Sudden cardiac death in diabetic patients

Sudden cardiac death (SCD/SCA) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1 hour of symptom onset) in a person with known/unknown cardiac disease.
Patients at risk for SCD may have prodromes of chest pain, fatigue, palpitations, and other nonspecific complaints.
In the Framingham Study, preexisting CAD was associated with a 2.8- to 5.3-fold increase in risk of SCD
Both left ventricular dysfunction and NYHA class were powerful risk factors for SCD in patients with either ischemic or nonischemic cardiomyopathy
An LVEF of less than 30 % (due to any etiology) is the single most powerful independent indicator for SCD

1. Diabetes mellitus and sudden cardiac death: Evidences, Mechanisms and Therapeutic Strategies DR. SUDHIR BHANDARI MD, DNB, MNAMS, FRCP (London), FRCP (Edinburgh) FELLOW AMERICAN COLLEGE OF ENDOCRINOLOGY (FACE) FELLOW AMERICAN COLLEGE OF PHYSICIANS (FACP) FELLOW INDIAN COLLEGE OF PHYSICIANS (FICP) FLLOW RESEARCH SOCIETY FOR THE STUDY OF DIABETES IN INDIA (FRSSDI) Consultant-Internal Medicine, Diabetes & Endocrinology HON. PHYSICIAN TO H.E.THE GOVERNOR OF RAJASTHAN Ex Vice Chancellor – Rajasthan University of Health Science, Rajasthan Professor Emeritus, SMS Medical college, Jaipur

2. SUDDEN CARDIAC DEATH/ARREST Sudden cardiac death (SCD/SCA) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1 hour of symptom onset) in a person with known/unknown cardiac disease. Patients at risk for SCD may have prodromes of chest pain, fatigue, palpitations, and other nonspecific complaints.

3. GENETIC CONTRIBUTORS TO SCD RISK Genetically Based Primary Arrhythmia Disorders Congenital long-QT interval syndrome, short-QT syndrome Brugada syndrome Catecholaminergic polymorphic (“idiopathic”) VT/VF Inherited Structural Disorders with Arrhythmic SCD Risk Hypertrophic cardiomyopathy Right ventricular dysplasia/cardiomyopathy Genetic Predisposition to Induced Arrhythmias and SCD Drug-induced “acquired” LQTS (drugs, electrolytes) Electrolyte and metabolic arrhythmogenic effects

4. Prior Episode of V.TACH Low LVEF. Previous Myocardial Infarction. Coronary Artery Disease Family History of SCD. Cardiomyopathy Congestive Heart Failure Long QT Syndrome. Right Ventricular Dysplasia. Risk Factors of Sudden Cardiac Death (SCD)

5. RISK FACTORS COMMON TO BOTH CHD & SCD NON MODIFIABLE Age Male Gender F/H/O CHD Genetic Factors MODIFIABLE Smoking Hypertension Hyperlipidemia Diabetes Mellitus Obesity Renal dysfunction Sedentary lifestyle

6. CORONARY ARTERY DISEASE In the Framingham Study, preexisting CAD was associated with a 2.8- to 5.3-fold increase in risk of SCD Both left ventricular dysfunction and NYHA class were powerful risk factors for SCD in patients with either ischemic or nonischemic cardiomyopathy An LVEF of less than 30 % (due to any etiology) is the single most powerful independent indicator for SCD

7. ARRHYTHMIAS PVCs and nonsustained VT during both the exercise and recovery phases of a stress test are predictive of increased risk Arrhythmias in the recovery phase appear to predict a higher risk than arrhythmias in the recovery phase A frequency cutoff of 10 PVCs/hour as a threshold level for increased risk is cited by most studies

8. Arrhythmic Cause of SCD Albert CM. Circulation . 2003;107:2096-2101. 12% Other Cardiac Cause 88% Arrhythmic Cause

9. Bayés de Luna A. Am Heart J. 1989;117:151-159. Underlying Arrhythmias of Sudden Cardiac Arrest Bradycardia 17% VT 62% Primary VF 8% Torsades de Pointes 13%

