Investigating the heart of the matter

The risk of Ischemic Heart Disease (IHD) is two to four times greater in diabetics and particularly higher in women with diabetes, Coronary Heart Disease (CHD) occurs at a younger age and women are affected as often as men.

In the Multiple Risk Factor Intervention Trial (MRFIT) the age-adjusted incidence of CHD was four times greater in people with diabetes than in those without diabetes. And the cardiac mortality in diabetics approached 70%.

Epidemiologically the risk of CHD is increased in patients with poor glucose control. In a study from Kuopio, Finland, the incidence of CHD mortality and events increased with each tertile of HbAIC (glycosylated haemoglobin) in elderly men with type 2 diabetes. The most important single risk factor associated with CHD death was the level of HbAIC. This was present after adjusting for sex, history of previous myocardial infarction (MI), current smoking, waist to hip ratio, systolic blood pressure high density lipoprotein cholesterol (HDL-C) and the duration of diabetes.

In the Framingham Heart Study, HbAIC was related to the development of cardiovascular disease (CVD) among older women but not men.

In this study heart failure (HF) was twice as common in diabetic men and five times more common in diabetic women compared to nondiabetic subjects.

In a study of a healthcare organisation of around 10,000 type 1 diabetic subjects, 12% initially had heart failure and the remainder developed HF at a rate of 3.3% a year. Conservatively, the prevalence of diabetes in HF patients is between 30-40%. HF has also been shown to be an independent risk factor for the development of diabetes. In the UKPDS (UK Prospective Diabetes Study) the prevalence of HF was proportional to the level of HbAIC.

The prognosis for patients with diabetes and HF is worse than that for nondiabetic HF patients.

In the Studies of Left Ventricular Dysfunction (SOLVD) and Randomized Evaluation for Strategies of Left Ventricular Dysfunction (RESOLVD), the presence of diabetes was an independent risk factor for mortality.

Mechanism of CVD in Diabetes Mellitus

There are many potential mechanisms for increased CV damage in diabetes including:

1. Hypertension
2. Abnormal clotting function due to changes in fibrinolysis, platelet adherence and plasminogen activation
3. Abnormal vascular reactivity
4. Abnormal lipid patterns and particles

A reduction of blood pressure has proven to be a major benefit. It decreases the risk of suffering a major cardiovascular event such as MI or stroke as has been shown in Hypertension Optimal Therapy (HOT) and UKPDS. The optimal blood pressure (BP) for diabetic patients appears to be <130/85 and <120/75 in patients with albuminuria, has been shown to be effective in lowering cardiac events in the UKPDS and HOT studies. The lowering of cholesterol reduces the risk of MI in patients with Diabetes Mellitus (DM) to an even greater extent than in nondiabetic individuals.

The American Diabetes Association (ADA) recommends a low LDL-C to <100mg/dl in diabetic patients. Etiology of heart failure in Diabetes Mellitus Diabetes Mellitus is clearly associated with an increased prevalence of HF and the probable reasons for this are the co-existence of hypertension, myocardial ischemia and specific diabetic cardiomyopathy (DC) known as cardiotoxic triad, which causes biochemical, physiological and anatomical alterations in cardiac tissue leading to cardiac dysfunction. Diabetic cardiomyopathy DC is characterised by myocellular hypertrophy and  myocardial fibrosis, which leads to diastolic dysfunction. Diastolic dysfunction is present in 50-60% of type 2 DM and has microalbuminuria. Diastolic dysfunction is related to HbAIC levels and the most likely reason for this is the accumulation of Advanced Glycosylation End Products in the myocardium. Lipotoxicity due to the accumulation of Free Fatty Acids and their oxidative products in the myocardium may also be a factor.

Hypertension can further damage myocardial contractility proteins and increase myocardial fibrosis-resulting in a hypertrophic state which gives mild diastolic and later systolic dysfunction. The addition of myocardial ischemia to Diabetic Cardiomyopathy and hypertension results into a severely dysfunctional myocardium, which can
result in terminal HF. Worsening of HF can occur if papillary muscle fibrosis causes insufficiency of the mitral valve, which adds a mechanical burden to the already dysfunctional myocardium.

