No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Post-mortem pathologic and genetic studies in “dead in bed syndrome” cases in type 1 diabetes mellitus
Abstract
Dead in bed syndrome is a poorly understood cause of sudden death in young people with type 1 diabetes. The underlying cause remains unknown. One possible explanation may involve prolongation of the QT interval followed by a terminal malignant arrhythmia. Risk factors associated with QT interval prolongation include hypoglycemia and cardiac autonomic neuropathy. We sought to identify myocardial cellular changes and genetic influences that may contribute to the pathogenesis of dead in bed syndrome. Post-mortem reports between 1994 and 2006 from the 2 largest Departments of Forensic Medicine in Australia were reviewed for dead in bed syndrome cases. Post-mortem heart sections were immunohistochemically stained for collagen types I and III and connective tissue growth factor (CTGF). Genomic DNA was prepared from post-mortem samples, and genetic analysis was performed in the SCN5A, G6PC, PHOX2B, and CTGF genes. Twenty-two dead in bed syndrome cases were identified and staining of heart sections for collagen I and III, and CTGF showed no differences between dead in bed syndrome cases and controls. Genetic screening of SCN5A revealed 3 silent polymorphisms A29A, E1061E, and D1819D and 1 protein-changing variant H558R. No genetic variants were found in G6PC, PHOX2B, and CTGF, and dead in bed syndrome cases were not associated with the G-945C CTGF promoter polymorphism. In conclusion, this study is the first to investigate potential pathogenic mechanisms underlying the dead in bed syndrome in type 1 diabetes with the results substantially adding to knowledge of this condition. Understanding the causes and triggers of dead in bed syndrome will be critical in facilitating the identification of patients with type 1 diabetes at highest risk of developing sudden death.
... Hypoglycaemia has been put forward as the most likely explanation but has been excluded in some cases [2][3][4]. The possibility that a cardiac ion channelopathy such as long QT syndrome or Brugada syndrome may cause death through a malignant arrhythmia in individuals with diabetes has been considered but never proven [5]. ...
... Another group has looked for genetic abnormalities in patients with diabetes who have died suddenly. Tu et al. [5] studied DNA retrospectively from 22 such cases and found no mutations in either the SCN5A gene or the G6PC, PHOX2B, and CTGF genes. The latter three genes are involved in gluconeogenesis/glycogenolysis, dysautonomia, and endothelial cell function, respectively; however, they did not analyze the GPD1L gene or any of the other Long QT genes. ...
Sudden unexpected nocturnal death among patients with diabetes occurs approximately ten times more commonly than in the general population. Malignant ventricular arrhythmia due to Brugada syndrome has been postulated as a cause, since a glucose-insulin bolus can unmask the Brugada electrocardiographic signature in genetically predisposed individuals. In this report we present a 16-year-old male with insulin-dependent diabetes who died suddenly at night. His diabetes had been well controlled, without significant hypoglycaemia. At autopsy, he had a full stomach and a glucose level of 7 mmol/L in vitreous humor, excluding hypoglycaemia. Genetic analysis of autopsy DNA revealed a missense mutation, c.370A>G (p.Ile124Val), in the GPD1L gene. A parent carried the same mutation and has QT prolongation. Mutations in this gene have been linked to Brugada syndrome and sudden infant death. The patient may have died from a ventricular arrhythmia, secondary to occult Brugada syndrome, triggered by a full stomach and insulin. The data suggest that molecular autopsies are warranted to investigate other cases of the diabetic dead-in-bed syndrome.
... Most studies to date have been performed in type 1 diabetes. The CTGF −945 G/C polymorphism was examined in a small cohort (n = 22) with type 1 diabetes and 'dead in bed syndrome, ' a cause of sudden death which may have a cardiac cause possibly related to underlying cardiac fibrosis [35]. The study reported no differences in CTGF staining in heart sections in those found with dead in bed syndrome compared to control heart sections, and no difference in the −945 G/C polymorphism genotype frequency compared to 119 healthy control subjects [35]. ...
... The CTGF −945 G/C polymorphism was examined in a small cohort (n = 22) with type 1 diabetes and 'dead in bed syndrome, ' a cause of sudden death which may have a cardiac cause possibly related to underlying cardiac fibrosis [35]. The study reported no differences in CTGF staining in heart sections in those found with dead in bed syndrome compared to control heart sections, and no difference in the −945 G/C polymorphism genotype frequency compared to 119 healthy control subjects [35]. Plasma CTGF levels are increased in type 1 diabetes, and are associated with end-stage kidney disease [19]. ...
Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes.
The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria).
The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD.
In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.
... However, frequent or recent exposure to hypoglycemia, as well as the development of cardiac autonomic neuropathy, blunts the sympathoadrenal response during hypoglycaemic episodes [18,35]. It has been hypothesized that subjects with polymorphisms of the ion channels genes which contribute to the cardiac conduction system might be vulnerable to the arrhythmogenic effects of hypoglycemia [36]. However, in susceptible patients who are at high cardiovascular risk, more than one mechanism might contribute to potentially fatal cardiac arrhythmias during hypoglycemia. ...
Hypoglycemia is common in patients with type 1 and type 2 diabetes (T1D, T2D), treated with insulin or sulfonylureas, and has multiple short- and long-term clinical implications. Whether acute or recurrent, hypoglycemia significantly affects the cardiovascular system with the potential to cause cardiovascular dysfunction. Several pathophysiological mechanisms have been proposed linking hypoglycemia to increased cardiovascular risk, including hemodynamic changes, myocardial ischemia, abnormal cardiac repolarization, cardiac arrhythmias, prothrombotic and proinflammatory effects, and induction of oxidative stress. Hypoglycemia-induced changes can promote the development of endothelial dysfunction, which is an early marker of atherosclerosis. Although data from clinical trials and real-world studies suggest an association between hypoglycemia and cardiovascular events in patients with diabetes, it remains uncertain whether this association is causal. New therapeutic agents for patients with T2D do not cause hypoglycemia and have cardioprotective benefits, whereas increasing the use of new technologies, such as continuous glucose monitoring devices and insulin pumps, has the potential to reduce hypoglycemia and its adverse cardiovascular outcomes in patients with T1D.
... Genetic factors affecting the function of cardiac ion channels and cardiac fibrosis have been suggested as an underlying predisposing factor. 51 Furthermore, in patients with type 2 diabetes or longstanding type 1 diabetes and established cardiovascular disease, functional and structural remodelling resulting in an ischaemic substrate to ventricular tachycardias may also be an important factor. ...
Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called ‘dead-in-bed syndrome’. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which results in bradycardia. Here, we provide an overview of the existing literature exploring potential mechanisms for hypoglycaemia-induced cardiac arrhythmias and studies linking hypoglycaemia to cardiac arrhythmias in patients with diabetes.
... It has been hypothesised that people with underlying polymorphisms of the ion channels, which contribute to the cardiac conduction system, might be particularly vulnerable. 72 Other experimental and observational studies have shown abnormalities of cardiac repolari sation along with profound bradycardia in some susceptible individuals with type 1 diabetes, 73 but what confers susceptibility or triggers the fatal event is unknown. ...
Hypoglycaemia has long been recognised as a dangerous side-effect of treatment of diabetes with insulin or insulin secretagogues. With its potential to disrupt cerebral function, hypoglycaemia can have a major effect on peoples' lives. Study findings have suggested that hypoglycaemia is associated with an increased risk of cardiovascular events and mortality. Different mechanisms by which hypoglycaemia might provoke cardiovascular events have been identified in experimental studies, and in clinical studies cardiac arrhythmias have been reported to be induced by hypoglycaemia, with one report describing sudden death during a severe episode. Emerging evidence suggests that the association between hypoglycaemia and cardiovascular events and mortality is likely to be multifactorial. The association is probably partly caused by confounding, with hypoglycaemia occurring more frequently in people with comorbidities who are also more likely to die than those without. However, people with type 1 or type 2 diabetes also seem at risk of hypoglycaemia-induced cardiovascular effects. This risk should be recognised by clinicians when agreeing glycaemic goals with patients and choosing appropriate glucose-lowering therapies.
... It has been suggested that inhibition of cardiac CCN2 may be a mechanism by which the thiazolidenedione diabetes medicines (Ihm et al. 2010) and angiotensin pathways modulators (Sukumaran et al. 2017) prevent diabetic and other cardiomyopathy, and CCN2 was more recently reported to prevent dilated cardiomyopathy, albeit in a non-diabetic mouse model (Koshman et al. 2015). In contrast, our group could not find evidence of increased myocardial CCN2 protein in diabetes cases of dead in bed syndrome which is thought to be arrhythmia mediated (Tu et al. 2010). At a circulating level, CCN2 increases with overt heart failure presence in humans suggesting that it may have some utility as a blood marker of this condition (Yagi et al. 2012), although some publications have suggested that it may have less utility than other circulating profibrosis markers in some forms of cardiomyopathy (Rubis et al. 2017) and in subclinical diabetic cardiomyopathy (Brooks et al. 2008). ...