10. ECG MARKERS Elevated resting heart rate Prolonged QRS duration Abnormal heart rate recovery (HRR < 12 bpm 1st min , < 22bpm after 2 min) Prolonged QT interval and Early repolarization syndrome ( horizontal or descending ST segments in inferior / lateral leads)

11. NUTRITIONAL RISK FACTORS Increased consumption of n-3 polyunsaturated fatty acids is inversely associated with SCD to a greater extent than nonfatal MI Heavy alcohol consumption ( > 5 drinks per day) is associated with an increased risk of SCD In contrast, light-to-moderate levels of alcohol consumption ( < 0.5 to 1 drinks per day) may be associated with reduced risks of SCD. High magnesium diet – low risk of SCD

12. PSYCHOSOCIAL Lower socioeconomic status Depression Anxiety Social isolation and Psychological stress have all been linked to an increase in cardiovascular mortality in diverse populations

13. BIOMARKERS AS RISK FACTORS INFLAMMATORY MARKERS CRP IL-1 receptor Fibrinogen IL-6 METABOLIC MARKERS Aldosterone Cystatin C Renin Vitamin D and PTH NEUROHORMONAL MARKERS BNP / NT-pro-BNP

14. In the setting of diabetes and obesity there is increased production of reactive oxygen species (ROS) and alterations in intracellular calcium homeostasis lead to ion channel remodelling , repolarization disturbances, and early and delayed after- depolarizations (EAD, DAD). Inflammatory cells and structural alterations such as cardiac fibrosis furthermore contribute to a pro-arrhythmic substrate.

15. Incidence of sudden cardiac death according to age among persons with and without diabetes mellitus. Vertical bars represent 95% confidence intervals. DM: diabetes mellitus; DM1: diabetes mellitus type 1; DM2: diabetes mellitus type 2. Lynge TH, Svane J, Pedersen- Bjergaard U, Gislason G, Torp -Pedersen C, Banner J, Risgaard B, Winkel BG, Tfelt -Hansen J. Sudden cardiac death among persons with diabetes aged 1-49 years: a 10-year nationwide study of 14 294 deaths in Denmark. Eur Heart J. 2020 Jul 21;41(28):2699-2706. doi : 10.1093/ eurheartj /ehz891. PMID: 31848583; PMCID: PMC7377578.

16. This study found that young persons with DM aged 1–35 years had >8-fold higher SCD as compared to young persons without DM. This study highlights the need for early cardiovascular risk monitoring and assessment in young persons with DM.

17.  Factors increasing the risk of sudden cardiac death in patients with diabetes and chronic heart failure.

18. Overview of factors modulating the risk for cardiac arrhythmia and sudden cardiac death (SCD) in the setting of diabetes and obesity.

19. AGEs: Acylated Glycosylation End Products

20. SCD is a common cause of death among young people with DM and highlights the need for increased awareness regarding risk of SCD among providers caring for young patients with DM. In addition to the importance of measuring and treating traditional modifiable risk factors (blood pressure, lipids, glucose) to prevent micro- and macrovascular complications and mitigating the risk of SCD as a complication of CAD and CHF, providers must be aware that SCD occurs in the absence of CAD and CHF and may be related to factors such as Sudden Arrhythmic Death Syndrome (SADS), Cardiac Autonomic Neuropathy (CAN), hypoglycemia, and possibly iatrogenic effects of QT prolonging medications.

21. This study identify the first time a causative link between elevated Branched Chain Amino Acids (BCAAs) and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure. Using an unbiased approach, we have identified BCAA metabolism as a novel modulator of cardiac electrical function and a mediator of cardiac arrhythmias and sudden death. This new mechanism linking BCAAs to pro-arrhythmia may not only be relevant for inherited BCAT2 deficiency, but also for acquired metabolic disorders such as diabetes, obesity, and heart failure in which BCAA metabolism is impaired.

