≥ 50%. All-cause mortality at 3 years was evaluated in 27 046 patients: 22 038 with HF-REF (4980 deaths) and 5008 with HF-PEF (828 deaths). Pulse pressure was analysed in quintiles in a multivariable model adjusted for the previously reported Meta-Analysis Global Group in Chronic Heart Failure prognostic variables. Heart failure and reduced ejection fraction patients in the lowest pulse pressure quintile had the highest crude and adjusted mortality risk (adjusted hazard ratio 1.68, 95% confidence interval 1.53-1.84) compared with all other pulse pressure groups. For patients with HF-PEF, higher pulse pressure was associated with the highest crude mortality, a gradient that was eliminated after adjustment for other prognostic variables. CONCLUSION: Lower pulse pressure (especially <53 mmHg) was an independent predictor of mortality in patients with HF-REF, particularly in those with an LVEF < 30% and systolic blood pressure <140 mmHg. Overall, this relationship between pulse pressure and outcome was not consistently observed among patients with HF-PEF.

NOS1AP Polymorphisms Modify QTc Interval Duration But Not Cardiac Arrest Risk in Hypertrophic Cardiomyopathy.

INTRODUCTION: The accurate prediction of the risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains elusive. Corrected QT interval (QTc) duration is a known risk factor in various cardiac conditions. Single nucleotide polymorphisms (SNPs) have been linked to QTc length, and to SCD. Here we investigated the role of 21 candidate SNPs in QTc duration and SCD events in patients with HCM. METHODS AND RESULTS: This HCM registry-based study included patients with an ECG, medical history, first SCD event data, and DNA available. Each individual SNP was assessed using logistic regression for associations with 2 outcomes: a prolonged QTc ( ≥440 milliseconds), and first SCD event (SCD, resuscitated cardiac arrest, and appropriate implantable cardioverter defibrillator (ICD) shock for ventricular fibrillation/ventricular tachycardia (VF/VT). In 272 HCM patients, there were 31 SCD events (8 SCD, 9 resuscitated cardiac arrest, 14 ICD shocks for VF/VT; 11%). A QTc ≥ 500 milliseconds was associated with SCD events on multivariate analysis (odds ratio [OR] = 4.0, 95% confidence interval [CI], 1.19-12.02, P = 0.016). In 228 Caucasian patients, 2 SNPs in the NOS1AP gene (rs10494366 and rs12143842) were associated with a prolonged QTc after correction for multiple testing. This remained significant after adjustment for current age, sex, and ≥1 SCD risk factor (OR 1.59 per copy of the minor allele, 95% CI 1.08-2.39, P = 0.022, and OR 1.63, 95% CI 1.09-2.49, P = 0.020, respectively). No SNPs were directly associated with SCD events. CONCLUSION: SNPs in the NOS1AP gene influence QTc interval duration but we have not demonstrated a direct association with the risk of SCD.

Heart failure in younger patients: the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).

AIM: Our understanding of heart failure in younger patients is limited. The Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) database, which consisted of 24 prospective observational studies and 7 randomized trials, was used to investigate the clinical characteristics, treatment, and outcomes of younger patients. METHODS AND RESULTS: Patients were stratified into six age categories: <40 (n = 876), 40-49 (n = 2638), 50-59 (n = 6894), 60-69 (n = 12 071), 70-79 (n = 13 368), and ≥80 years (n = 6079). Of 41 926 patients, 2.1, 8.4, and 24.8% were younger than 40, 50, and 60 years of age, respectively. Comparing young (<40 years) against elderly (≥80 years), younger patients were more likely to be male (71 vs. 48%) and have idiopathic cardiomyopathy (63 vs. 7%). Younger patients reported better New York Heart Association functional class despite more severe left ventricular dysfunction (median ejection fraction: 31 vs. 42%, all P < 0.0001). Comorbidities such as hypertension, myocardial infarction, and atrial fibrillation were much less common in the young. Younger patients received more disease-modifying pharmacological therapy than their older counterparts. Across the younger age groups (<40, 40-49, and 50-59 years), mortality rates were low: 1 year 6.7, 6.6, and 7.5%, respectively; 2 year 11.7, 11.5, 13.0%; and 3 years 16.5, 16.2, 18.2%. Furthermore, 1-, 2-, and 3-year mortality rates increased sharply beyond 60 years and were greatest in the elderly (≥80 years): 28.2, 44.5, and 57.2%, respectively. CONCLUSION: Younger patients with heart failure have different clinical characteristics including different aetiologies, more severe left ventricular dysfunction, and less severe symptoms. Three-year mortality rates are lower for all age groups under 60 years compared with older patients.