Across the years the CCNs have been increasingly implicated in the development of obesity, diabetes and its complications. Evidence for this is currently derived from their dysregulation in key metabolic pathological states in humans, animal and in vitro models, and also pre-clinical effects of their bioactivities. CCN2 is the best studied in this disease process and the other CCNs are yet to be better defined. Key steps where CCNs may play a pathogenic metabolic role include: (i) obesity and insulin resistance, where CCN2 inhibits fat cell differentiation in vitro and CCN3 may induce obesity and insulin resistance; (ii) elevated blood glucose levels to diabetes mellitus onset, where CCN2 may contribute to pancreatic beta cell and islet function; and (iii) in diabetes complications, such as nephropathy, retinopathy, liver disease (NAFLD/NASH), CVD and diabetes with heart failure. In contrast, CCN1, CCN2 and possibly CCN3, may have a reparative role in wound healing in diabetes, and CCN2 in islet cell development. In terms of CCN2 regulation by a diabetes metabolic environment and related mechanisms, the author’s laboratory and others have progressively shown that advanced glycation-end products, protein kinase C isoforms, saturated fatty acids, reactive oxygen species and haemodynamic factors upregulate CCN2 in relevant cell and animal systems. Recent data has suggested that CCN2, CCN3 and CCN6 may affect energy homeostasis including in regulating glycolysis and mitochondrial function. This paper will address the current data implicating CCNs in diabetes and its complications, focusing on recent aspects with translational clinical relevance and future directions.
... During hypoglycemia especially among old diabetic patients with coronary artery disease, myocardial ischemia may occur. In addition to decrease myocardial perfusion, hypoglycemia can create changes in the conduction system of the heart, and these changes including Prolongation of the QT interval [5], [6] and prolongation repolarization [7] Cardiac arrhythmias may consequence during hypoglycemia and may lead to the complication of sudden cardiac death [8]. The effect of insulin induce hypoglycemia on potassium, troponin T, C-Reactive Protein, MDA as well as the effect of insulin on heart rate, PR interval and QRS duration will be examinated. ...
... The initial report has since been followed by other observational studies, including more recently, detailed autopsies ( 95 ) and genetic analyses ( 96 ). Another recent series involving 2 large registries in the Pittsburgh area of the United States concluded that this mode of death was increased tenfold compared with nondiabetic individuals and associated with male sex, a high HbA1c and insulin dose, and low body mass index ( 97 ). ...
... DNA was isolated from peripheral blood and the PHOX2B coding regions were PCR amplified and sequenced as previously described. 7 A segment spanning the PHOX2B polyalanine repeat sequence was PCR amplified with a fluorescently labeled reverse primer and sized on an ABI3730xl DNA analyzer with PeakScanner software. ...
Objective:
To determine the contribution of sequence variations in PHOX2B to sudden unexpected death in epilepsy (SUDEP).
Methods:
Patients who died of SUDEP were identified in 2 major Australian cohorts, the Epilepsy Genetics research program in Melbourne and postmortem cases at the Department of Forensic Medicine in Sydney. Coding exons of the PHOX2B gene were sequenced and a fluorescent sizing assay was used to measure the PHOX2B polyalanine repeat sequence.
Results:
Sequencing of 68 cases of SUDEP identified a 15-nucleotide deletion in the PHOX2B polyalanine repeat region in one case, a 16-year-old adolescent with focal dyscognitive seizures from age 5 years. This deletion was verified using a fluorescent sizing assay. Two synonymous variants were identified in 4 cases, but no PHOX2B polyalanine repeat expansion alleles or point mutations were found.
Conclusions:
The absence of PHOX2B polyalanine repeat expansion alleles or point mutations in 68 Australian cases of SUDEP, with one deletion of uncertain significance, shows that PHOX2B mutations are not a common risk factor for SUDEP.
... Une seule équipe, celle de Tu E et al. a, à ce jour, abordé cette question sous l'angle anatomo-pathologique, biochimique et génétique, à partir de fragments autopsiques [21]. L'ADN génomique a été préparé à partir d'échantillons postmortem de myocarde de sujets décédés de « Dead-in-bed » syndrome, soit un total de 22 sujets. ...
The “Dead-in-bed” syndrome refers to a few subjects with type 1 diabetes (T1D), very young and without forerunners sign except for a high frequency of severe hypoglycemia. These unexplained deaths are up to 10 times more frequent than in the paired non-diabetic population, the sequence could be due to hyperinsulinemia, hypoglycemia, hypokalemia, parallel activation of the sympathetic system and genetic predisposition to trigger severe and fatal rhythm and/or conduction disturbances. However severe nocturnal hypoglycemia is common and rarely causes such dramatic consequences. Hypoglycaemia causes QT prolongation systematically but whose magnitude varies among individuals, probably because of genetic predisposition as in long QT syndrome family. Autonomic neuropathy seems harmless and may even be protective by reducing sympathetic response. Prevention could go through a screening of subjects at risk among youth with T1D. Glucose sensors and closed loop pumps are the first to offer solutions to many of them..
Aim: Irritable bowel syndrome (IBS) defined by chronic or recurrent abdominal pain or discomfort and changes in bowel habits, is the most common functional gastrointestinal disorder. Studies proved that polymorphisms in the genes were one of the key roles in the underlying IBS. This study aimed to investigate the genotypes and allele frequencies of the IBS-associated single nucleotide polymorphism (SNP) from the genes GNB3 (rs54443) and SCN5A (rs8015124) in unrelated, healthy Malays of Malaysia. Material and Methods: The genomic DNA of 404 subjects was set to nested, multiplex, and allele-specific PCR to determine the aforementioned SNPs. The PCR results were validated through the Sanger sequencing analysis. Results: Malays possessed a slightly higher frequency of wild (C) than mutant (T) alleles in the rs5443 with 56.3 vs 43.7%. However, the frequencies of the alleles were equivalent in the subset of Malay females (C-50%, T-50%). For rs1805124, only 18.6% of Malays carried the mutant allele G with less than 10 subjects being homozygous mutant GG carriers. Concurrently, the Hardy-Weinberg equilibrium of the SNPs in the study was not deviated. Conclusion: IBS is a common gastrointestinal problem that has significantly reduced the life quality of oneself and become an economic burden to societies. Though the mutant alleles were rather low, the IBS-associated polymorphisms, rs5443 and rs1805124 were noted to be commonly present in the Malays. Further research on the local IBS patients is recommended to affirm the association of rs5443 and rs1805124 polymorphisms and the syndrome.
Background
Type 1 diabetes is a significant, life-long condition which affects many people worldwide. One of the most feared causes of type 1 diabetes mortality, overnight mortality, often caused by the dead in bed syndrome, is largely underreported. A systematic literature search was undertaken to understand the frequency, risk factors, causes and impact that diabetes-related technologies have on overnight mortality, in this population.
Methods
MEDLINE (Ovid), Embase (Ovid) and Cochrane were searched to June 2021, using defined inclusion and exclusion criteria. Quality appraisal was undertaken.
Results
Overall, 26 records met the inclusion criteria. Large-scale cohort studies examined data up to 2013, and there were no studies published after 2018. The proportion of deaths attributable to the dead in bed syndrome was between 2 to 5% of deaths in children, adolescents, and young adults, with a slight decrease in proportion of dead in bed syndrome since 1991.
Conclusion
Overnight mortality is occurring for people with type 1 diabetes, reported as recently as in 2018. Living alone, alcohol and illicit substances consistently appear as risk factors, and the impact of technology on overnight mortality is not fully understood, with more recent data, from larger cohort studies being required.
Objective:
To investigate the association between diabetic ketoacidosis (DKA) and prolonged QTc interval and to assess for correlation between DKA severity and QTc prolongation.
Study design:
Retrospective observational study in a pediatric hospital. Patients admitted with DKA diagnosed by laboratory criteria and an ECG performed during a period of acidosis were identified using Looking Glass Clinical Analytics. Data including age, sex, pH, electrolytes, anion gap and ECG variables were collected. Patients were excluded if they had a prior diagnosis of prolonged QTc or were taking QTc prolonging medications. Severity of DKA was classified as mild (pH 7.24-7.3), moderate (pH 7-7.24) or severe (pH <7). ECGs were read by a pediatric electrophysiologist and QTc interval was manually calculated utilizing Bazett's formula.
Results:
Ninety-six patients were included (mean age 15.2 ± 4.2 years, pH 7.12 ± 0.12, bicarbonate 8.6 ± 3.7 mmol/L, potassium 5.3 ± 1.1 mEq/L). Mean QTc interval for all patients in DKA was 454 ± 32 msec. Mean QTc in the mild group was 441 ± 22 msec, moderate group 460 ± 36 msec and severe group 461 ± 34 msec. There was a significant difference in QTc interval across DKA severity groups (p=0.05). There was a significant association between higher anion gaps and greater QTc intervals (r=0.21, P = .04).
Conclusions:
33% of pediatric patients with DKA demonstrated QTc prolongation on ECG. Severity of DKA and worsening acidosis were associated with increased prolongation of the QTc. Further study is required to evaluate the clinical impact of these findings.
