Introduction Obesity and sedentary life style. By 2025 300 million will be affected by Diabetes Mellitus. Cardiovascular disease accounts for 80% of death among diabetic patients.
Definition “A distinct entity characterized by the presence of abnormal myocardial performance or structure in the absence of epicardial coronary artery disease, hypertension and significant valvular disease.” First described in 1972.(Ruber et al) On the basis of observations in 4 diabetic patients without evidence of HT, CAD, valvular or congenital heart disease.
Epidemiology Diabetes affects 180 million people worldwide. 2/3 of patients with established CVD have impaired glucose homeostasis; affects 30% of heart failure patients. Every 1% increase in HBA1c leads to an 8% increase in heart failure.
In United Kingdom Prospective Diabetes Study(UKPDS), it was found that For HBA1c <6%, there occurred 2.3 HF events /100 person – years. For HBA1c >10%, there occurred 11.9 HF events /100 person – years Prevalence of HF in general population: 1-4%. Prevalence of HF in diabetic population: 15%.
Pathology Enhanced thickening of capillary basement membrane. Myocellular atrophy and hypertrophy. Myocardial and interstitial fibrosis. Fat droplet deposition.
Other characteristics Early changes in diastolic function – affects up to 75% asymptomatic diabetic patients. Collagen deposition. Presence of advanced glycosylation end products(AGEs). Late compromise of LV systolic function.
Pathogenesis1) HYPERGLYCEMIA – Excess AGE and Reactive Oxygen Species(ROS) formation with deactivation of NO. Myocardial collagen deposition and fibrosis.
2) FATTY ACIDS Impaired glycolysis, pyruvate oxidation, lactate uptake results in apoptosis. Alteration of myocardial bioenergetics and contraction/relaxation coupling.
3) PROTEIN KINASE C Activation of DAG/PKC signal tranduction pathway Reduction in tissue blood flow. Increased vascular permeability. Alterations in neovascularization. Enhanced extracellular matrix deposition.
4) RENIN ANGIOTENSIN SYSTEM(RAS) Activation of stretch receptors in heart activates RAS and the SNS Cardiomyocyte hypertrophy and apoptosis.5) ALDOSTERONE INDUCED FIBROSIS Existence of local cardiac renin- angiotensin-aldosterone system have been demonstrated. Myofibroblast growth with interstitial and focal perivascular accumulation of collagen.
6) HYPOXIA INDUCED FACTOR 1/ VASCULAR ENDOTHELIAL GROWTH FACTOR HIF - 1α activation via hypoxia/free radicals induces angiopoietin, PGF,PDGF-β and VEGF. In diabetes, VEGF and its receptors are decreased significantly leading to impaired angiogenesis.
7) ENDOTHELIAL DYSFUNCTION Impaired endothelial NO production. Increased vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules ,platelet and vascular growth factors which enhance vasomotor tone and vascular permeability and limit growth and remodelling .
Stages of diabeticSTAGES cardiomyopathy CHARACTERISTICS FUNCTIONAL STRUCTURAL METHODS FEATURES FEATURESEarly stage Depletion of GLUT4 No overt functional Normal LV size, wall Sensitive Increased FFA abnormalities or thickness, and mass methods such as Carnitine deficiency possible strain, strain rate, Ca2 homeostasis changes overt diastolic and Insulin resistance dysfunction myocardial tissue but normal ejection velocity fractionMiddle stage Apoptosis and necrosis Abnormal diastolic Slightly increased LV Conventional Increased AT II dysfunction and mass, echocardiograph Reduced IGF-I normal or wall thickness, or size y or Increased TGF-1 slightly decreased sensitive Mild CAN ejection methods such as fraction strain, strain rate, and myocardial tissue velocityLate stage Microvascular changes Abnormal diastolic Significantly Conventional Hypertension dysfunction and increased LV echocardiograph CAD ejection size, wall thickness, y Severe CAN fraction and mass
Clinical features Symptoms -Typically pts c/o months of fatigue, weakness, reduced exercise tolerance due to CHF. -May also present as Arrythmia or Sudden Death. Physical Signs -Tachycardia -Jugular venous distension -Gallop heart sounds
Diagnosis CXR- Cardiomegaly ECG- Normal or low QRS voltage , abn axis, non specific ST seg abnormalities, conduction defects. 2D Echo Tissue doppler echo Intravenous contrast echo Computed tomography Magnetic resonance imaging
2D ECHO Preserved LV ejection fraction. Reduced early diastolic filling. Prolongation of isovolumetric relaxation and increased atrial filling. Pre – ejection period(PEP) increased. LV ejection time(LVET)decreased. PEP/LVET increased.