22. Identification of a novel mouse model of sudden death and pro-arrhythmia through an N-ethyl-N- nitrosourea (ENU) mutagenesis screen, uncovering a novel pro-arrhythmic role for branched chain amino acid (BCAA) dysregulation . mTOR : mammalian target of rapamycin .

23. Potential pro-arrhythmic pathways related to branched chain amino acid (BCAA) dysregulation . AMPK: adenosine monophosphate (AMP)-activated protein kinase; mTOR : mammalian target of rapamycin ; ROS: reactive oxygen species

24. Using an unbiased approach, this study identified BCAA metabolism as a novel modulator of cardiac electrical function and a mediator of cardiac arrhythmias and sudden death. This new mechanism linking BCAAs to pro-arrhythmia may not only be relevant for inherited BCAT2 deficiency, but also for acquired metabolic disorders such as diabetes, obesity, and heart failure in which BCAA metabolism is impaired. Since cellular BCAA metabolism is reflected by BCAA plasma levels, the latter may serve as a circulating prognostic biomarker of arrhythmia and SCD risk. Moreover, such metabolic mechanisms are modifiable through e.g. dietary interventions, providing novel preventive and therapeutic targets that overcome the drawbacks of conventional anti-arrhythmic approaches targeting ion channels or transporters. Additionally, we here provide the first proof of concept that pharmacological inhibition of the mTOR pathway can abolish the pro-arrhythmic events provoked by elevated BCAAs.

25. The pathogenesis of SCA in patients with diabetes is believed to be due to acute atherosclerotic CAD. However, other mechanisms, including diabetic autonomic neuropathy, QT interval prolongation, diabetic cardiomyopathy, diabetic nephropathy, poor diabetes control, and hypoglycemia, may independently contribute to SCA.

26. Cardiac Autonomic Neuropathy (CAN) is a microvascular complication, the development of which is associated with obesity, smoking, hypertension, and dyslipidemia. Chronic high glucose levels promote oxidative stress and inflammation, which are responsible for the vascular endothelial, cardiac, and neuronal damage. It is essential the prevention of CAN or early and adequate treatment because its progression is associated with the appearance of diabetic nephropathy

27. Diabetic autonomic neuropathy is associated with a decrease in parasympathetic and an increase in sympathetic tone, increasing the susceptibility to arrhythmias. Patients with diabetic autonomic neuropathy may also develop electrocardiographic abnormalities such as QT prolongation, predisposing them to lethal ventricular arrhythmias. Whitsel et al. showed that diabetes patients without diagnosed pre-existing heart disease in the upper quartile of the QT index (QTI > 107%) had a 3-fold increased risk of SCA. Diabetic autonomic neuropathy is also associated with resting tachycardia, exercise intolerance, intraoperative and perioperative cardiovascular instability, silent myocardial ischemia, and increased mortality

28. Evolution of symptoms of cardiac autonomic neuropathy (CAN) in diabetes. Patients display reduced variability in heart rate and resting tachycardia in the early phase of parasympathetic dysfunction, which underlie the reduced exercise tolerance and the increased arrhythmogenesis . Later stages of CAN involve sympathetic denervation and cause hemodynamic dysregulation and silent myocardial ischemia. 

29. Diabetic cardiomyopathy is a condition in which pathologic changes in the myocardium develop without cardiovascular disease. It could contribute to ECG abnormalities, such as non-specific ST-T wave changes and QT prolongation. Autopsy of patients with diabetic cardiomyopathy revealed areas of myocardial fibrosis resulting from microvascular disease

30. High HbA1c levels, associated with poor glycemic control, increase the risk of SCD Hypoglycemia increases the risk of mortality and arrhythmias in equally both diabetes and nondiabetes STEMI patients. Hypoglycemia activates the sympathetic nervous response, producing catecholaminemediated adverse effects on the myocardium. Catecholamine excess driven by hypoglycemia is also associated with platelet activation, leukocyte mobilization, and coagulation that may result in ischemic damage to the myocardium and endothelial dysfunction