In health hypoglycaemia is rare and occurs only in circumstances like extreme sports. Hypoglycaemia in type 1 Diabetes (T1D) and advanced type 2 Diabetes (T2D) are the result of interplay between absolute or relative insulin access and defective glucose counterregulation. The basic mechanism is, failure of decreasing insulin and failure of the compensatory increasing counterregulatory hormones at the background of falling blood glucose. Any person with Diabetes on anti-diabetic medication who behaves oddly in any way whatsoever is hypoglycaemic until proven otherwise. Hypoglycaemia can be a terrifying experience for a patient with Diabetes. By definition, hypoglycaemic symptoms are subjective and vary from person to person and even episode to episode in same person. Fear of iatrogenic hypoglycaemia is a major barrier in achieving optimum glycaemic control and quality of life which limits the reduction of diabetic complications. Diabetes patients with comorbidities especially with chronic renal failure, hepatic dysfunction, major limb amputation, terminal illness, cognitive dysfunction etc. are more vulnerable to hypoglycaemia. In most cases, prompt glucose intake reverts hypoglycaemia. Exogenous insulin in T1D and insulin treated advanced T2D have no control by pancreatic regulation. Moreover, failure of increase of glucagon and attenuated secretion in epinephrine causes the defective glucose counterregulation. In this comprehensive review, I will try to touch all related topics for better understanding of hypoglycaemia.
Sudden cardiac death (SCD) occurs frequently in forensic practice and results in no visible pathological changes that can be detected in an autopsy. In recent years, the genetic background has been emphasized when examining SCD cases. The aim of this study is to establish a feasible system to detect SCD‐related genes for forensic DNA laboratories. Forty‐five reported SCD‐associated single nucleotide polymorphisms (SNPs) from sodium voltage‐gated channel alpha subunit 5 (SCN5A) were considered in our experiment. We established a SNaPshot assay for the typing of 45 SNPs using multiplex PCR and the minisequencing technique. Two multiplex PCRs were performed and optimized to cover 14 and 16 DNA fragments. The SCD victims came from the Chinese Han population residing in Shanxi and Chongqing provinces and were examined and compared with a non‐SCD group and with normal healthy individuals. A missense mutation at rs1805124 (H558R) was detected in the Chinese Han population in this study. A SNaPshot assay can be performed in any forensic DNA laboratory and would be capable of meeting the increasing demand for SCD detection. This method would also be beneficial for screening at‐risk in family members of SCD victims.
This article is protected by copyright. All rights reserved
Globally sudden cardiac death is one of the leading causes of death. Epidemiologists in many different countries have studied the changing incidence of sudden cardiac death, while cardiologists and geneticists have investigated relevant risk factors and potential preventative treatments, especially in patients with inherited diseases of cardiac muscle. For their part, pathologists are responsible for determining the precise cause of sudden death, but there is considerable variation in the way in which they approach this increasingly complex task. In this review, the methods that should be used in routine practice are described. The ideal autopsy involves careful scrutiny of the clinical records, a full macroscopic and microscopic examination, further laboratory tests and the formulation of a final diagnosis. The written report should conclude with a clear and concise clinico-pathological summary stating, in particular, whether family members should be referred for screening. If a uniform method of investigation is adopted, it will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions, and, importantly, permit future trends in the patterns of disease that cause sudden death to be monitored.
Introduction: Hypoglycemia occurs commonly in insulin requiring individuals with either Type 1 or Type 2 Diabetes.
Areas Covered: This article will review recent information on the pro-inflammatory and pro-atherothrombotic effects of hypoglycemia. Additionally, effects of hypoglycemia on arrhythmogenic potential and arterial endothelial dysfunction will be discussed. Effects of hypoglycemia on cardiovascular morbidity and mortality from large clinical studies in Type 1 and Type 2 DM will also be reviewed.
Expert Commentary: The relative and absolute risk of severe hypoglycemia leading to death and serious adverse events in both cardiovascular and other organ systems has been highlighted following the publication of recent large clinical trials focused on glucose control and outcomes. It would be helpful if future studies could develop broader end points to include minor and moderate hypoglycemia as well as more robust methods for capturing hypoglycemia contemporaneously with adverse events. In addition, perhaps consideration of including hypoglycemia as a primary outcome, may help identify the possible cause and effect of hypoglycemia on cardiovascular morbidity and mortality.
Mortality from hypoglycaemia is rare but has the potential to cause death from cerebral damage by depriving the brain of an essential fuel. Activating the sympathoadrenal system may also cause profound changes within the cardiovascular system. These are particularly important to those with pre-existing ischaemic heart disease. They may contribute to the well-described, albeit rare scenario of the 'dead-in-bed syndrome'. Recent data have suggested that aggressive intensive glycaemic control and associated hypoglycaemia might increase mortality in type 2 diabetes. There are a number of plausible mechanisms by which hypoglycaemia might provoke mortality, but the epidemiological evidence is contradictory and the pathological process unclear. Nevertheless, potential risks should be considered by clinicians both when agreeing glycaemic goals with patients and choosing glucose-lowering therapy.
The diagnosis and management of hypoglycemia is straight forward in almost all cases. The mainstay of treatment lies in glucose infusion. When death due to suspected hypoglycemia whether accidental, intentional, or homicidal intent occurs, it has complex ramifications. Such deaths are investigated to establish the cause. We report a case of an accidental overdose of insulin where communication failure was the central point. We review literature on hypoglycemia, management, prevention strategies, post-mortem findings, and medico-legal aspects.
We propose a study design with controlled hypoglycaemia induced by subcutaneous injection of insulin and matched control episodes to bridge the gap between clamp studies and studies of spontaneous hypoglycaemia. The observed prolongation of the heart rate corrected QT interval (QTc) during hypoglycaemia varies greatly between studies.
We studied ten adults with type 1 diabetes (age 41±15years) without cardiovascular disease or neuropathy. Single-blinded hypoglycaemia was induced by a subcutaneous insulin bolus followed by a control episode on two occasions separated by 4weeks. QT intervals were measured using the semi-automatic tangent approach, and QTc was derived by Bazett's (QTcB) and Fridericia's (QTcF) formulas.
QTcB increased from baseline to hypoglycaemia (403±20 vs. 433±39ms, p<0.001). On the euglycaemia day, QTcB also increased (398±20 vs. 410±27ms, p<0.01), but the increase was less than during hypoglycaemia (p<0.001). The same pattern was seen for QTcF. Plasma adrenaline levels increased significantly during hypoglycaemia compared to euglycaemia (p<0.01). Serum potassium levels decreased similarly after insulin injection during both hypoglycaemia and euglycaemia.
Hypoglycaemia as experienced after a subcutaneous injection of insulin may cause QTc prolongation in type 1 diabetes. However, the magnitude of prolongation is less than typically reported during glucose clamp studies, possible because of the study design with focus on minimizing unwanted study effects.
Background:
QT-wave abnormalities have been detected in type 1 diabetes mellitus (T1DM). Prolongation of the heart rate corrected QT interval (QTc) has been associated with cardiovascular mortality. We evaluated how often QT/QTc abnormalities are present in youth with T1DM and if they are associated with disease parameters.
Methods:
Sixty-two T1DM youngsters and equal age- and gender-matched controls were studied. Demographic, anthropometric, and laboratory data were determined. QT was measured on a 12-lead resting electrocardiogram. QTc was calculated using Bazett's formula.
Results:
T1DM patients had significantly longer QT/QTc than controls, but significance disappeared after adjustment for confounders. Abnormally prolonged QTc≥440 ms was observed six times more frequently in those with T1DM. QT was correlated with age, age at disease onset, but not with glycated hemoglobin or diabetes duration; QTc was only correlated with pubertal stage.
Conclusions:
T1DM youths have a sixfold increased risk for QT/QTc prolongation and should have regular follow-up for cardiac autonomic dysfunction.
Cardiovascular disease (CVD) remains the leading cause of death in people with diabetes, and the risk of CVD for adults with diabetes is at least two to four times the risk in adults without diabetes. Complications of diabetes, including not only CVD but also microvascular diseases such as retinopathy and nephropathy, are a major health and financial burden. Diabetes is a disease of glucose intolerance, and so much of the research on complications has focused on the role of hyperglycemia. Clinical trials have clearly demonstrated the role of hyperglycemia in microvascular complications of diabetes, but there appears to be less evidence for as strong of a relationship between hyperglycemia and CVD in people with diabetes. Hypoglycemia has become a more pressing health concern as intensive glycemic control has become the standard of care in diabetes. Clinical trials of intensive glucose lowering in both type 1 and type 2 diabetes populations has resulted in significantly increased hypoglycemia, with no decrease in CVD during the trial period, although several studies have shown a reduction in CVD with extended follow-up. There is evidence that hypoglycemia may adversely affect cardiovascular risk in patients with diabetes, and this is one potential explanation for the lack of CVD prevention in trials of intensive glycemic control. Hypoglycemia causes a cascade of physiologic effects and may induce oxidative stress and cardiac arrhythmias, contribute to sudden cardiac death, and cause ischemic cerebral damage, presenting several potential mechanisms through which acute and chronic episodes of hypoglycemia may increase CVD risk. In this review, we examine the risk factors and prevalence of hypoglycemia in diabetes, review the evidence for an association of both acute and chronic hypoglycemia with CVD in adults with diabetes, and discuss potential mechanisms through which hypoglycemia may adversely affect cardiovascular risk.
Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is characterized by an absence of any identifiable cause of death at post-mortem, suggesting an underlying arrhythmogenic predisposition. This study sought to identify SUDEP cases in a review of post-mortem records and to undertake genetic studies in key familial long QT syndrome (LQTS) genes. All autopsies performed from 1993-2009 at a forensic centre in Sydney, Australia were reviewed and SUDEP cases identified. DNA was extracted from post-mortem blood and the three most common LQTS genes, ie, KCNQ1, KCNH2 (HERG) and SCN5A, were amplified and analyzed. Sixty-eight SUDEP cases were identified (mean age of 40 ± 16 years). Genetic analysis revealed 6 (13%) non-synonymous (amino acid changing) variants in KCNH2 (n = 2) and SCN5A (n = 4), all previously reported in LQTS patients. Specifically, KCNH2 Arg176Trp and SCN5A Pro1090Leu were identified once in SUDEP cases and absent in control alleles. Both DNA variants have been previously identified in the pathogenesis of LQTS. The cause of SUDEP is currently unknown. Our results indicate that investigation of key ion channel genes should be pursued in the investigation of the relationship between epilepsy and sudden death.
In the triennium 2006-2008, 261 women in the UK died directly or indirectly related to pregnancy. The overall maternal mortality rate was 11.39 per 100,000 maternities. Direct deaths decreased from 6.24 per 100,000 maternities in 2003-2005 to 4.67 per 100,000 maternities in 2006–2008 (p = 0.02). This decline is predominantly due to the reduction in deaths from thromboembolism and, to a lesser extent, haemorrhage. For the first time there has been a reduction in the inequalities gap, with a significant decrease in maternal mortality rates among those living in the most deprived areas and those in the lowest socio-economic group. Despite a decline in the overall UK maternal mortality rate, there has been an increase in deaths related to genital tract sepsis, particularly from community acquired Group A streptococcal disease. The mortality rate related to sepsis increased from 0.85 deaths per 100,000 maternities in 2003-2005 to 1.13 deaths in 2006-2008, and sepsis is now the most common cause of Direct maternal death. Cardiac disease is the most common cause of Indirect death; the Indirect maternal mortality rate has not changed significantly since 2003-2005. This Confidential Enquiry identified substandard care in 70% of Direct deaths and 55% of Indirect deaths. Many of the identified avoidable factors remain the same as those identified in previous Enquiries. Recommendations for improving care have been developed and are highlighted in this report. Implementing the Top ten recommendations should be prioritised in order to ensure the overall UK maternal mortality rate continues to decline.
The essential tasks of forensic pathology involve investigation of the cause and process of death, especially in traumatic and unexpected sudden deaths, largely including unwitnessed deaths. Thus, agonal and postmortem interference is inevitable and unpredictable in all forensic procedures; this is not particular to forensic biochemistry, but also occurs in morphology and toxicology. Therefore, findings should be assessed based on the postmortem data established through serial investigations of autopsy materials using easily accessible standardized procedures. With respect to this, biochemical procedures have advantages of standardization, quality assurance, quantitative analyses, statistic assessment and availability of multiple markers, despite several problems involved in the selection and collection of materials and applicability of analytical procedures. The main purpose of using postmortem biochemistry as well as molecular biology is to investigate the systemic pathophysiological changes involved in the death process that cannot usually be detected by morphological methods; these may be called 'pathophysiological vital reactions'. These procedures can provide useful support for pathological evidence by 'visualization' of functional alterations, and are also essential for the pathognomonic assessment of both the cause and process of death as part of routine laboratory investigations involved in 'full autopsy' in the context of social risk management.
Continuous glucose monitoring is technology revolution in diabetology similar to holter ECG monitoring in cardiology. With goal of the diabetes treatment to achieve almost normal glucose concentration in blood, continuous glucose monitoring can help in hypoglycemia risk reduction. Continuous glucose monitoring offers actual value of glycemia longitudinal whole day, with possibility of analyzing records and signalization when programmed thresholds are exceeded. It offers immediate patients reaction by modification of insulin treatment, food intake or physical activity, and also retrospective analysis of records. Subsequently it is possible to improve long-term treatment. Special contribution of continuous glucose monitoring is in recognizing undetectable hypoglycemias, especially during sleep.
Twenty four men with insulin dependent diabetes and different degrees of autonomic neuropathy were studied to establish the response of the QT interval to various heart rates. Nine men with autonomic neuropathy had a longer QT interval than 13 healthy individuals and 15 patients who had diabetes without, or with only mild, autonomic neuropathy. Those with autonomic neuropathy also had a proportionally greater lengthening of the QT interval for a given increase in RR interval. The results of this study suggest a basis for the finding that sudden death is more common in patients with diabetic autonomic neuropathy.
SCN5A encodes the alpha-subunit of the ion channel that carries Na current in human heart. From a human cardiac cDNA library we recloned SCN5A. The new clone hH1b differed from existing clones hH1 in four and from hH1a in three positions. The common polymorphism H558R was uniquely present in hH1b. Voltage clamp study showed minor but potentially important kinetic differences between hH1b and the other clones. More dramatically, when the LQT3 mutation M1766L was introduced into the different clones, Na current was markedly reduced in the hH1 and hH1a backgrounds, whereas in hH1b the Na current was not reduced. Immunocytochemistry experiments showed a trafficking defect for M1766L Na channels in hH1 and hH1a but not in hH1b. The double-mutation M1766L/H558R in the hH1a background restored normal trafficking and current including persistent late current, suggesting the disease phenotype was the result of a "double hit" that included the common polymorphism, H558R. These results show that the choice of background clone must be carefully considered in mutagenesis studies. This also represents an example of intragenic complementation, the first for such a large protein.
Our understanding of the genetic basis of disease has expanded with the identification of rare DNA sequence variations ("mutations") that evoke inherited syndromes such as cystic fibrosis, congenital epilepsy, and cardiac arrhythmias. Common sequence variants ("polymorphisms") have also been implicated as risk factors in multiple diseases. Mutations in SCN5A, the cardiac Na(+) channel gene, that cause a reduction in Na(+) current may evoke severe, life-threatening disturbances in cardiac rhythm (i.e., Brugada syndrome), isolated cardiac conduction disease, or combinations of these disorders. Conduction disease is manifest clinically as heart rate slowing (bradycardia), syncope, or "lightheadedness". Recent electrophysiologic studies reveal that mutations in particular families exhibiting cardiac conduction disease cause marked effects on several competing voltage-dependent gating processes, but nonetheless cause a mild "net" reduction in Na(+) current. Here we show that a common SCN5A polymorphism (H558R) in the Na(+) channel I-II interdomain cytoplasmic linker, present in 20% of the population, can mitigate the in vitro effects of a nearby mutation (T512I) on Na(+) channel function. The mutation and the polymorphism were both found in the same allele of a child with isolated conduction disease, suggesting a direct functional association between a polymorphism and a mutation in the same gene.
Experimental hypoglycaemia leads to abnormal cardiac repolarization manifest by a lengthened QT interval and caused by adrenergic stimulation. However it is less clear whether spontaneous clinical episodes lead to similar changes. We have therefore measured cardiac ventricular repolarization and counterregulatory responses in patients with Type 1 diabetes during hypoglycaemic and euglycaemic nights.
We studied 22 patients with Type 1 diabetes (mean age 40.4+/-17.2 years, duration of diabetes 17.2+/-9.3 years, HbA1c 8.2+/-1.2% overnight). Measurements were taken hourly of blood glucose, plasma potassium, catecholamines and high resolution electrocardiograms.
Hypoglycaemia (blood glucose level <2.5 mmol/l) occurred on 7 of the 22 nights. During overnight hypoglycaemia, QTc interval increased by 27 ms (+/-15) above baseline, compared with 9 ms (+/-19) during nights with no nocturnal hypoglycaemia (p=0.034, 95%CI 2, 35). Adrenaline increased by 0.33 nmol/l (+/-0.21) above baseline during hypoglycaemia, compared with -0.05 nmol/l (+/-0.08) during euglycaemia (p=0.001, 95%CI 0.19, 0.56 nmol/l). There was no significant difference between potassium, and noradrenaline concentrations between the two groups.
QTc interval lengthens significantly during spontaneous nocturnal hypoglycaemia. Increases are generally less than those observed during experimental hypoglycaemia and could reflect attenuated sympathoadrenal responses during clinical episodes. The clinical relevance of these changes is uncertain but is consistent with the hypothesis that clinical hypoglycaemia can cause abnormal cardiac repolarization and an attendant risk of cardiac arrhythmia.
The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030.
Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations' population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries.
The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people >65 years of age.
These findings indicate that the "diabetes epidemic" will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.
We examined long-term total and cause-specific mortality in a nationwide, population-based Norwegian cohort of patients with childhood-onset type 1 diabetes.
All Norwegian type 1 diabetic patients who were diagnosed between 1973 and 1982 and were under 15 years of age at diagnosis were included (n=1,906). Mortality was recorded from diabetes onset until 31 December 2002 and represented 46,147 person-years. The greatest age attained among deceased subjects was 40 years and the maximum diabetes duration was 30 years. Cause of death was ascertained by reviews of death certificates, autopsy protocols and medical records. The standardised mortality ratio (SMR) was based on national background statistics.