GRADES OF DIASTOLIC DYSFUNCTION Grade 1- Abnormal Relaxation Pattern Reversal of E/A ratio Develop normally with age. Patients will not have any symptoms of heart failure. E/A ratio- Ratio between early(E) and late (atrial – A) ventricular filling velocity. E caused by accumulation of blood in the atria during previous systole. A created by atrial contraction.
GRADE II - Pseudonormal Filling Dynamics Moderate diastolic dysfunction. Elevated left atrial filling pressure. Symptoms of heart failure. E/A ratio appears normal.GRADE III – Reversible Restrictive Diastolic dysfunction Reversal of diastolic abnormalities on echo on performing Valsalva maneuver. E/A ratio > 2.GRADE IV – Fixed Restrictive Diastolic Dysfunction No reversibility of echo abnormalities. E/A ratio > 2
Trans-mitral valve spectral Doppler flow patternin a normal subject (upper panel), in a patientwith milddiastolic dysfunction (abnormal relaxation;middle panel),and in a patient with severe (restrictive) diastolicdysfunction (lower panel)
TISSUE DOPPLER ECHO In standard echo , high velocity low amplitude filter looks at blood flow through valves . TDI applies high velocity low amplitude filter to myocardium thus looking at myocardial tissue velocities. Results independent of pre load. Subtle systolic and diastolic dysfunction can be defined.
INTRAVENOUS CONTRAST ECHO Non invasive means of assessing integrity of the coronary microcirculation and myocardial perfusion. Relies on resonance of microbubble contrast agents when excited by diagnostic usg freq. producing increased backscatter from blood.
Contrast echocardiographic sequence with microbubble contrast agentdefining myocardial perfusion withindifferent myocardial segmentsFrame i) is immediately following a high power ultrasound flash which destroysthe micro-bubbles within the myocardium. Frames ii)–iv) show replenishmentofmicro-bubbles in the septum and lateral walls within 2 heartbeats. A clear
TreatmentGLYCAEMIC CONTROLLIFESTYLE MODIFICATIONβ BLOCKERS Chronic stimulation of SNS inc. heart rate and altered gene expression cardiac remodelling in both HF and diabetes. Traditionally β blockers were not used ( insulin resistance and hypoglycemia unawareness).
But with recent advances in understanding of heart failure and importance of SNS, β blockers have become essential in treatment of HF. COPERNICUS(Carvedilol Prospective Randomized Cumulative Survival) study 67% reduction in morbidity and mortality in HF patients treated with carvedilol.
ACE INHIBITORS HOPE( Heart Outcomes Prevention Evaluation) study Decreased cardiovascular morbidity and mortality in diabetic patients. 33% reduction in rate of development of new HF. ARBs – additive effects on hemodynamic measurements, neurohormonal activity and LV remodelling with ACE ≠.
Cardiovascular morbidity and mortality in the HOPE study, illustrating a greater benefit in the diabetic patients ALL PATIENTS DIABETIC PATIENTSDeath from 26% 37%cardiovascular causesMI 20% 22%Stroke 32% 33%All- cause mortality 16% 24%Revascularisation 15% 17%
STATINS Direct effect on cholesterol metabolism. Augments collateral blood flow downstream of activated plaques. Enhances endothelial cell NO synthase activity. Prevents upregulation of VEGF mRNA. Prevents AGE related damage.
Newer therapeutic directions PARP inhibitors[poly(ADP-ribose) polymerase 1] Functions as DNA-nick-sensor enzyme. Hyperglycemia overproduction of mitochondrial superoxideDNA strand breaksactivation of PARPinhibits GAPDHaccumulation of glycolytic intermediatesactivate major transducers of hyperglycemic damage(AGE formation and PKC pathway). PARP inhibitors block all those pathways. Trials are going on.