31. Hyperglycaemia is at the core of both microvascular and macrovascular complications in T2DM, with microvascular complications increasing the risk of macrovascular complications. In addition to blood pressure and lipid control, to reduce CVD risk in people with T2D, intensive treatment of hyperglycaemia should be initiated early with the goal of achieving and maintaining control and will be particularly beneficial in the long run when used at the early stages of disease

32. CLINICAL FEATURES Patients at risk for SCD may have prodromes of chest pain, fatigue, palpitations, and other nonspecific complaints. History and associated symptoms, to some degree depend on the underlying etiology of SCD A prior history of LV impairment (ejection fraction < 30-35%) is the most potent common risk factor for sudden death.

33. Coronary artery disease Previous cardiac arrest Syncope Prior myocardial infarction, esp within 6 months Ejection fraction less than 30-35% H/O frequent ventricular ectopy (>10 PVC/h or NSVT) Dilated cardiomyopathy Previous cardiac arrest Syncope Ejection fraction less than 30-35% Use of inotropic medications

34. 3. Hypertrophic cardiomyopathy Previous cardiac arrest Unexplained Syncope ( recent , in young) Family history of one or more premature HCM-related deaths, particularly if sudden and multiple Symptoms of heart failure Drop in SBP or ventricular ectopy upon stress testing Palpitations Multiple, repetitive (or prolonged) nonsustained bursts of ventricular tachycardia on serial ambulatory ( Holter ) ECGs Massive LV hypertrophy (wall thickness, ≥30 mm), particularly in young patients

35. 4. Valvular disease Valve replacement within 6 months Syncope History of frequent ventricular ectopy Symptoms associated with severe uncorrected AS/MS 5. Long QT syndrome Family history of long QT and SCD Medications that prolong the QT interval Bilateral deafness

36. Name Major mechanism ANP,BNP 1) Affecting blood pressure through acting on vascular smooth muscle cells 2) Preventing vascular smooth muscle cell growth and proliferation and vascular fibrosis 3) Acting on the heart itself to suppress cardiac hypertrophy and fibrosis Ang II 1) Cardiac hypertension and oxidative stress 2) Promoting and suppressing coronary angiogenesis, via VEGF and TSP-1 produced from hypertrophied cardiomyocytes under chronic Hypoxia C peptide Na + , K + -ATPase and PKC-α cTn Oxidative stress and inflammatory damage CK-MB Apoptosis, Myocardial injury, Oxidative Stress and Inflammation CTGF Cardiac fibrosis, hs-CRP Inflammation, oxidative stress Hcy Oxidative stress IL-1 β Promoting cardiomyocyte apoptosis by activating the IRAK-2/CHOP pathway of endoplasmic reticulum stress TNF- α Cardiac fibrosis, inflammation IL-6 Cardiac remodeling, fibrosis and cardiomyocyte apoptosis 8-OHdG Oxidative stress and DNA oxidation MMPs Cardiac fibrosis βARK1, β-adrenergic receptor kinase 1; CTGF,connective tissue growth factor; cTn,cardiac troponin; CK-MB, creatine kinase MB isoenzyme; Hcy , homocysteine; hs -CRP, hypersensitive-c-reactive-protein; 8-OHdG, 8-hydroxy-2 deoxyguanosine; MMPs,matrix metalloproteinase. VEGF,vascular endothelial-derived growth factor;TSP-1, thrombospondin 1 Biomarkers of Sudden Cardiac Death

37. Emerging markers of SCD Microvolt T wave alternans Contrast enhanced MR imaging of postinfarction border QT Variability MIBG Imaging Derivatives of heart rate variability methods Familial clustering

38. Given the ever-rising prevalence of obesity and DM, identification of affected patients at risk for cardiac arrhythmias and SCD will become increasingly important. Our insight into pro-arrhythmic mechanisms in the setting of these metabolic disorders has significantly increased in recent years as a result of basic and translational research combining clinical, epidemiologic, genetic, molecular, metabolic, and electrophysiological investigations Metabolic markers may furthermore prove useful as circulating prognostic biomarkers of risk of arrhythmia and SCD