During follow-up 103 individuals died. The mortality rate was 2.2/1000 person-years. The overall SMR was 4.0 (95% CI 3.2-4.8) and was similar for males and females. For ischaemic heart disease the SMR was 20.2 (7.3-39.8) for men and 20.6 (1.8-54.1) for women. Acute metabolic complications of diabetes were the most common cause of death under 30 years of age (32%). Cardiovascular disease was responsible for the largest proportion of deaths from the age of 30 years onwards (30%). Violent death accounted for 28% of the deaths in the total cohort (35% among men and 11% among women).
Childhood-onset type 1 diabetes still carries an increased mortality risk when compared with the general population, particularly for cardiovascular disease. To reduce these deaths, attention should be directed to the prevention of acute metabolic complications, the identification of psychiatric vulnerability and the early detection and treatment of cardiovascular disease and associated risk factors.
Systemic sclerosis (scleroderma) is a life-threatening autoimmune disease that is characterized by the presence of specific autoantibodies and fibrosis of the skin and major internal organs.
We genotyped a polymorphism (G-945C) in the promoter of the connective-tissue growth factor (CTGF) gene in 1000 subjects in two groups: group 1, consisting of 200 patients with systemic sclerosis and 188 control subjects; and group 2, consisting of 300 patients with systemic sclerosis and 312 control subjects. The combined groups represented an estimated 10% of patients with systemic sclerosis in the United Kingdom. We tested the effect of the polymorphism on the transcription of CTGF.
The GG genotype was significantly more common in patients with systemic sclerosis than in control subjects in both groups, with an odds ratio for the combined group of 2.2 (95% confidence interval [CI], 1.5 to 3.2; P<0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of anti-topoisomerase I antibodies (odds ratio, 3.3; 95% CI, 2.0 to 5.6; P<0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% CI, 1.9 to 5.0; P<0.001). We observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo.
The G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis.
The aims of this study were to provide a contemporary picture of mortality and causes of death in Europe following a diagnosis of type 1 diabetes made before the 15th birthday, and to examine excess mortality by country for possible links to incidence level or national prosperity.
Thirteen population-based EURODIAB registers in 12 countries followed-up 28,887 children diagnosed since 1989, either by record linkage to population registers or through contact with doctors providing care.
There were 141 deaths in the cohort during 219,061 person-years of follow-up compared with 69.1 deaths expected from national mortality rates, a standardised mortality ratio (SMR) of 2.0 (95% CI 1.7-2.4). The SMR varied from 0 to 4.7 between countries, but showed little relationship with the country's incidence rate or gross domestic product (US$ per capita). The SMR did not change significantly with attained age, calendar period or time since diagnosis. The female SMR (2.7; 95% CI 2.0-3.5) was greater than the male SMR (1.8; 95% CI 1.4-2.2), although absolute numbers of excess deaths were similar in the two sexes. One-third of deaths were classified as directly attributable to diabetes (many with mention of ketoacidosis) and half were unrelated to diabetes. There was a non-significant excess of accidental/violent deaths (48 observed vs 40.7 expected; SMR 1.2; 95% CI 0.9-1.6) but little excess in suicides (11 observed, 10.2 expected; SMR 1.1; 95% CI 0.5-1.9).
Before the onset of late complications, significant excess mortality existed following the diagnosis of type 1 diabetes in childhood, even in recent years. Variation between countries in this excess could not be explained.
One third of autopsy-negative sudden unexplained deaths (SUDs) can be attributed to a cardiac channelopathy. Typically, paraffin-embedded tissue (PET) is the only source of DNA available for genetic analyses. We examined different DNA extraction procedures, involving 2 deparaffinization methods, 2 digestion methods, 4 laboratory-based purification methods, and 5 commercial kits. Mutational analysis involving 25 RYR2 exons was performed on PET DNA from 35 SUD cases to evaluate the feasibility of using PET DNA for genetic testing. With the best PET-DNA extraction method, an average of only two thirds of the region of interest could be evaluated. Although we initially identified 5 missense mutations in 5 of 35 SUD cases, repeated analysis failed to confirm these mutations. DNA from PET should be considered error prone and unreliable in comprehensive surveillance of SUD-associated genes. Given these shortcomings, the standard autopsy for SUD should include archiving EDTA-preserved blood or frozen tissue to facilitate postmortem genetic testing.
Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria.
In a group of diabetic (n=9) and control (n=6) baboons after a 5-year duration of diabetes, renal tissue CTGF and TIMP-1 were detected by immunohistochemistry and compared with glomerular basement membrane (GBM) thickness and mesangial volume measurements from electron photomicrographs of renal biopsies. Urinary albumin levels were measured at 5 and 10 years of diabetes.
GBM thickness, CTGF protein, and TIMP-1 protein were increased after 5 years of diabetes (each P<.05). Tubular fibronectin scores correlated with tubular CTGF scores (r=0.72, P=.002). In diabetic animals, GBM thickness correlated with tubular and total CTGF levels (P=.002 and P=.04, respectively), whereas mesangial cell and total matrix volume correlated with glomerular TIMP-1 (P=.02 and P=.01, respectively). Tubular CTGF scores (P=.008) and GBM thickness (P=.03) at 5 years in diabetes each predicted the degree of albuminuria at 10 years.
These results suggest that early increases in renal CTGF protein contribute to incipient diabetic nephropathy and that renal CTGF may have utility as an early marker for progression to dysfunction in the diabetic kidney.
To determine the causes of death in Australians with type 1 diabetes mellitus who died aged 40 years or younger.
Retrospective review of autopsy reports at the Department of Forensic Medicine, Sydney, New South Wales, 1 January 1994-31 December 2006.
Causes of mortality in people with type 1 diabetes aged <40 years.
Of the 26 682 autopsy reports, 1914 were for individuals with diabetes (type 1, 400; type 2, 1514). Cardiovascular disease accounted for 51% of deaths (169/333) in people with type 1 diabetes aged >40 years, versus 13% among those aged <or= 40 years (9/67; P=0.001). Acute complications of diabetes (27%; 18/67), unnatural deaths (28%; 19/67), and sudden unexpected deaths (22%; 15/67) were the predominant causes of death in young individuals with diabetes. Sudden unexpected death was more common in those with type 1 diabetes compared with a sex-matched control population in the same age range (22% v 5%; Xi(2) P<0.001). Of the sudden unexpected deaths, 10 people were found dead in an undisturbed bed with no cause of death found at autopsy ("dead-in-bed" syndrome; mean age [SD], 30.2 [9.4] years; males : females=4 :1).
In deceased young people with type 1 diabetes examined by the Coroner, acute diabetic complications, unnatural causes, and sudden unexpected deaths were the predominant causes of death. The relatively high frequency of sudden unexpected deaths, such as dead-in-bed syndrome, requires further investigation.
Differential survival associated with insulin-dependent diabetes mellitus (IDDM) was evaluated in a cross country study using four population-based IDDM cohorts from Japan (n = 1,374), Israel (n = 610), Allegheny County, Pennsylvania (n = 995), and Finland (n = 5,144). For the purpose of this cross-country comparison, the Allegheny County' cohort was taken to be representative of the United States. The mortality status as of January 1, 1990, was determined for all individuals who were diagnosed with diabetes at the age of less than 18 years between 1965 and 1979 and who were taking insulin at the time of hospital discharge. The results showed that the mortality experience for IDDM individuals in Japan and the United States was much worse than that in Finland and israel. The age-adjusted mortality rates (per 100,000 person-years) for the four cohorts were 760 (Japan), 158 (Israel), 408 (Allegheny County), and 250 (Finland). By using the mortality data from Allegheny County, Pennsylvania, to extrapolate to the US IDDM mortality experience, the authors estimated 2,396 deaths among individuals with IDDM in the United States. It was calculated that 1,261 (53%) of these deaths would not have occurred in the United States given Finland's mortality rates. It is critical to determine why individuals with IDDM in the United States have a poorer outcome.
Differential survival associated with insulin-dependent diabetes mellitus (IDDM) was evaluated in a crosscountry study using four population-based IDDM cohorts from Japan (n=1,374), Israel (n= 610), Allegheny County, Pennsylvania (n=995), and Finland (n=5,144).For the purpose of this cross-country comparison, the Allegheny County cohort was taken to be representative of the United States. The mortality status as of January 1, 1990, was determined for all individuals who were diagnosed with diabetes at the age of less than 18 years between 1965 and 1979 and who were taking insulin at the time of hospital discharge. The results showed that the mortality experience for IDDM individuals in Japan and the United States was much worse than that in Finland and Israel. The age-adjusted mortality rates (per 100,000 person-years) for the four cohorts were 760 (Japan), 158 (Israel), 408 (Allegheny County), and 250 (Finland). By using the mortality data from Allegheny County, Pennsylvania, to extrapolate to the US IDDM mortality experience, the authors estimated 2,396 deaths among individuals with IDDM in the United States. It was calculated that 1,261 (53%) of these deaths would not have occurred in the United States given Finland's mortality rates. It is critical to determine why individuals with IDDM in the United States have a poorer outcome. Am J Epidemiol 1995;142:612–18.
