Blood flows from the SCN toward the OVLT within a new brain vascular portal pathway.

The suprachiasmatic nucleus (SCN) sets the phase of oscillation throughout the brain and body. Anatomical evidence reveals a portal system linking the SCN and the organum vasculosum of the lamina terminalis (OVLT), begging the question of the direction of blood flow and the nature of diffusible signals that flow in this specialized vasculature. Using a combination of anatomical and in vivo two-photon imaging approaches, we unequivocally show that blood flows unidirectionally from the SCN to the OVLT, that blood flow rate displays daily oscillations with a higher rate at night than in the day, and that circulating vasopressin can access portal vessels. These findings highlight a previously unknown central nervous system communication pathway, which, like that of the pituitary portal system, could allow neurosecretions to reach nearby target sites in OVLT, avoiding dilution in the systemic blood. In both of these brain portal pathways, the target sites relay signals broadly to both the brain and the rest of the body.

A Single-Short Partial Reprogramming of the Endothelial Cells decreases Blood Pressure via attenuation of EndMT in Hypertensive Mice.

Background: Small artery remodeling and endothelial dysfunction are hallmarks of hypertension. Growing evidence supports a likely causal association between cardiovascular diseases and the presence of endothelial-to-mesenchymal transition (EndMT), a cellular transdifferentiation process in which endothelial cells (ECs) partially lose their identity and acquire additional mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases. Methods: Using a partial reprogramming of ECs, via overexpression of Oct-3/4, Sox-2, and Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertensive mice. Primary ECs were infected with lentiviral vectors (LV) containing the specific EC marker cadherin 5 (Cdh5) and the fluorescent reporter enhanced green fluorescence protein (EGFP) with empty vector (LVCO) or with OSK (LV-OSK). Confocal microscopy and western blotting analysis were used to confirm the OSK overexpression. Cellular migration, senescence, and apoptosis were evaluated. Human aortic ECs (HAoECs) from male and female normotensive and hypertensive patients were analyzed after OSK or control treatments for their endothelial nitric oxide synthase (eNOS) levels, nitric oxide (NO), and genetic profile. Male and female normotensive (BPN/3J) and hypertensive (BPH/2J) mice were treated with an intravenous (i.v.) injection of LVCO or LV-OSK and evaluated 10 days post-infection. The blood pressure, cardiac function, vascular reactivity of small arteries, in vivo EGFP signal and EndMT inhibition were analyzed. Results: OSK overexpression induced partial EC reprogramming in vitro , and these cells showed endothelial progenitor cell (EPC)-like features with lower migratory capability. OSK treatment of hypertensive BPH/2J mice normalized blood pressure and resistance arteries hypercontractility, via the attenuation of EndMT and elastin breaks. EGFP signal was detected in vivo in the prefrontal cortex of both BPN/3J and BPH/2J-treated mice, but OSK induced angiogenesis only in male BPN/3J mice. OSK-treated human ECs from hypertensive patients showed high eNOS activation and NO production, with low ROS formation. Single-cell RNA analysis showed that OSK alleviated EC senescence and EndMT, restoring their phenotypes in human ECs from hypertensive patients. Conclusion: Overall, these data indicate that OSK treatment and EC reprogramming can decrease blood pressure and reverse hypertension-induced vascular damage.

Acute poisoning by chlorpyrifos differentially impacts survival and cardiorespiratory function in normotensive and hypertensive rats.

Hypertension is the most important and well-known risk factor for cardiovascular disease (CVD). Recently, acute organophosphate (OP) poisoning has also been pointed as a CVD risk factor. Despite this evidence, no studies have contrasted the acute toxicosis and cardiovascular (CV) effects of OP poisoning under conditions of normotension and hypertension. In this work, adult male normotensive Wistar and Spontaneously Hypertensive rats (SHR) were intraperitoneally injected with saline or chlorpyrifos (CPF), an OP compound, monitored for acute toxicosis signs and 24-h survival. After poisoning, blood pressure, heart rate and ventilation were recorded, the Bezold-Jarisch Reflex (BJR), the Chemoreflex (CR) were chemically activated, as well as the cardiac autonomic tone (AUT) was assessed. Erythrocyte and brainstem acetylcholinesterase and plasmatic butyrylcholinesterase (BuChE) activities were measured as well as lipid peroxidation, advanced oxidation protein products (AOPP), nitrite/nitrate levels, expression of catalase, TNFα and angiotensin-I converting enzyme (ACE-1) within the brainstem. CPF induced a much more pronounced acute toxicosis and 33 % lethality in SHR. CPF poisoning impaired ventilation in SHR, the BJR reflex responses in Wistar rats, and the chemoreflex tachypneic response in both strains. CPF inhibited activity of cholinesterases in both strains, increased AOPP and nitrite/nitrate levels and expression of TNFα and ACE-1 in the brainstem of Wistar rats. Interestingly, SHR presented a reduced intrinsic BuChE activity, an important bioscavenger. Our findings show that, CPF at sublethal doses in normotensive rats lead to lethality and much more pronounced acute toxicity signs in the SHR. We also showed that cardiorespiratory reflexes were differentially impacted after CPF poisoning in both strains and that the cardiorespiratory disfunction seems to be associated with interference in cholinergic transmission, oxidative stress and inflammation. These results points to an increased susceptibility to acute toxicosis in hypertension, which may impose a significant risk to vulnerable populations.

Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement.

Cell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long-term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high-throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement-induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53-mediated cell death. Cumulatively, this work establishes advanced, high-throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death.

The Role of Arginine-Vasopressin in Stroke and the Potential Use of Arginine-Vasopressin Type 1 Receptor Antagonists in Stroke Therapy: A Narrative Review.

Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging as potential targets to treat edema formation and subsequent elevation in intracranial pressure, both significant causes of mortality in acute stroke. Here, we summarize the current knowledge on the mechanisms leading to AVP hyperexcretion in acute stroke and the subsequent secondary neuropathological responses. Furthermore, we discuss the work supporting the predictive value of measuring copeptin, a surrogate marker of AVP in stroke patients, followed by a review of the experimental evidence suggesting AVP receptor antagonists in stroke therapy. As we highlight throughout the narrative, critical gaps in the literature exist and indicate the need for further research to understand better AVP mechanisms in stroke. Likewise, there are advantages and limitations in using copeptin as a prognostic tool, and the translation of findings from experimental animal models to clinical settings has its challenges. Still, monitoring AVP levels and using AVP receptor antagonists as an add-on therapeutic intervention are potential promises in clinical applications to alleviate stroke neurological consequences.

Intermittent exposure to chlorpyrifos results in cardiac hypertrophy and oxidative stress in rats.

Forbidden in some countries due to its proven toxicity to humans, chlorpyrifos (CPF) still stands as an organophosphate pesticide (OP) highly used worldwide. Cardiotoxicity assessment is an unmet need in pesticide regulation and should be deeply studied through different approaches to better inform and generate an appropriate regulatory response to OP use. In the present study, we used our 4-week intermittent OP exposure model in rats to address the CPF effects on cardiac morphology allied with cardiovascular functional and biomolecular evaluation. Rats were intermittently treated with CPF at doses of 7 mg/kg and 10 mg/kg or saline (i.p.) and assessed for cardiac morphology (cardiomyocyte diameter and collagen content), cardiopulmonary Bezold-Jarisch reflex (BJR) function, cardiac autonomic tone, left ventricle (LV) contractility, cardiac expression of NADPH oxidase (Nox2), catalase (CAT), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2) and cardiac levels of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive substances (TBARS). Plasma butyrylcholinesterase (BuChE) and brainstem acetylcholinesterase (AChE) were also measured. Intermittent exposure to CPF induced cardiac hypertrophy, increasing cardiomyocyte diameter and collagen content. An impairment of cardioinhibitory BJR responses and an increase in cardiac vagal tone were also observed in CPF-treated animals without changes in LV contractility. CPF exposure increased cardiac Nox-2, CAT, SOD1, and TBARS levels and inhibited plasma BuChE and brainstem AChE activities. Our data showed that intermittent exposure to CPF induces cardiac hypertrophy together with cardiovascular reflex impairment, imbalance of autonomic tone and oxidative stress, which may bring significant cardiovascular risk to individuals exposed to OP compounds seasonally.

Contraception and Pre-Conception Counselling in Cardiac Patients: We Can Do Better. Experience From a Tertiary Centre in New Zealand.