Sex differences in outcomes after acute coronary syndrome vary with age: a New Zealand national study.

AIMS: This study investigated age-specific sex differences in short- and long-term clinical outcomes following hospitalization for a first-time acute coronary syndrome (ACS) in New Zealand (NZ). METHODS AND RESULTS: Using linked national health datasets, people admitted to hospital for a first-time ACS between January 2010 and December 2016 were included. Analyses were stratified by sex and 10-year age groups. Logistic and Cox regression were used to assess in-hospital death and from discharge the primary outcome of time to first cardiovascular (CV) readmission or death and other secondary outcomes at 30 days and 2 years. Among 63 245 people (mean age 69 years, 40% women), women were older than men at the time of the ACS admission (mean age 73 vs. 66 years), with a higher comorbidity burden. Overall compared with men, women experienced higher rates of unadjusted in-hospital death (10% vs. 7%), 30-day (16% vs. 12%) and 2-year (44% vs. 34%) death, or CV readmission (all P < 0.001). Age group-specific analyses showed sex differences in outcomes varied with age, with younger women (<65 years) at higher risk than men and older women (≥85 years) at lower risk than men: unadjusted hazard ratio of 2-year death or CV readmission for women aged 18-44 years = 1.51 [95% confidence interval (CI) 1.21-1.84] and aged ≥85 years = 0.88 (95% CI 0.83-0.93). The increased risk for younger women was no longer significant after multivariable adjustment whereas the increased risk for older men remained. CONCLUSION: Men and women admitted with first-time ACS have differing age and comorbidity profiles, resulting in contrasting age-specific sex differences in the risk of adverse outcomes between the youngest and oldest age groups.

Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry.

BACKGROUND: Aotearoa/New Zealand has a multiethnic population. Patients with hypertrophic cardiomyopathy (HCM) are enrolled in the national Cardiac Inherited Diseases Registry New Zealand. Here, we report the characteristics of Cardiac Inherited Diseases Registry New Zealand HCM probands with and without pathogenic or likely pathogenic (P/LP) genetic variants for HCM, and assess genetic testing yield and variant spectrum by self-identified ethnicity. METHODS: Probands with HCM and enrolled in Cardiac Inherited Diseases Registry New Zealand who have undergone clinical genetic testing over a 17-year period were included. Clinical data, family history, and genetic test results were analyzed. RESULTS: Of 336 probands, 121 (36%) were women, 220 (66%) were European ethnicity, 41 (12%) were Maori, 26 (8%) were Pacific people, and 49 (15%) were other ethnicities. Thirteen probands (4%) presented with sudden death and 19 (6%) with cardiac arrest. A total of 134 (40%) had a P/LP variant identified; most commonly in the MYBPC3 gene (60%) followed by the MYH7 gene (24%). A P/LP variant was identified in 27% of Maori or Pacific probands versus 43% European or other ethnicity probands (P=0.022); 16% of Maori or Pacific probands had a variant of uncertain significance identified, compared with 9% of European or other ethnicity probands (P=0.092). Women more often had a P/LP variant identified than men (48% versus 35%; P=0.032), and variant-positive probands were younger at clinical diagnosis than variant of uncertain significance/variant-negative probands (39±17 versus 50±17 years; P<0.001) and more likely to have experienced cardiac arrest or sudden death events over their lifetime (P=0.002). CONCLUSIONS: Carriage of a P/LP variant in HCM probands is associated with presentation at younger age, and cardiac arrest or sudden death events. Maori or Pacific probands were less likely to have a P/LP variant identified than European or other ethnicity probands.

Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve KCNH2 -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here, we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. Methods: We quantified cell-surface trafficking of 18,796 variants in KCNH2 using a Multiplexed Assay of Variant Effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping (APC). We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1,458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian LQTS penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. Results: Variant MAVE trafficking scores and APC peak tail currents were highly correlated (Spearman Rank-order ρ = 0.69). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian LQTS penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became non-significant when peak-tail current and penetrance estimates were also available. The area under the ROC for 20-year event outcomes based on patient-specific sex and QTc (AUC 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (AUC 0.86 [0.83-0.89]) or attainable APC peak tail current data (AUC 0.84 [0.81-0.88]). Conclusion: High throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale while LQTS penetrance estimates and APC peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants. Clinical Perspective: What is new?: A two-order of magnitude increase in the set of calibrated functional data for KCNH2 -LQTS is provided by two complementary KCNH2 assays Proactively available variant scores are presented for all possible missense variants by using a LQTS penetrance estimation framework conditioned on high-throughput MAVE dataVariant functional data, in addition to patient features of corrected QT interval and sex, significantly improve modeling of 20-year cardiac event outcomesWhat are the clinical implications?: Readily available MAVE scores for thousands of variants may facilitate classification of new variants discovered in individuals with suspected LQTS Scores and penetrance estimates are readily searchable at variantbrowser.org for community inquiry Both automated patch-clamp data and quantitative LQTS penetrance estimates, conditioned on MAVE data, improve prediction of 20-year cardiac event outcomes in a large cohort of KCNH2 heterozygotes.

Prognostic modelling of clinical outcomes after first-time acute coronary syndrome in New Zealand.

OBJECTIVE: The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) was established to investigate the drivers of secondary events after first-time acute coronary syndrome (ACS), including addressing inequitable outcomes by ethnicity. Herein, the first clinical outcomes and prognostic modelling approach are reported. METHODS: First, in 28 176 New Zealanders with first-time ACS from a national registry, a clinical summary score for predicting 1-year death/cardiovascular readmission was created using Cox regression of 20 clinical variables. This score was then calculated in the 2015 participant MENZACS study to represent clinical risk. In MENZACS, Cox regression was used to assess N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a prognostic marker for death/cardiovascular readmission in four models, adjusting for (1) age and sex; (2) age, sex, ethnicity; (3) clinical summary score; (4) clinical summary score and ethnicity. RESULTS: Of the 2015 MENZACS participants (mean age 61 years, 79% male, 73% European, 14% Maori, 5% Pacific people), 2003 were alive at discharge. Of the 2003, 416 (20.8%) experienced all-cause death/cardiovascular readmission over a median of 3.5 years. In a simple model, age, male sex, Maori ethnicity and NT-proBNP levels were significant predictors of outcome. After adjustment for the clinical summary score, which includes age and sex, NT-proBNP and ethnicity were no longer statistically significant: log2(NT-proBNP) hazard ratio (HR) 1.03, 95% confidence interval (95% CI) 0.98 to 1.08, p=0.305; Maori ethnicity HR 1.26, 95% CI 0.97 to 1.62, p=0.084. CONCLUSIONS: In 2015 patients with first-time ACS, recurrent events were common (20.8%). Increasing NT-proBNP levels and Maori ethnicity were predictors of death/cardiovascular readmission, but not after adjustment for the 20 clinical risk factors represented by the clinical summary score. TRIAL REGISTRATION NUMBER: ACTRN12615000676516.

Acute coronary syndrome registry enrolment status: differences in patient characteristics and outcomes and implications for registry data use (ANZACS-QI 36).

AIMS: Clinical registry-derived data are widely used to represent patient populations. In New Zealand (NZ), a national registry-the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry-aims to include all patients undergoing coronary angiography; other acute coronary syndrome (ACS) patients are also registered but without complete capture. This study compares national hospitalization data of all first-time ACS admissions in NZ with patients in the ANZACS-QI registry, to investigate the use of clinical registry-derived data in research and in assessing clinical care. METHODS AND RESULTS: Patients admitted with first-time ACS in the NZ National Hospitalisation Dataset between 1 January 2015 and 31 December 2016 were included. Clinical characteristics and time to 12-month clinical outcomes were compared between patients captured and not-captured in the registry. A total of 16 569 patients were admitted with first-time ACS, median age 69 years, 61% male; 60% (n = 9918) were enrolled in ANZACS-QI. Registry-captured patients were younger, more often male, and with a lower comorbidity burden than non-captured patients. Overall, 16% patients died within 12 months, 15% experienced a non-fatal cardiovascular (CV) readmission, and 28% either died or were readmitted. Patients not captured in the registry were more than twice as likely to have experienced death or a non-fatal CV readmission within 12 months as captured patients. CONCLUSIONS: First-time ACS patients captured in the ANZACS-QI registry had very different clinical characteristics and outcomes than those not captured. Cardiovascular registry-derived data are dependent on registry design and may not be representative of the wider patient population; this must be considered when using registry-derived data.