When a patient with diabetes presents with HF, evaluation for Coronary Artery Disease (CAD) is essential because re-vascularisation can significantly improve myocardial function. Diabetic Cardiomyopathy shows the same biochemical and molecular abnormalities in the myocardium that  occur with haemodynamic overload. In addition, hyperglycemia has been shown to activate Protein Kinase C and other mitogenic factors. Activation of these pathways leads to decreased myocardial performance, which leads to activation of the Renin- Angiotensin (RAS) and Sympathetic Systemic (SNS). This is initially a protective mechanism but sustained stimulation of the RAS and SNS leads to progressive loss of cardiac myocytes because of myocardial apoptosis and necrosis leading to further dysfunction and eventually failure.

ADA has set forth a consensus statement on the diagnosis of CAD and DM. Indications for cardiac testing in patients with diabetes testing is warranted in patients with the

1. Typical or atypical cardiac
2. Resting ECG suggestive of
ischemia or infarction
3. Peripheral or Carotid
Occlusive Arterial Disease
4. Sedentary lifestyle, age
>35 and plans to begin a
vigorous exercise programme
5. Two or more of the risk
factors listed below in addition to diabetes

a. Total cholesterol >240mg/dl, LDL-C >160mg/dl or HDL-C <35mg/dl b. BP >140/90
c. Smoking
d. Family history of premature CAD
e. Positive micro/macro albuminuria test

Early detection of heart failure

According to the American College of Cardiology (ACC) and American Heart Association (AHA) HF Guidelines, diabetes is a risk factor for heart failure. Older age, longer duration of diabetes, insulin utilisation and obesity are also risk factors for HF. The major risk factor forcongestive HF in diabetic patients is hypertension, which occurs in 75% of type 2 DM. Therefore awareness of these risk factors should alert prudent physicians to the

possibility that HF is present in their diabetic patients and prompt them to look for symptoms and signs of HF. Unfortunately many patients with HF do not have symptoms
and signs of HF because of inactivity. A simple in office exercise tolerance test, either walking the patient or performing a graded exercise test, can be very revealing.
Screening of patients suspected of having HF with plasma Brain Naturetic Peptide (BNP) has a sensitivity of 92% and specificity of 72% for HF. 2-D Echo and Pulsed Doppler Echocardiography,is needed to visualise the structural and functional changes in HF in diabetic patients before initiating treatment of HF. Treatment

Treatment of hyperglycemia should theoretically reduce cardiac events. Based on pathophysiological, epidemiological and clinical observations, glycemic control
should be considered as part of a comprehensive management strategy for HF in diabetic patients. With hyperglycemia and the inability of glucose to enter the myocardiocytes due to hypo insulinemia, the myocardium shifts to utilisation of FFA which promotes and increases myocardial work load and ischemia. Increased FFA which occurs with hyperglycemia and insulin resistance may increase sympathetic activity and myocardial calcium levels. And it may be cardiotoxic and arrhythmogenic.

Some but not all sulfanylureas block energy sensitive potassium channels in the myocardium and coronary arteries and can with acute ischemia worsen the extent of cardiac event.

Melformin was the most beneficial treatment for obese patients in the UKPDS, producing a substantial decrease in cardiac events and mortality.

Thiazolinidiones (TZDs)
Have not been part of long-term trials focused on CVD. TZDs increase  LDL-C, but the LDL-C particle is increased in size to a potentially less atheromatous particle. Furthermore, TZD increases HDL-C levels and the larger more cardio protective HDL-2 levels and decreases triglyceride levels. With each 1% reduction in LDL-C there is 1% reduction in cardiac events, but with each 1% increase in HDL-C there is 3% decrease in cardiac events. TZDs appear to improve endothelial function and reduce vascular smooth muscle cell proliferation and migration, and this may reduce atheroma formation. TZDs decrease myocardial FFA levels and reversed FFAinduced myocardial apoptosis. However, there is some concern regarding TZD use in patients with a high risk for HF because of the potential of the drugs to induce

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