BACKGROUND: Physiological changes in pregnancy can precipitate decompensation in women with pre-existing cardiac disease leading to suboptimal fetal outcome in addition to maternal risk. Many women born with congenital heart disease are living into childbearing years, and rheumatic heart disease (RHD) remains a significant problem within Maori and Pasifika communities in New Zealand. AIMS: To assess documentation of contraception advice and pre-conception counselling in women with pre-existing cardiac disease of childbearing potential and to explore potential barriers to these conversations. METHODS: We conducted a retrospective review of electronic clinic letters of 194 women with modified World Health Organization (mWHO) class 2 or above heart disease. This was followed by a survey of our cardiology team. RESULTS: Fifty-one (51) women with RHD and 143 women with non-RHD were identified. Thirty-eight per cent (38%) of women had documented discussions about contraception and pre-conception counselling. Women with RHD were less likely to receive discussions about contraception than women with non-RHD. All surveyed members of our cardiology team agreed that women with cardiac disease should have planned pregnancies and the majority reported always or usually discussing contraception. Factors such as lack of time, cultural barriers and presence of family members were identified. Many felt that the subject was outside of their expertise or admitted that they simply did not think about it. CONCLUSIONS: Advice regarding contraception in addition to pre-pregnancy counselling should be given to all patients with pre-existing cardiovascular disease of potential child-bearing potential. Our study shows much room for improvement.

Cardiac disease in pregnancy and the multidisciplinary team: the Wellington experience.

AIM: To define the range and severity of cardiac disease in pregnant women in New Zealand, as well as the maternal and neonatal morbidity and mortality compared with the background obstetric population. METHODS: We retrospectively audited pregnant women with cardiac comorbidity seen by a multidisciplinary team at a tertiary referral centre consisting of midwives, cardiologists, obstetricians and anaesthetists in 2016-2017. RESULTS: Seventy-two women were referred to the multidisciplinary team. The most common referral reasons were arrhythmia (n=20, 27.8%), congenital anomalies (n=19, 26.4%) and palpitations (n=10, 13.9%). Fifty-two of these women were found to be at increased risk of morbidity or mortality. A specific delivery plan was devised for 37 of these women (69.8%). There was no serious maternal morbidity or mortality. Instrumental delivery rates were higher for women with cardiac comorbidity than the background obstetric population (19.2% vs 10.8%, p=0.049), however, neonatal admissions were not increased (11.5% compared with 16.5%). CONCLUSION: Multidisciplinary review of obstetric patients with cardiac disease provides an important service to ensure risk modification prior to conception and throughout pregnancy and the puerperium.

Intermittent Exposure to Chlorpyrifos Differentially Impacts Neuroreflex Control of Cardiorespiratory Function in Rats.

Previous studies showed that chlorpyrifos (CPF) acute exposure impaired cardiorespiratory reflexes. Evidence also indicates that continuous exposure to organophosphorus compounds impairs cardiovascular function. However, the effect of intermittent exposure to CPF, as may be experienced in the real world, on tonic and reflex cardiorespiratory function remains unexplored. Wistar rats were injected with saline or CPF for 4 weeks (3 times/week) or 12 weeks (once/week) at the doses of 7 mg/kg and 10 mg/kg. After exposure, blood pressure (BP), heart rate (HR), respiratory rate (fR), tidal volume (VT), and minute volume (VE) were recorded. Systolic BP and pulse interval (PI) variability, HR spectrum, spontaneous baroreflex and chemoreflex function were also evaluated. Plasma butyrylcholinesterase and brainstem acetylcholinesterase activities were quantified. Enzymatic activity of the CPF animals was reduced after both treatment periods. Baseline BP, HR, and fR, as well as systolic BP and PI variability indices, did not change, after CPF treatment. VT and VE were elevated in CPF animals. CPF exposure increased the very low-frequency component of the HR spectrum. Baroreflex gain was reduced after CPF 4-week exposure. Chemoreflex bradycardia was reduced in the CPF-treated rats. These data show that intermittent exposure to CPF impairs cardiorespiratory function in rats. These results may have important clinical implications for workers seasonally exposed to these compounds.

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.

Inpatient detection of cardiac-inherited disease: the impact of improving family history taking.

OBJECTIVES: 'Idiopathic' cardiac conditions such as dilated cardiomyopathy (DCM) and resuscitated sudden cardiac death (RSCD) may be familial. We suspected that inpatient cardiology services fail to recognise this. Our objective was to compare diagnostic value of family histories recorded by inpatient cardiology teams with a multigenerational family tree obtained by specially trained allied professionals. METHODS: 2 experienced cardiology nurses working in 2 tertiary adult cardiac units were trained in cardiac-inherited diseases and family history (FHx) taking, and established as regional coordinators for a National Cardiac Inherited Disease Registry. Over 6 months they sought 'idiopathic' cardiology inpatients with conditions with a possible familial basis, reviewed the FHx in the clinical records and pursued a minimum 3-generation family tree for syncope, young sudden death and cardiac disease (full FHx). RESULTS: 37 patients (22 males) were selected: mean age 51 years (range 15-79). Admission presentations included (idiopathic) RSCD (14), dyspnoea or heart failure (11), ventricular tachycardia (2), other (10). 3 patients had already volunteered their familial diagnosis to the admitting team. FHx was incompletely elicited in 17 (46%) and absent in 20 (54%). 29 patients (78%) provided a full FHx to the coordinator; 12 of which (41%) were strongly consistent with a diagnosis of a cardiac-inherited disease (DCM 7, hypertrophic cardiomyopathy 3, long QT 1, left ventricular non-compaction 1). Overall, a familial diagnostic rate rose from 3/37(8%) to 12/37 (32%). CONCLUSIONS: Adult cardiology inpatient teams are poor at recording FHx and need to be reminded of its powerful diagnostic value.

