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Myocardial Perfusion and Contractile Function in Diabetes Mellitus

Mette Marie Madsen 

Summary

The prevalence of diabetes mellitus – especially type 2 diabetes – is increasing dramatically worldwide and concurrently, the frequency of diabetes-related cardiac diseases. Components responsible for development of diabetic cardiovascular disease seem to comprise endothelial dysfunction, ongoing systemic inflammation, pro-thrombotic dysbalance, functional and structural changes in the myocardial tissue and blood supply, diabetic nephropathy, and autonomic neuropathy. Even at a very early state of diabetes, cardiovascular changes such as reduced hyperaemic response to pharmacologically induced myocardial vasodilation as well as diastolic and systolic dysfunction of the left ventricle can be observed. The mechanisms behind these changes are unclear. Furthermore, when cardiovascular disease is established concomitant diabetes mellitus is associated with a substantially worse prognosis.

The aims of this PhD thesis were:
To evaluate potential abnormalities in the regulating mechanisms of myocardial perfusion in type 2 diabetic patients without signs of cardiovascular disease. This included assessment of myocardial perfusion with positron emission tomography and [13N]ammonia 1) during rest, 2) during adenosine-induced maximal myocardial hyperaemia, and 3) during maximal myocardial hyperaemia combined with systemic blockade of a-receptors. Measurements were obtained at 2 different days in randomised order: One day with and one day without systemic inhibition of endogenous nitric oxide synthase (with L-NAME) and thereby of endothelial-dependent vasodilation.

To evaluate diastolic and systolic function of the left ventricle including performance of the longitudinal myocardial fibres at rest and during adenosine-induced maximal myocardial hyperaemia in type 2 diabetic patients compared to healthy control subjects (subgroups from study 1). Left ventricular function was assessed with conventional echocardiography and tissue Doppler imaging. The systolic function of the left ventricular function was correlated to myocardial perfusion.

To evaluate 3 years clinical outcome in diabetic patients with ST-segment elevation myocardial infarction (STEMI) randomised to primary angioplasty or fibrinolysis. Subgroup analyses of results from the DANAMI-2 database were done in patients with and without diabetes.

Study 1 showed that type 2 diabetic patients had a reduced hyperaemic myocardial perfusion compared to healthy control subjects. Endothelial and cardiac autonomic nerve function seemed to play a minimal role in the reduced hyperaemic myocardial perfusion. The well-known linear correlation between resting perfusion and cardiac work (reflected by rate-pressure product) in healthy subjects appeared to be abolished in type 2 diabetes and during NO-synthase inhibition.
Study 2 showed that type 2 diabetic patients had a reduced diastolic function and impaired function of the longitudinal myocardial muscle layers at rest. Maximal myocardial hyperaemia induced increase in contractility of the longitudinal muscle fibres in both groups while the diastolic function and global ejection fraction increased in the control subjects only. A significant positive correlation was found between myocardial perfusion and performance of the longitudinal fibres at rest and during hyperaemia in the diabetic patients while this correlation was found to be negative in the control group.
The results from study 3 showed that non-diabetic patients randomised to primary angioplasty had a highly significant reduction in reinfarction rate compared to non-diabetic patients randomised to fibrinolysis. In contrast, diabetic patients had an increased reinfarction rate when randomised to primary angioplasty compared to fibrinolysis.

From these results it can be concluded that

  1. Endothelial and cardiac autonomic nerve function seems to play only a minimal role in the reduced hyperaemic myocardial perfusion in type 2 diabetic patients.
  2. The correlation between cardiac work and myocardial perfusion found in healthy control subjects seem to be disturbed by systemic NO synthase inhibition and in the type 2 diabetic state.
  3. Type 2 diabetic patients are unable to improve their impaired diastolic function and LVEF in response to myocardial hyperaemia while performance of the longitudinal myocardial layers increases.
  4. The longitudinal myocardial layers in type 2 diabetic patients show a clear dependency of global myocardial perfusion while the longitudinal function in healthy middle-aged control subjects seems much less prone to changes in myocardial perfusion.
  5. Diabetes mellitus may minimise or even abolish the beneficial effect of primary coronary angioplasty compared to fibrinolysis on the risk of clinical reinfarction after acute ST-segment elevation myocardial infarction.