39. Metformin has been shown to ameliorate mitochondrial dysfunction, calcium dysregulation , and repolarization abnormalities in animal models in addition to decreasing plasma BCAA levels and activating AMPK. SGLT2 inhibitors are now recommended as antidiabetic therapy and have recently shown promising anti-arrhythmic effects in patients with DM. Mechanistically , SGLT2 inhibitors may ameliorate intracellular sodium and calcium dysregulation in addition to reducing fibrosis, cardiomyopathy, and inflammation, thereby reducing pro-arrhythmia in the setting of metabolic disorders through various mechanimsm . Potential novel therapeutics include those targeting mitochondria, aimed at reducing production of ROS or preventing mitochondrial calcium overload, and ROS-induced membrane depolarization .

40. Joshua J. Joseph. Circulation. Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association, Volume: 145, Issue: 9, Pages: e722-e759, DOI: (10.1161/CIR.0000000000001040) © 2022 American Heart Association, Inc.

41. The response to a cardiac arrest is driven by two urgent principles: (1) maintenance of continuous artificial cardiopulmonary support until return of spontaneous circulation (2) restoration of spontaneous circulation as quickly as possible. Management of Cardiac Arrest

42. ACE: angiotensin-converting enzyme; GLP-1R: receptor for glucagon-like peptide-1; SGLT-2: sodium/glucose cotransporter 2; AR: aldose reductase Pharmacological strategies for management of main causes and symptoms of diabetic cardiac autonomic neuropathy (DCAN).

43. Preventive (left panel) and therapeutic (middle panel) strategies and targets (right panel) to prevent arrhythmias and sudden cardiac death in patients with diabetes and obesity. GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter Preventive Therapeutic Arrhythmia prevention

44. This study showed that patients with diabetes hospitalized due to COVID-19 had an increased risk of CVD, coronary heart disease, stroke incidence, and mortality than those who were not COVID-19 infected, suggesting more careful prevention and management among patients with COVID-19ti

45. The members of the European Society of Cardiology posit that we reasonably might screen (or continue to monitor) for cardiac dysfunction in Patients who had demonstrated cardiac dysfunction during their COVID infection; Patients with clinical symptoms of dyspnea, exercise intolerance, long COVID symptoms; Anyone who had elevated cardiac troponin levels during infection

46. Interconnection between diabetes, heart failure, and SARS-CoV-2.

47. Molecular mechanisms of SARS-CoV-2 infection

48. COVID-19 patients were more likely to develop numerous cardiovascular conditions compared to uninfected participants, which may have contributed to their higher risks of death. “The findings indicate that patients with COVID-19 should be monitored for at least a year after recovering from the acute illness to diagnose cardiovascular complications of the infection, which form part of long COVID

49. Key take‐home messages and clinical perspective Achieving and maintaining glycaemic control plays a critical role in reducing microvascular and macrovascular complications for people with T2D The pathogenesis of SCA in patients with diabetes is believed to be due to acute atherosclerotic CAD. However, other mechanisms, including diabetic autonomic neuropathy, QT interval prolongation, diabetic cardiomyopathy, diabetic nephropathy, poor diabetes control, and hypoglycemia, may independently contribute to SCA . Separately, and independent of glycaemic control, agents from the SGLT2 inhibitor and GLP‐1RA class have been shown to reduce CV risk in individuals with established/high risk of CVD Metabolic markers may furthermore prove useful as circulating prognostic biomarkers of risk of arrhythmia and SCD. One size does not fit all in T2D; HbA1c goals and treatments need to be individualized, with glycaemic targets achieved safely Physiological control (e.g., less glycaemic variability, more time in range) is associated with a lower risk of CV complications; monitoring technology has the potential to facilitate more physiological control and guide therapeutic needs.

50. Thank you