Sudden cardiac death is an unpredictable and devastating event, particularly in the young. A significant proportion of sudden deaths in the young are unexplained-no cause is identified either during life or at post-mortem. This is seen in a subgroup of young patients with type 1 diabetes who have dead in bed syndrome, where these victims are in good health, retire to bed, only to be found dead the following morning in a bed which is undisturbed, suggesting no terminal struggle or seizure. The underlying cause of dead in bed syndrome remains unknown, but is likely to be due to a terminal malignant arrhythmia. A plausible hypothesis is that it may be secondary to QT interval prolongation (followed by a degenerate ventricular tachycardia), caused by a number of factors including acute hypoglycaemia, on a background of cardiac autonomic neuropathy, and possible genetic influences. It is envisaged that understanding the causes and triggers of dead in bed syndrome will allow appropriate therapeutic interventions to be initiated in high-risk patients with type 1 diabetes, with the ultimate goal to prevent sudden death.
Short-term mortality risk in young diabetic people is an indicator of quality of care. We assessed this in the Italian incident population-based registry of Turin. The study base included 1210 incident cases (n=677 aged 0-14 years and n=533 aged 15-29 years) with diabetes, onset period 1974-2000 in the Province of Turin, Italy. The relevant timescale for analysis was the time since the onset of diabetes to death, or till 31 December 2003. Standardized mortality ratio (SMR) for all-cause mortality was computed using the Italian population as a standard, by 5 years, age group, sex, and calendar period. Mean attained age of the incident cohort was 29.7 years (range 5.2-49.7 years). During a mean follow-up period of 15.8 years (range 2.0-29.9 years), there were 19 deaths in 15,967. Nine person-years of observation (n=9.5 expected deaths), giving an all-cause mortality rate of 1.19/1000 person-years (95% CI 0.76-1.87) and an SMR of 1.96 (1.25-3.08). In no cases did death occur at the onset of diabetes or in childhood. Out of 19 deaths, 9 were diabetes related (n=6 coma and n=3 end-stage renal disease). In Cox regression analysis, the hazard ratio (HR) was higher in adult-onset than in childhood-onset diabetes (HR=3.90, 95% CI 1.14-13.39), independently of calendar period and gender. (1) Children and young adults with type 1 diabetes experienced a two-fold higher short-term mortality risk than Italian people of similar age and sex and (2) the risk was higher in adult-onset than in childhood-onset diabetes. The quality of diabetes care should be improved to prevent early deaths.
The suggestion of an increase in the number of sudden deaths of young people with Type 1 diabetes in the UK has been investigated. It was suggested that such deaths were due to hypoglycaemia and related to the increasing use of human insulin. In total we were notified of 50 deaths of people with Type 1 diabetes under age 50 years in the UK in 1989 which our informants (relatives, physicians, and pathologists) considered sudden and unexpected. An autopsy had been done in all cases and we supplemented this with detailed clinical information from relatives and case records. Of the 50 cases we excluded five with a definite cause of death, 11 suicides or self-poisonings, six cases of ketoacidosis, and four in which there was insufficient information about the circumstances of death to drawn any conclusions. Of the other 24 cases, two patients had been found with irreversible hypoglycaemic brain damage and died after a period of artificial ventilation. The most puzzling group were 22, aged 12-43 years, most of whom had gone to bed in apparently good health and been found dead in the morning. Nineteen of the 22 were sleeping alone at the time of death and 20 were found lying in an undisturbed bed. Most had uncomplicated diabetes and in none were anatomical lesions found at autopsy. There are major difficulties in diagnosing hypoglycaemia post-mortem, but the timing of death and other circumstantial evidence suggests that hypoglycaemia or a hypoglycaemia-associated event was responsible. All patients were taking human insulin at the time of death but most had been changed from animal insulin between 6 months and 2 years earlier and there was nothing to implicate the species of insulin as a factor in these deaths.
The mortality status of all individuals in Norway with the onset of Type 1 (insulin-dependent) diabetes mellitus from 1973 through 1982 and age at onset below 15 years was determined as of 1 July 1988. Of the 1908 cases included in the follow-up, 20 had died (15 males and 5 females) and 10 had emigrated. A two-fold increased risk for early mortality was exhibited among this cohort. Life-table analyses did not find sex or age at onset of Type 1 diabetes to be statistically significant predictors of survival when controlling for diabetes duration. A review of death certificates revealed that accidents and suicides accounted for 40% of the deaths in the total cohort and that this cause of death occurred only among male subjects. Acute diabetes related complications were the underlying causes of death for 35% of the subjects. Diabetic renal disease and death by cardiovascular disease were not documented in this young cohort with a maximum age of 30 years and maximum diabetes duration of 15.5 years. This is the first mortality report of a population-based registered cohort of Type 1 diabetic patients for Norway. While still being at increased risk for premature death, this cohort appears to be at decreased risk of early death when compared to a cohort of young diabetic patients from Oslo, Norway diagnosed in 1925-1955, suggesting improvements in the survival of individuals with Type 1 diabetes in Norway.
Patients with Type 1 diabetes and autonomic neuropathy have an increased risk of sudden death for which the mechanism remains obscure. Prolongation of the QT interval on the electrocardiogram may occur with sympathetic dysfunction and is also associated with ventricular arrhythmia and sudden death. We have therefore measured the QT interval in patients with Type 1 diabetes with normal, borderline, and definitely abnormal autonomic function tests and in non-diabetic control subjects. The maximum QT interval was measured on 12-lead electrocardiograms recorded at rest and then plotted against the RR interval. The QT interval was above the upper 95% limit for the non-diabetic control subjects in 5 diabetic patients with abnormal autonomic function tests (33%), but in no cases with normal or borderline tests. Multivariate analysis confirmed that autonomic score contributed significantly (p less than 0.025) to the variance in QT interval. The raw Valsalva ratio alone also contributed significantly to the variance in QT interval (p = 0.025). Heart rate variability, heart rate response to standing, age, sex, and the presence of symptoms of autonomic neuropathy did not contribute significantly.
Mortality and the causes of death have been studied in a population-based cohort of 4919 childhood onset IDDM cases. Enrolment began in 1977 and at the time of study there had been a maximum duration of disease of 13.5 years, with a total of 33,721 person years at risk. Survival status was ascertained by linkage to the Swedish Cause-of-Death register. Death certificates, autopsy protocols, and hospital records were scrutinized for classification of causes of deaths. Twenty males and 13 females with IDDM died before the age of 28.5 years. This corresponds to a Standardized Mortality Rate for age of 262% (95% confidence limits, 172-400) for the boys and 384% (95% confidence limits, 232-635) for girls. Seven patients died of ketoacidosis, four at onset of diabetes. Nine cases were found 'dead in bed', having been seen apparently healthy 1-2 days before death. One of these cases had signs of cerebral haemorrhages at autopsy and another one had signs of bite marks in the mouth, but otherwise all autopsies were normal and no evidence of alcohol or other intoxication was found. In a well-educated population with good access to inexpensive diabetes care, there is still a two- to threefold excess mortality among young onset insulin-dependent diabetic individuals including a high frequency of unexplained deaths in bed.
Glycogen storage disease (GSD) type 1a is caused by the deficiency of D-glucose-6-phosphatase (G6Pase), the key enzyme in
glucose homeostasis. Despite both a high incidence and morbidity, the molecular mechanisms underlying this deficiency have
eluded characterization. In the present study, the molecular and biochemical characterization of the human G6Pase complementary
DNA, its gene, and the expressed protein, which is indistinguishable from human microsomal G6Pase, are reported. Several mutations
in the G6Pase gene of affected individuals that completely inactivate the enzyme have been identified. These results establish
the molecular basis of this disease and open the way for future gene therapy.
Case reports from the United Kingdom (UK) in 1989 have suggested that the introduction of human insulin in 1985 was associated with an increased risk of sudden death in insulin-treated diabetic patients. If human insulin increases the risk of sudden death, the number of these should have increased during the period where human insulin was introduced. We therefore identified all cases of sudden death in Denmark in younger insulin-treated diabetic patients, age at death below 50 years. During this period the consumption of human insulin went from 0.2% to 70% of the total consumption in Denmark. The total number of cases fulfilling the inclusion criteria was 226, and the annual number of sudden deaths did not change during the study period (p = 0.14). The number of deaths due to hypoglycaemia and cases with unexplained cause of death also remained constant (test for trend: p = 0.44). Chronic alcohol abuse or acute alcohol intoxication was found in 50% of the 135 patients dying from hypoglycaemia, ketoacidosis or unknown cause of death (including found dead in bed), while this was the case in only 16% of the remaining 91 cases dying from other natural causes. We conclude that introduction of human insulin in Denmark was not followed by an increase in sudden deaths among younger insulin-treated diabetic patients.
The incidence of unexplained deaths ('dead in bed syndrome') in Norwegian diabetic patients under the age of 40 was investigated during the period 1981-1990. During this 10-year period there were 240 deaths of all causes in the age group 0-39 years. Sixteen of these cases fulfilled the following criteria of the 'dead in bed syndrome': (1) patient found dead in an undisturbed bed; (2) patient observed to be in good health condition the day before; (3) no clinical evidence of late complications (except background retinopathy in two cases). Of the 16 cases ascertained, 10 were males and 6 females. The age range was 7-35 years, and the duration of diabetes varied between a few months and 26 years. Autopsy, performed in 13 cases, did not reveal any cause of death. Nine patients had been using insulin regimens with multiple daily doses. Twelve patients were reported as having had frequent episodes of hypoglycaemia, with nocturnal episodes in 10 cases. There was apparently an increasing incidence of unexplained deaths during the study period, with 12 of 16 cases occurring in the years 1988 to 1990.