Family acceptability of school-based echocardiographic screening for rheumatic heart disease in a high-risk population in New Zealand.

AIM: Echocardiographic screening for rheumatic heart disease has been piloted in high-risk areas in New Zealand and internationally, and fulfils most of the criteria for a targeted screening programme. The question of acceptability of rheumatic heart disease screening has not been assessed, and the aim of our study was to assess parental acceptability of a school-based echocardiographic screening programme in a high-risk population in New Zealand. METHODS: A post-screening questionnaire was developed to survey parents of children who underwent echocardiographic screening. The families of 34 children with abnormal scan results and a sample of 80 children with normal scan results were surveyed by phone within 4 months of screening. RESULTS: Positive results were seen in all survey questions in both normal and abnormal scan groups. All families were supportive of an ongoing screening programme. Of children with abnormal results, 62% of their parents reported that they would treat their child differently; however, all responses were positive health-promoting outcomes. CONCLUSION: The study showed strong positive support for school-based echocardiographic screening by a community with high acute rheumatic fever incidence. The study did not detect any short-term negative effects in those with abnormal results. The survey result shows family and community support for the establishment of echocardiographic screening programmes in high acute rheumatic fever areas provided there is adequate infrastructural support.

100% Efficient three-dimensional coronary MR angiography with two-dimensional beat-to-beat translational and bin-to-bin affine motion correction.

PURPOSE: To develop a flexible image navigator for 3D coronary MR angiography that allows respiratory motion of variable complexity to be compensated for on different temporal scales. METHODS: A two-dimensional (2D) golden radial image navigator is proposed; translational motion is compensated for on a beat-to-beat basis, and residual affine motion is compensated for on a bin-to-bin basis in a two-step procedure. The method does not use a respiratory gating window and therefore achieves 100% scan efficiency and a predictable scan time. The proposed method was tested in 11 healthy volunteers and compared against a navigator-gated and tracked acquisition. RESULTS: The proposed method achieved comparable quantitative and qualitative image quality to a 6-mm navigator-gated and tracked scan while reducing the scan time by a factor of approximately 2. Combined motion correction using image navigators improved visualization of the coronary arteries in four of 11 subjects in comparison with translational correction only, and image quality was maintained in the remaining cases. In one case, visualization of the left anterior descending coronary artery was degraded using combined correction compared with translation correction only. CONCLUSIONS: The feasibility of correcting for 2D translational motion on a beat-to-beat basis as well as affine motion on a bin-to-bin basis has been demonstrated.

Elevated baseline cardiac troponin levels in the elderly - another variable to consider?

AIMS: This study aimed to determine the frequency of baseline high-sensitivity troponin T (hs-TnT) elevation in different age groups presenting to the Emergency Department without acute coronary syndromes (ACS) or other acute illnesses known to cause to troponin elevation. We additionally sought to determine whether the relationship between age and hs-TnT was independent of co-morbidities. METHODS: We retrospectively analysed data on all patients presenting to the Emergency Department (ED) between November 2010 and June 2011 in whom hs-TnT was measured. Patients presenting with acute coronary syndromes (ACS) or other acute illness known to elevate hs-TnT levels were excluded. Demographics, clinical characteristics and diagnosis were recorded, together with hs-TnT assay results. RESULTS: Of 3219 patients with hs-TnT testing in the ED during the study period, 526 with proven/suspected ACS and 1376 with other acute medical conditions known to elevate troponin concentrations were excluded. The percentage of patients with hs-TnT concentrations elevated above the upper reference limit (>14ng/L) increased with age: <50 years (1.8%), 50-69 years (7.3%), ≥70 years (41.5%), p=0.001. Multivariate analysis identified age over 70 years (p<0.001) as the strongest independent predictor of elevated hs-TnT. Other independent predictors included atrial fibrillation (p<0.001), age 50-69 years (p<0.001) male gender (p<0.001), previous heart failure (p<0.007) and previous ischaemic heart disease (p<0.04). CONCLUSIONS: Hs-TnT elevations (>14ng/L) are common in elderly patients presenting to the ED without ACS or other acute illnesses known to cause to troponin elevation. This finding appears to be independent of the higher burden of co-morbidities in this age group.