Outcomes for working age patients after first-time acute coronary syndrome - ANZACS-QI 35.

BACKGROUND: Acute coronary syndrome (ACS) events and the ongoing burden of disease can have a significant impact on the subsequent life-course of working age people. METHODS: We report 12-month clinical outcomes for 10,822 patients hospitalized with first-time ACS between 2015-2016 and enrolled in the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry, with a focus on people of working age (defined as <65 years). RESULTS: Nearly half (48%) of first-time ACS occurred in people of working age. Compared to those >65 years, these patients had a high burden of cardiovascular risk factors, and were more likely to be male (75% vs 60%), to be of non-European ethnicity (36% vs 15%), and to be living in areas of high deprivation. Subsequent clinical events were common in the younger patients, with 15% dying or being readmitted for cardiovascular causes within 12 months despite high rates of angiography (96%), revascularization (74%) and evidence-based medical therapy at the time of the index ACS event. CONCLUSIONS: The high risk factor burden and subsequent high rate of clinical events in working age patients reinforces the need for a longer-term focus on strategies to improve clinical outcomes following first-time ACS.

Genetic testing in Polynesian long QT syndrome probands reveals a lower diagnostic yield and an increased prevalence of rare variants.

BACKGROUND: New Zealand has a multiethnic population and a national cardiac inherited disease registry (Cardiac Inherited Disease Registry New Zealand [CIDRNZ]). Ancestry is reflected in the spectrum and prevalence of genetic variants in long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to study the genetic testing yield and mutation spectrum of CIDRNZ LQTS probands stratified by self-identified ethnicity. METHODS: A 15-year retrospective review of clinical CIDRNZ LQTS probands with a Schwartz score of ≥2 who had undergone genetic testing was performed. RESULTS: Of the 264 included LQTS probands, 160 (61%) reported as European, 79 (30%) NZ Maori and Pacific peoples (Polynesian), and 25 (9%) Other ethnicities, with comparable clinical characteristics across ethnic groups (cardiac events in 72%; age at presentation 28±19 years; corrected QT interval 512±55 ms). Despite comparable testing (5.3±1.4 LQTS genes), a class III-V LQTS variant was identified in 35% of Polynesian probands as compared with 63% of European and 72% of Other probands (P<.0001). Among variant-positive CIDRNZ LQTS probands (n=148), Polynesians were more likely to have non-missense variants (57% vs 39% and 25% in probands of European and Other ethnicity, respectively; P=.005) as well as long QT syndrome type 1-3 variants not reported elsewhere (71% vs European 22% and Other 28%; P<.0001). Variants found in multiple probands were more likely to be shared within the same ethnic group; P<.01). CONCLUSION: Genetic testing of Polynesian LQTS probands has a lower diagnostic yield, despite comparable testing and clinical disease severity. Rare LQTS variants are more common in Polynesian LQTS probands. These data emphasize the importance of increasing the knowledge of genetic variation in the Polynesian population.

A Population-Based Registry of Patients With Inherited Cardiac Conditions and Resuscitated Cardiac Arrest.