The voltage-gated cardiac sodium channel, SCN5A, is responsible for the initial upstroke of the action potential. Mutations in the human SCN5A gene cause susceptibility to cardiac arrhythmias and sudden death in the long QT syndrome (LQT). In this report we characterize the genomic structure of SCN5A. SCN5A consists of 28 exons spanning approximately 80 kb on chromosome 3p21. We describe the sequences of all intron/exon boundaries and a dinucleotide repeat polymorphism in intron 16. Oligonucleotide primers based on exon-flanking sequences amplify all SCN5A exons by PCR. This work establishes the complete genomic organization of SCN5A and will enable high-resolution analyses of this locus for mutations associated with LQT and other phenotypes for which SCN5A may be a candidate gene.
There is circumstantial evidence implicating hypoglycaemia in the sudden overnight death of young patients with insulin-dependent (Type 1) diabetes mellitus (IDDM), the mechanism of which is unknown. We have investigated the effects of hypoglycaemia on the electrocardiogram in 15 patients with diabetes (8 with IDDM and 7 with NIDDM) using a high resolution computer-based system. Patients were randomized to either 2 h of euglycaemia or hypoglycaemia (at around 3 mmol l(-1)) during the afternoon, using hyperinsulinaemic glucose clamps, the two visits separated by a period of at least 4 weeks. Corrected QT interval (QTc), plasma potassium, and adrenaline were measured at baseline and at 0, 60, and 120 min. The degree of QTc lengthening (from baseline) during clamped hypoglycaemia was greater compared to the euglycaemic control period in patients with IDDM (median[range] at 60 min, 156[8 to 258] vs 6[-3 to 28] ms, p <0.02) and NIDDM (120 min, 128[16 to 166] vs 4[-3 to 169] ms, p <0.05). The fall in plasma potassium was greater during clamped hypoglycaemia compared to euglycaemia in those with NIDDM (p <0.03) but not in those with IDDM (p> 0.06). The rise in plasma adrenaline was greater during clamped hypoglycaemia in both groups (IDDM p <0.02, NIDDM p <0.02) and there was a strong relationship between the rise in adrenaline and increase in QTc (r = 0.73, p <0.0001). These data demonstrate alteration of ventricular repolarization with lengthening of the QT interval during hypoglycaemia and suggest a possible mechanism by which hypoglycaemia could cause ventricular arrhythmias.
Long QT syndrome (LQT) is a cardiac disorder causing syncope and sudden death from arrhythmias. LQT is characterized by prolongation of the QT interval on electrocardiogram, an indicationof abnormal cardiac repolarization. Mutations in KVLQT1, HERG, SCN5A, and KCNE1, genes encoding cardiac ion channels, cause LQT. Here, we define thecomplete genomic structure of three LQT genesand use this information to identify disease-associated mutations. KVLQT1 is composed of 16 exonsand encompasses approximately 400 kb. HERG consists of 16 exons and spans 55 kb. Three exons make up KCNE1. Each intron of these genes contains the invariant GT and AG at the donor and acceptor splice sites, respectively. Intron sequences were used to design primer pairs for the amplification of all exons. Familial and sporadic cases affected bymutations in KVLQT1, HERG, and KCNE1 can nowbe genetically screened to identify individuals at risk of developing this disorder. This work has clinical implications for presymptomatic diagnosis and therapy.
Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF- beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF- beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF- beta induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF- beta induced CTGF expression. Furthermore, we found that both TGF- beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF- beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.
Idiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970. A genetic basis of CCHS has been proposed because of the reports of four families with two affected children, because of mother-child transmission, and because of a recent report of a polyalanine expansion mutation in PHOX2b in a subset of CCHS subjects. We, therefore, studied genes pertinent to early embryologic development of the ANS including mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), engrailed-1 (EN1), TLX3, endothelin converting enzyme-1 (ECE1), endothelin-1 (EDN1), PHOX2a, and (C) 2003 Wiley-Liss, Inc.
We examined the prevalence of defects in arrhythmia-related candidate genes among patients with unexplained sudden cardiac death (SCD).
Patients with unexplained sudden death may constitute up to 5% of overall SCD cases. For such patients, systematic postmortem genetic analysis of archived tissue, using a candidate gene approach, may identify etiologies of SCD.
We performed analysis of KCNQ1 (KVLQT1), KCNH2 (HERG), SCN5A, KCNE1, and KCNE2 defects in a subgroup of 12 adult subjects with unexplained sudden death, derived from a 13-year, 270-patient autopsy series of SCD. Archived, paraffin-embedded myocardial tissue blocks obtained at the original postmortem examination were the source of deoxyribonucleic acid for genetic analysis.
Two patients were found to have the same HERG defect, a missense mutation in exon 7 (nucleotide change G1681A, coding effect A561T). The mutation was heterozygous in Patient 1, but Patient 2 appeared to be homozygous for the defect. Patch-clamp recordings showed that the A561T mutant channel expressed in human embryonic kidney cells failed to generate HERG current. Western blot analysis implicated a trafficking defect in the protein, resulting in loss of post-translational processing from the immature to the mature form of HERG. No mutations were detected among the remaining four candidate genes.
In this autopsy series, only 2 of 12 patients with unexplained sudden death were observed to have a defect in HERG among five candidate genes tested. It is likely that elucidation of SCD mechanisms in such patients will await the discovery of multiple, novel arrhythmia-causing gene defects.
Mutations in the cardiac sodium channel gene (SCN5A) may lead to a broad spectrum of familial arrhythmias, including long QT syndrome (LQTS), idiopathic ventricular fibrillation (IVF), and isolated cardiac conduction diseases. Recent studies have shown that polymorphisms in the SCN5A gene also play an important role in the manifestation of disorders involving cardiac excitability. In this study, we investigated the polymorphisms of the SCN5A gene in Han Chinese and its relation to Brugada syndrome (BS).
Genomic DNA was isolated from 120 unrelated healthy volunteers and 48 unrelated Brugada syndrome patients by means of standard procedures. All exons including the putative splicing sites of the SCN5A gene were amplified by PCR and sequenced directly or after subcloning using an ABI Prism 377 DNA sequencer.
A total of 5 single nucleotide polymorphisms (SNPs) were identified in the Han Chinese population, including 3 novel ones: G87A(A29A), 4245 + 82A > G, and G6174A. The allele frequencies of each SNP in the Han Chinese population were as follows: G87A (A29A) 27.5%, A1673G (H558R) 10.4%, 4245 + 82A > G 32.8%, C5457T (D1819D) 41.3%, and G6174A 44.9%. S1102Y and 10 other SNPs identified in other ethnic populations were not detected in this study. There was no significant difference in the allele frequency of A1673G (H558R) between different ethnic populations (all P > 0.5). On the other hand, the allele frequency of C5457T (D1819D) among Han Chinese was similar to its frequency among Japanese (P > 0.5), but higher than that among Americans (P < 0.005). The allele G1673 (R558) was over-represented in BS patients compared to controls (P < 0.005), but there was no significant difference in genotype frequencies at this locus. There were also no differences in either the allele or genotype frequencies of the 4 other identified SNPs when comparing BS patients with healthy controls.
The distribution of SCN5A SNPs may vary between different ethnicities. The polymorphism of A1673G might be associated with BS and may contribute to a susceptibility to BS in Han Chinese.
The temporal and spatial expression of transforming growth factor (TGF)-beta(1) and connective tissue growth factor (CTGF) was assessed in the left ventricle of a myocardial infarction (MI) model of injury with and without angiotensin-converting enzyme (ACE) inhibition. Coronary artery ligated rats were killed 1, 3, 7, 28, and 180 days after MI. TGF-beta(1), CTGF, and procollagen alpha1(I) mRNA were localized by in situ hybridization, and TGF-beta(1) and CTGF protein levels by immunohistochemistry. Collagen protein was measured using picrosirius red staining. In a separate group, rats were treated for 6 months with an ACE inhibitor. There were temporal and regional differences in the expression of TGF-beta(1), CTGF, and collagen after MI. Procollagen alpha1(I) mRNA expression increased in the border zone and scar peaking 1 week after MI, whereas collagen protein increased in all areas of the heart over the 180 days. Expression of TGF-beta(1) mRNA and protein showed major increases in the border zone and scar peaking 1 week after MI. The major increases in CTGF mRNA and protein occurred in the viable myocardium at 180 days after MI. Long-term ACE inhibition reduced left ventricular mass and decreased fibrosis in the viable myocardium, but had no effect on cardiac TGF-beta(1) or CTGF. TGF-beta(1) is involved in the initial, acute phase of inflammation and repair after MI, whereas CTGF is involved in the ongoing fibrosis of the heart. The antifibrotic benefits of captopril are not mediated through a reduction in CTGF.
To describe the age- and sex-specific mortality in a cohort of young type 1 diabetic patients and to analyze the causes of death with special focus on suicide, accidents, and unexplained deaths.