Characterization and correction of eddy-current artifacts in unipolar and bipolar diffusion sequences using magnetic field monitoring.

Diffusion tensor imaging (DTI) of moving organs is gaining increasing attention but robust performance requires sequence modifications and dedicated correction methods to account for system imperfections. In this study, eddy currents in the "unipolar" Stejskal-Tanner and the velocity-compensated "bipolar" spin-echo diffusion sequences were investigated and corrected for using a magnetic field monitoring approach in combination with higher-order image reconstruction. From the field-camera measurements, increased levels of second-order eddy currents were quantified in the unipolar sequence relative to the bipolar diffusion sequence while zeroth and linear orders were found to be similar between both sequences. Second-order image reconstruction based on field-monitoring data resulted in reduced spatial misalignment artifacts and residual displacements of less than 0.43 mm and 0.29 mm (in the unipolar and bipolar sequences, respectively) after second-order eddy-current correction. Results demonstrate the need for second-order correction in unipolar encoding schemes but also show that bipolar sequences benefit from second-order reconstruction to correct for incomplete intrinsic cancellation of eddy-currents.

First-in-human evaluation of a sirolimus-eluting coronary stent on an integrated delivery system: the DIRECT study.

AIMS: The DIRECT study is a first-in-human evaluation of the safety and efficacy of the Svelte sirolimus-eluting coronary stent mounted on a fixed-wire, "all-in-one" integrated delivery system (IDS) in patients with de novo coronary artery lesions. The system permits easy delivery, deployment and post-dilatation of a cobalt-chromium stent eluting sirolimus from a fully bioabsorbable amino acid coating. The stent on its IDS has a very low profile, and is designed specifically to facilitate direct stenting. METHODS AND RESULTS: Patients with symptomatic ischaemic heart disease and a single de novo native coronary lesion suitable for percutaneous coronary intervention were prospectively enrolled at four New Zealand sites. The lesion length had to be <23 mm and the vessel reference diameter 2.5-3.5 mm. The primary safety and efficacy endpoints were target vessel failure (TVF) and angiographic in-stent late lumen loss (LLL) at six months, respectively. Twenty-nine of 30 enrolled patients completed six-month follow-up. TVF occurred in two patients (7%). The in-stent LLL was 0.22 ± 0.27 mm. No patient had clinically-driven target lesion revascularisation. Intravascular ultrasound neointimal volume was 3.3 ± 4.4 mm3 and volume obstruction was 2.7 ± 4.5% at six months. Optical coherence tomography showed 98 ± 4% strut coverage at a depth of 0.12 ± 0.06 mm. No patient developed stent thrombosis. CONCLUSIONS: Percutaneous coronary intervention using the Svelte sirolimus-eluting coronary stent mounted on an IDS appears safe and effective in de novo coronary artery lesions, with minimal in-stent proliferation and excellent stent strut coverage at six months.

Education increases reserve against Alzheimer's disease--evidence from structural MRI analysis.

INTRODUCTION: The aim of this study was to determine whether years of schooling influences regional cortical thicknesses and volumes in Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls. METHODS: Using an automated image analysis pipeline, 33 regional cortical thickness and 15 regional volumes measures from MRI images were determined in 121 subjects with MCI, 121 patients with AD, and 113 controls from AddNeuroMed study. Correlations with years of schooling were determined and more highly and less highly educated subjects compared, controlling for intracranial volume, age, gender, country of origin, cognitive status, and multiple testing. RESULTS: After controlling for confounding factors and multiple testing, in the control group, subjects with more education had larger regional cortical thickness in transverse temporal cortex, insula, and isthmus of cingulate cortex than subjects with less education. However, in the AD group, the subjects with more education had smaller regional cortical thickness in temporal gyrus, inferior and superior parietal gyri, and lateral occipital cortex than the subjects with less education. No significant difference was found in the MCI group. CONCLUSION: Education may increase regional cortical thickness in healthy controls, leading to increased brain reserve, as well as helping AD patients to cope better with the effects of brain atrophy by increasing cognitive reserve.

Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.

BACKGROUND: Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. OBJECTIVE: The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1-40 years old. METHODS: Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1-40 years. RESULTS: Over 26 months (2006-2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months-40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%-27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype-genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%-27%). CONCLUSION: Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.