BACKGROUND: The relative proportion of each cardiac inherited disease (CID) causing resuscitated sudden cardiac arrest (RSCA) on a population basis is unknown. OBJECTIVES: This study describes the profile of patients with CIDs presenting with RSCA; their data were collected by the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ). METHODS: Data were collated from CIDRNZ probands presenting with RSCA (2002 to 2018). RESULTS: CID was identified in 115 (51%) of 225 RSCA cases: long QT syndrome (LQTS) (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%]), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 9 [8%]), and dilated cardiomyopathy (n = 5 [4%]). Seventy-one (62%) of 115 were male. Of 725 probands from the CIDRNZ with CID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%) of 36; LQTS, 48 (20%) of 238; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354. Incident activity was: normal everyday activities, 44 (40%); exercising, 33 (30%); concurrent illness, 13 (12%); sleeping, 10 (9%); drugs/medication, 9 (8%); and emotion, 2 (2%). LQTS and CPVT predominated in those <24 years of age, 30 (77%) of 39; cardiomyopathies and BrS predominated in those >24 years of age, 49 (64%) of 76. For those >40 years of age, HCM was the most common (33%) CID. A genetic diagnosis in patients with CID was made in 48 (49%) of 98 tested. Diagnosis by age range was as follows: age 1 to 14 years, 78%; age 15 to 24 years, 53%; age 25 to 39 years, 54%; and age >40 years, 26%. CONCLUSIONS: The commonest CID identified after RSCA was LQTS; the most common CID cause of RSCA for those >40 years of age was HCM. CPVT was the CID most likely to present with RSCA and HCM the least. Genetic yield decreases with age. Only one-third of RSCA cases due to CID occurred while exercising.

Development and validation of a cardiovascular risk score for patients in the community after acute coronary syndrome.

OBJECTIVE: Following acute coronary syndrome (ACS), patients are managed long-term in the community, yet few tools are available to guide patient-clinician communication about risk management in that setting. We developed a score for predicting cardiovascular disease (CVD) risk among patients managed in the community after ACS. METHODS: Adults aged 30-79 years with prior ACS were identified from a New Zealand primary care CVD risk management database (PREDICT) with linkage to national mortality, hospitalisation, pharmaceutical dispensing and regional laboratory data. A Cox model incorporating clinically relevant factors was developed to estimate the time to a subsequent fatal or non-fatal CVD event and transformed into a 5-year risk score. External validation was performed in patients (Coronary Disease Cohort Study) assessed 4 months post-ACS. RESULTS: The PREDICT-ACS cohort included 13 703 patients with prior hospitalisation for ACS (median 1.9 years prior), 69% men, 58% European, median age 63 years, who experienced 3142 CVD events in the subsequent 5 years. Median estimated 5 year CVD risk was 24% (IQR 17%-35%). The validation cohort consisted of 2014 patients, 72% men, 92% European, median age 67 years, with 712 CVD events in the subsequent 5 years. Median estimated 5-year risk was 33% (IQR 24%-51%). The risk score was well calibrated in the derivation and validation cohorts, and Harrell's c-statistic was 0.69 and 0.68, respectively. CONCLUSIONS: The PREDICT-ACS risk score uses data routinely available in community care to predict the risk of recurrent clinical events. It was derived and validated in real-world contemporary populations and can inform management decisions with patients living in the community after experiencing an ACS.

Long QT molecular autopsy in sudden unexplained death in the young (1-40 years old): Lessons learnt from an eight year experience in New Zealand.

BACKGROUND: To review long QT syndrome molecular autopsy results in sudden unexplained death in young (SUDY) between 2006 and 2013 in New Zealand. METHODS: Audit of the LQTS molecular autopsy results, cardiac investigations and family screening data from gene-positive families. RESULTS: During the study period, 365 SUDY cases were referred for molecular autopsy. 128 cases (35%) underwent LQTS genetic testing. 31 likely pathogenic variants were identified in 27 cases (21%); SCN5A (14/31, 45%), KCNH2 (7/31, 22%), KCNQ1 (4/31, 13%), KCNE2 (3/31, 10%), KCNE1 (2/31, 7%), KCNJ2 (1/31, 3%). Thirteen variants (13/128, 10%) were ultimately classified as pathogenic. Most deaths (63%) occurred during sleep. Gene variant carriage was more likely with a positive medical history (mostly seizures, 63% vs 36%, p = 0.01), amongst females (36% vs 12%, p = 0.001) and whites more than Maori (31% vs 0, p = 0.0009). Children 1-12 years were more likely to be gene-positive (33% vs 14%, p = 0.02). Family screening identified 42 gene-positive relatives, 18 with definitive phenotypic expression of LQTS/Brugada. 76% of the variants were maternally inherited (p = 0.007). Further family investigations and research now support pathogenicity of the variant in 13/27 (48%) of gene-positive cases. CONCLUSION: In New Zealand, variants in SCN5A and KCNH2, with maternal inheritance, predominate. A rare variant in LQTS genes is more likely in whites rather than Maori, females, children 1-12 years and those with a positive personal and family history of seizures, syncope or SUDY. Family screening supported the diagnosis in a third of the cases. The changing classification of variants creates a significant challenge.