A population-based incident childhood diabetes register, covering onset cases since 1 July 1977, was linked to the Swedish Cause of Death Register up to 31 December 2000. The official Swedish population register was used to calculate age- and sex-standardized mortality rates (SMRs), excluding neonatal deaths. To analyze excess risks for specific diagnoses, case subjects were compared with five nondiabetic control subjects, matched by age, sex, and year of death. Death certificates were collected for all case and control subjects. For case subjects with an unclear diagnosis, hospital records and/or forensic autopsy reports were obtained.
Mean age- and sex-SMR was 2.15 (95% CI 1.70-2.68) and tended to be higher among females (2.65 vs. 1.93, P = 0.045). Mean age at death was 15.2 years (range 1.2-27.3) and mean duration 8.2 years (0-20.7). Twenty-three deaths were clearly related to diabetes; 20 died of diabetic ketoacidosis. Only two case subjects died with late diabetes complications (acute coronary infarction). Thirty-three case subjects died with a diagnosis not directly related to diabetes; 7 of them committed suicide, and 14 died from accidents. There was no significant difference in traffic accidents (odds ratio 1.02 [95% CI 0.40-2.37]). Obvious suicide tended to be increased but not statistically significantly so (1.55 [0.54-3.89]). Seventeen diabetic case subjects were found deceased in bed without any cause of death found at forensic autopsy. Only two of the control subjects died of similar unexplained deaths.
In a well-developed health care system, there is still a significant excess mortality in young type 1 diabetic patients. We confirm a very large proportion of unexplained deaths in bed, which should be further studied. There is no clear excess death rate caused by suicide or traffic accidents among young diabetic subjects.
This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD).
Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases.
From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 +/- 10.9 years) were referred by medical examiners/coroners to Mayo Clinic's Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation.
Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 +/- 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p < 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases.
In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD.
Excessive fibrosis contributes to an increase in left ventricular stiffness. The goal of the present study was to investigate the role of connective tissue growth factor (CCN2/CTGF), a profibrotic cytokine of the CCN (Cyr61, CTGF, and Nov) family, and its functional interactions with brain natriuretic peptide (BNP), an antifibrotic peptide, in the development of myocardial fibrosis and diastolic heart failure. Histological examination on endomyocardial biopsy samples from patients without systolic dysfunction revealed that the abundance of CTGF-immunopositive cardiac myocytes was correlated with the excessive interstitial fibrosis and a clinical history of acute pulmonary congestion. In a rat pressure overload cardiac hypertrophy model, CTGF mRNA levels and BNP mRNA were increased in proportion to one another in the myocardium. Interestingly, relative abundance of mRNA for CTGF compared with BNP was positively correlated with diastolic dysfunction, myocardial fibrosis area, and procollagen type 1 mRNA expression. Investigation with conditioned medium and subsequent neutralization experiments using primary cultured cells demonstrated that CTGF secreted by cardiac myocytes induced collagen production in cardiac fibroblasts. Further, G protein-coupled receptor ligands induced expression of the CTGF and BNP genes in cardiac myocytes, whereas aldosterone and transforming growth factor-beta preferentially induced expression of the CTGF gene. Finally, exogenous BNP prevented the production of CTGF in cardiac myocytes. These data suggest that a disproportionate increase in CTGF relative to BNP in cardiac myocytes plays a central role in the induction of excessive myocardial fibrosis and diastolic heart failure.
The cause of sudden death in young people remains unknown in up to 50% of postmortem cases. Mutations in the ion channel genes are known to cause primary arrhythmogenic disorders such as long QT and Brugada syndromes, which can present with sudden cardiac death and a negative autopsy. In this study, 59 sudden unexplained deaths occurring in Australians aged </=35 years with a negative autopsy, from 1994-2002, were studied. Genomic DNA was extracted from paraffin-embedded tissues. Genetic analysis of the KCNQ1 and SCN5A genes was performed using denaturing high-performance liquid chromatography and direct DNA sequencing. Nine DNA sequence variants were identified in the KCNQ1 gene and 9 sequence variants were identified in the SCN5A gene. In total, 23 out of 59 cases were found to have at least one DNA variant in KCNQ1 or SCN5A, of which one, H558R in the SCN5A gene, caused an amino acid substitution. None of the DNA variants were determined to be disease causing as they were also identified in control populations. In conclusion, no disease-causing mutations were found in the KCNQ1 or SCN5A genes in this cohort. A more selective screening approach, including only individuals with a clinical or family history of arrhythmogenic disorders, may yield greater success in identifying disease-causing mutations in cohorts of young individuals who have died suddenly.
To examine mortality rates and causes of death among subjects diagnosed with type 1 diabetes aged <or=29 years.
Subjects with type 1 diabetes from a population-based register in Yorkshire, U.K., diagnosed between 1978 and 2004 were linked to the U.K. National Health Service Central Register for death notifications. Deaths were coded using ICD-9 (1979-2000) and ICD-10 (2001-2005). Standardized mortality ratios (SMRs) were calculated using expected numbers of deaths from U.K. mortality rates by cause of death and age at diagnosis.
A total of 4,246 individuals were followed up, providing 50,471 person-years of follow-up. Mean follow-up length was 12.8 years for individuals aged 0-14 years and 8.3 for those aged 15-29 years. Overall, 108 patients died, of whom 77 (71%) were male. A total of 74 (1.7/1,000 person-years) deaths occurred in inidividuals aged 0-14 years and 34 (4.6/1,000 person-years) in those aged 15-29 years. The SMR was 4.7 (95% CI 3.8-5.6) overall, similar for males and females, but higher for individuals aged 15-29 years (SMR 6.2 [95% CI 4.3-8.6]) compared with those aged 0-14 years (4.2 [3.3-5.3]). The SMR rose with increasing disease duration. A total of 47 of 108 deaths (44%) occurred from diabetes complications, 32 of which were acute and 15 chronic. Twenty-two percent (n = 24) of deaths were attributed to accidents or violence (SMR 2.1 [95% CI 1.4-3.2]), including six suicides. Sixteen percent of all deaths were related to drug misuse (including insulin but excluding tobacco and alcohol) (SMR 6.4 [95% CI 3.7-10.2]).
Subjects with type 1 diabetes diagnosed under 30 years of age had a 4.7-fold excess mortality risk. Nearly half of the deaths were due to acute or chronic complications of diabetes. Drug misuse-related deaths may be an emerging trend in this population warranting further investigation.
Connective tissue growth factor (CTGF) has been recently reported as a mediator of myocardial fibrosis; however, the significance of plasma CTGF concentration has not been evaluated in patients with heart failure. The aim of this study was to investigate the clinical utility of plasma CTGF concentration for the diagnosis of heart failure.
We evaluated fifty-two patients with chronic heart failure. The plasma concentration of CTGF and other markers of fibrosis were assessed and compared with clinical and echocardiographic data. Plasma CTGF was significantly elevated in symptomatic patients in proportion to their NYHA classes and was significantly correlated with plasma brain natriuretic peptide (BNP) concentration (r=0.395, P<0.01). Plasma CTGF was also correlated with plasma transforming growth factor beta (TGF-beta) (r=0.512, P<0.01), matrix metalloproteinase (MMP)-2 (r=0.391, P<0.05) and tissue inhibitor of MMP (TIMP)-2 (r=0.354, P<0.05) concentrations. Interestingly, plasma CTGF was correlated with E/E' value evaluated by tissue Doppler echocardiography (r=0.593, P=0.012), but not with systolic function and left ventricular mass.
Our study suggests that plasma CTGF concentration is a novel diagnostic marker for cardiac dysfunction and may provide additional specific information about myocardial fibrosis in chronic heart failure patients.
Glucose-6-phosphatase-alpha (G6PC) is a key enzyme in glucose homeostasis that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis. Mutations in the G6PC gene, located on chromosome 17q21, result in glycogen storage disease type Ia (GSD-Ia), an autosomal recessive metabolic disorder. GSD-Ia patients manifest a disturbed glucose homeostasis, characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. G6PC is a highly hydrophobic glycoprotein, anchored in the membrane of the endoplasmic reticulum with the active center facing into the lumen. To date, 54 missense, 10 nonsense, 17 insertion/deletion, and three splicing mutations in the G6PC gene have been identified in more than 550 patients. Of these, 50 missense, two nonsense, and two insertion/deletion mutations have been functionally characterized for their effects on enzymatic activity and stability. While GSD-Ia is not more prevalent in any ethnic group, mutations unique to Caucasian, Oriental, and Jewish populations have been described. Despite this, GSD-Ia patients exhibit phenotypic heterogeneity and a stringent genotype-phenotype relationship does not exist.
Idiopathic congenital central hypoventilation syndrome: diagnosis and manage-ment
- Weese-Mayer
- De
- Keens Dc Tg Shannon
- Silvestri
Weese-Mayer DE, Shannon DC, Keens TG, Silvestri JM. Idiopathic congenital central hypoventilation syndrome: diagnosis and manage-ment. American Thoracic Society. Am J Respir Crit Care Med 1999; 160:368-73.
A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation
- Viswanathan
WHO Diamond Project Group
- WHO MPfCD