Ischemic Heart Disease in Diabetes

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Slide 1 :

“SWEET HEART” WHEN CHOKED !? Dr.P.SURESHKUMAR MD;Ph.D CONSULTANT DIABETOLOGIST KOZHIKKODE

Slide 2 :

INTRODUCTION Ischemic Heart Disease is the leading cause for Major morbidity and mortality in Diabetes Mellitus. Despite the recent introduction of major new therapeutic approaches to treat IHD including pharmacological, surgical and interventional approaches, the morbidity and mortality of IHD in Diabetes remain at a high level.

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INTRODUCTION-contd. Mortality in MI is mostly related to the extend of myocardial tissue damage, the membrane instability, and the delay in affecting remedial measures( recovery time). All these are integrally related to the state of cellular metabolism and the efficiency of the myocardial tissue in handling oxidative energy metabolism.

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INTRODUCTION-contd. Most of the interventions to treat IHD aims at increasing the O2 delivery to the HEART (Thrombolysis, Revascularisation, ACE-I, Antiplatelets) or at decreasing the O2 demand by the HEART (Beta-blockers and Nitrates). But, the compromised energy metabolism of the Myocardium (which is the central abnormality in IHD) is not been targeted well in the therapeutic point of view.

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INTRODUCTION-contd. Improving the O2 utilization and thus improving the Efficiency of myocardium could have an additive benefit on the efficacy of the existing treatments But with the present enchantment of interventional procedures, this aspect of Metabolic Management is become the “Lost Child of Cardiology”

Slide 6 :

WHAT IS TYPE 2 DIABETES? It is a heterogeneous disorder, with heterogeneity in phenotype and genotype! Hence, Metabolic management also should be heterogeneous. Understanding this complexity is vital to the clinical diagnosis and management in various situations. Primarily a product of Muscle IR.

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HNF1a HNF4 a PDX1 NEUROD1 HNF1ß TCF 7L2 Adenyl Cyclase GLP1 Kir1.6 SUR1

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Hyperbolic relation between IS x bCF Bonora E. et al. Diabetes Care, 2002; 26 (7): 1153-1141.

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Diabetes is equally a disorder of Fat metabolism as of Glucose metabolism. Fat is having a stronger causal relation than Glucose in the secondary metabolic perturbations! Lipotoxicity is the fundamental metabolic defect both at Beta-cell level as well as at the Muscle tissue level.

Slide 10 :

Myocardium and Diabetes FFA is the major metabolic substrate(60-70%) in normal myocardium 30-40% is provided by Glucose In Diabetes this is almost exclusively FFA Glucose is the most energy efficient substrate (ATP/O2) Ischemia demands the most efficient energy management-Absent in diabetes.

Slide 11 :

Metabolic pathways for Fat and Glucose

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mTE1 cTE1 Apoptosis

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Slide 14 :

Difference Between Normal and Diabetic Myocardium

Slide 15 :

Ischemia

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Slide 17 :

Therapeutic Possibilities 2)-ReduceFFA Supply 3)-Inhibit Acyl-CoA tranfer across the IMM 4)-Inhibit Beta Oxidation 1)-IncreaseGlucose Utilisation

Slide 18 :

GIK Therapy First metabolic therapy for AMI introduced by Sodi Pollares in 1962 Various studies over last 45 years found varying benefits Study in 2005 found no significant benefit More studies needed to prove benefits Mechanism: more Glu utilization, less FFA oxidation, Na+-K+-ATPase activation, Less Ca++ influx, Decreases Inflammation etc.

Slide 19 :

Dichloroacetate Improves PDH activity and thus Glucose Oxidation Most animal studies showed improved Myocardial efficiency, But improvements in cardiac function in clinical trials debated by various researchers. Clinical utility limited due to short half life.

Slide 20 :

Inhibiting Fatty Acid Oxidation Can increase Glucose utilization by stimulating PDH which is regulated by the ratio of NADH+/ NAD, and Acetyl CoA/CoA Theoretically can be done by inhibiting :uptake of FA from serum, Transport across Mit. membrane, and Beta Oxidation Inhibition of Lipolysis by HSL by non selective Beta blockers-Carvedilol,Nicotinic Acid and its derivatives-Acipimox-(less AE like Flushing and high UA than Niacin)

Slide 21 :

CPT1 Inhibition Oxfenicin Oxfenicin and Nicotinic acid combination Perhexiline-introduced 30 yrs back, initially thought to be vaso-dilatory, then classified as Ca-channel blocker, use limited for long time by side effects like PN,Hepatotoxicity,Hypoglycemia- Later Safe dosage identified as 0.15-0.6 mg/L plasma concn.) Now(1996) identified as Blocker of CPT1 and 2. This ‘Old –New Drug’ require further investigations. Etomoxir- Activates SERCA2, a-MHC, and PPARa. Liver toxicity limited Use-Limited clinical data.

Slide 22 :

Endogenous CPT1 inhibition Malonyl-CoA –Regulated by ACC and MCD MCD inhibition is a promising New approach- further clinical studies needed.

Slide 23 :

Inhibition of Fatty Acid ß-Oxidation Trimetazidine- Widely used in Europe and Asia. Inhibits the enzyme-LC 3KAT and weakly inhibits CPT1 Mildronate: Inhibitor of Carnitine bio-synthesis. All studies in Russia- So limited reference in other literatures Ranolazine (similar chemical structure of TMZD)-Approved y US-FDA in 2006-

Slide 24 :

Ranolazine A Selective inhibitor of late Na+ current, thus decreasing the Ca++ flux and reduces Myocardial cell apoptosis Also decrease fatty acid oxidation and improves Glucose oxidation MARISA,CARISA,ERICA studies showed 33% reduction in infarct size, increased contractility and Stroke Volume. Further studies(MERLIN-STEACS) going on.

Slide 25 :

SUMMARY IHD threatens the human health world wide, and till date , there is no absolutely effective method to prevent it Metabolic perturbations occur in all patients with IHD, especially worse in diabetes Mellitus. Importance of optimizing the energy management of the heart during ischemia is better recognized recently by physicians and cardiologists alike.

Slide 26 :

SUMMARY Other than improving the anatomical recovery(PTCA,CABG) and decreasing oxygen demand(Beta-blockers and vasodilators), Optimizing energy metabolism will shift the management of IHD from a more organ specific to Cell specific levels and will extend the benefits of recovery in larger number of patients, especially in the energy mismanaged state-Diabetes Mellitus

Slide 27 :

THIS IS ALL WHAT I DID! THANKS FOR BEARING

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