Detection of sudden death syndromes in New Zealand.

AIM: To investigate regional variations in the detection of sudden death syndromes across New Zealand by assessing registrations in the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ). METHODS: The CIDRNZ has been a national entity since 2009, with a hub in Auckland and locally funded regional coordinators (Midland, Central) linked with multidisciplinary cardiac genetic teams. Registration is consent-based and voluntary, and involves the collection of clinical/genetic information and permits genetic testing and research. Registry data were extracted from the CIDRNZ in October 2015 and results are expressed as registrations per 100,000 people by district health board area. RESULTS: The CIDRNZ has 1,940 registrants from 712 families, 46% of whom are definitely or probably affected by cardiac inherited disease. There are clear regional differences in registration frequencies between regions and between the North and South Islands, both for overall registrations (56/100,000 and 14/100,000, respectively; p<0.001) and for long QT syndrome registrations (15/100,000 and 6/100,000, respectively; p<0.001). Regions with local coordinators have the highest number of registrations. CONCLUSION: The detection of sudden death syndromes in New Zealand through a cardiac genetic registry is possible but much work is needed to improve regional variation in the detection/reporting of these conditions across the country.

Must every child with long QT syndrome take a beta blocker?

Long QT syndrome is the most commonly recognised cause of sudden cardiac death in children. With a prevalence of 1 in 2000, family screening is identifying large numbers of hitherto asymptomatic gene carriers in the community, about a third of whom have a normal QT interval. The mainstay of treatment is long term uninterrupted beta blocker therapy, a treatment with many potential side effects. This article reviews the evidence and suggests a cohort who may, after assessment in a specialised cardiac-genetic clinic, be spared this treatment because of very low baseline risk. These are asymptomatic boys and prepubertal girls with a heart rate corrected QT interval persistently less than 470 ms who do not indulge in high risk activities (especially swimming) and do not have a missense mutation in the c-loop region of the KCNQ1 (long QT 1) gene.

Is heart rate a risk marker in patients with chronic heart failure and concomitant atrial fibrillation? Results from the MAGGIC meta-analysis.

AIM: To investigate the relationship between heart rate and survival in patients with heart failure (HF) and coexisting atrial fibrillation (AF). METHODS AND RESULTS: Patients with AF included in the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) meta-analysis were the main focus of this analysis (3259 patients from 17 studies). The outcome was all-cause mortality at 3 years. Heart rate was analysed as a categorical (tertiles; T1 ≤77 b.p.m., T2 78-98 b.p.m., T3 ≥98 b.p.m.) and continuous variable. Cox proportional hazard models were used to compare the risk of all-cause death between tertiles of baseline heart rate. Patients in the highest tertile were more often female, less likely to have an ischaemic aetiology or diabetes, had a lower ejection fraction but higher blood pressure and New York Heart Association (NYHA) class. Higher heart rate was associated with higher mortality in patients with sinus rhythm (SR) but not in those in AF. In patients with heart failure and reduced ejection fraction (HF-REF) and AF, death rates per 100 patient years were lowest in the highest heart rate tertile (T1 18.9 vs. T3 15.9) but this difference was not statistically significant (P = 0.10). In patients with heart failure and preserved ejection fraction (HF-PEF), death rates per 100 patient years were highest in the highest heart rate tertile (T1 14.6 vs. T3 16.0, P = 0.014). However, after adjustment for other important prognostic variables, higher heart rate was no longer associated with higher mortality in HF-PEF (or HF-REF). CONCLUSIONS: In this meta-analysis of patients with HF, heart rate does not have the same prognostic significance in patients in AF as it does in those in SR, irrespective of ejection fraction or treatment with beta-blocker.