This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.”

The most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic β-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.1 2 Insulin secretion declines with advancing age,3 4 and this decline may be accelerated by genetic factors.5 6 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.7 8 The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)9 even when they do not have overt diabetes mellitus.10 The metabolic syndrome commonly precedes the development of type 2 diabetes by many years11 ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk.

Recently, new criteria have been accepted for the diagnosis of diabetes.9 The upper threshold of fasting plasma glucose for the …

https://cdr.lib.unc.edu/downloads/m900nw482

Diabetes and cardiovascular disease : A statement for healthcare professionals from the American heart association

There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the β-oxidation of long-chain fatty acids. The control of fatty acid β-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via β-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and β-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid β-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid β-oxidation and how alterations in fatty acid β-oxidation can contribute to heart disease. The implications of inhibiting fatty acid β-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.

Myocardial Fatty Acid Metabolism in Health and Disease

Impedance cardiography was introduced over 20 years ago as a noninvasive and unobtrusive technique for measuring systolic time intervals and cardiac output. Although our understanding of the physiological events reflected in the impedance cardiogram has become more refined, the technique's theoretical basis remains somewhat controversial and acceptance of its validity has relied heavily upon empirical validation. Largely as a consequence of this status, there have been inadequate grounds on which to develop sound methodological standardization. Currently, the methodological approaches that have been most frequently adopted may be viewed as representing the standard. The various aspects of impedance methodology are discussed, and alternative approaches described, with the objective of providing an informed basis for choosing among these methodological alternatives. It is recommended that studies utilizing impedance cardiography should be reported with clear and detailed methodological description. This should help clarify the extent to which methodological differences may underlie any discrepant research observations, as well as facilitate the emergence of improved methodological standards.

Methodological Guidelines for Impedance Cardiography

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.

Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases

Echocardiographic assessment of right ventricular function remains difficult and challenging. However, there is considerable clinical need for a simple, reproducible, and reliable parameter of right ventricular function in patients with right-sided heart disease. The purpose of this study was to assess the clinical value of a Doppler-derived index, combining systolic and diastolic intervals of the right cycle, in assessing global right ventricular function in patients with primary pulmonary hypertension. The study population comprised 26 consecutive patients with primary pulmonary hypertension and 37 age-matched normal subjects. The sum of right ventricular isovolumetric contraction time and isovolumetric relaxation time was obtained by subtracting right ventricular ejection time from the interval between cessation and onset of the tricuspid inflow velocities with pulsed-wave Doppler echocardiography. An index of combined right ventricular systolic and diastolic function was obtained by dividing the sum of both isovolumetric intervals by ejection time. The index was compared with available parameters of systolic or diastolic function, clinical symptoms, and survival. Right ventricular isovolumetric contraction time and isovolumetric relaxation time were prolonged significantly in patients with primary pulmonary hypertension (85 ± 41 msec and 135 ± 43 msec) compared with normal subjects (38 ± 7 msec and 49 ± 9 msec, respectively; p p p

Doppler echocardiographic index for assessment of global right ventricular function

Recent epidemiologic studies have suggested that cardiac disease in common in diabetics and may often have a noncoronary basis. To examine the status of the left ventricle, 17 adult-onset diabetics of familial type without hypertension or obesity underwent hemodynamic study and were compared to 9 controls of similar age.

Of the 17, 12 subjects had no significant occlusive lesions by coronary angiography. From this group eight without heart failure had a modest, but significant, elevation of left ventricular end-diastolic pressure. End-diastolic and stroke volumes were reduced, but ejection fraction and mean rate of fiber shortening were within normal limits. The left ventricular end-diastolic pressure/volume ratio was significantly higher than controls. Afterload increments effected a significant increase of filling pressure compared to normals without a stroke volume response, consistent with a preclinical cardiomyopathy. Four patients with prior heart failure had similar but more extensive abnormalities. None had local dyskinesia by angiography, and lactate production was not observed during pacing-induced tachycardia. Left ventricular biopsy in two patients without ventricular decompensation showed interstitial collagen deposition with relatively normal muscle cells. These findings suggest a myopathic process without ischemia.

Postmortem studies were performed in 11 uncomplicated diabetics. Nine were without significant obstructive disease of the proximal coronary arteries, and the majority succumbed with cardiac failure. On left ventricular sections, none had evident luminal narrowing of the intramural vessels. All nine exhibited periodic acid-Schiff-positive material in the interstitium. Collagen accumulation was present in perivascular loci, between myofibers, or as replacement fibrosis. Multiple samples of left ventricle and septum revealed enhanced triglyceride and cholesterol concentrations, as compared to controls. Thus, a diffuse extravascular abnormality may be a basis for cardiomyopathic features in diabetes.

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Evidence for Cardiomyopathy in Familial Diabetes Mellitus

Previous studies relating systolic time intervals and measures of cardiac performance have suggested that the time intervals may be useful indices of myocardial contractility. To explore this possibility, systolic times and left ventricular (LV) performance and contractility were measured nearly simultaneously in 14 normal subjects and 56 patients with cardiac disease. Preejection period (PEP) and the ratio of PEP to LV ejection time (LVET) changed significantly with acute inotropic influences (exercise and isoproterenol), were normal in patients with right or left ventricular overloads in whom cardiac index and ejection fraction were depressed but contractile element velocity at peak dP/dt and the Frank-Levinson contractility index were normal, and were significantly abnormal in patients with either clinically evident or occult LV decompensation in whom the measures of contractility were reduced. Correlations of PEP and PEP/LVET with measures of both performance and contractility were insignificant for p...

Systolic time intervals as measures of the contractile state of the left ventricular myocardium in man.

Depression of myocardial contractility after ethanol ingestion in man has previously been shown only in patients with heart disease. In the present study, normal subjects, aged 23-30 years, ingested six ounces of 43% alcohol over a two hour period (Group I, 6 subjects) or a one hour period (Group II, 5 subjects). Systolic time intervals were measured every 15 min from simultaneous ECG, phonocardiogram and carotid pulse tracings. Heart rate, total electromechanical systole and left ventricular ejection time (LVET) were not changed at any time from pre-alcohol values and, except for a small (5 mm Hg) and transient change in diastolic pressure in Group II, aortic pressures also were unchanged. However, in Group I, after 60 min, at a blood ethanol of 74 ± 3 mg%, left ventricular depression was manifested by increased pre-ejection period (PEP) from 90 ± 2 to 96 ± 3.1 msec, isovolumic time (IVT) from 44 ± 3.5 to 52 ± 4 (P < .01), and PEP/LVET ratio from 0.299 ± 0.009 to 0.323 ± 0.01 (P < .05). Further depressio...

Depression of myocardial contractility with low doses of ethanol in normal man.

Previous studies of the effect of angiotensin on myocardial contractility have yielded conflicting results. Possible reasons for the observed disparities include differences in techniques for measuring contractility, in species (dog, cat, and man), in myocardial state (normal or diseased), in preparation observed (heart-lung, isolated heart, papillary muscle, atrial myocardium, intact heart), and in dosage schedule. Moreover, there are no reported studies in the intact human heart, normal or diseased, in which contractility measurements are based on velocity-force relations. To resolve the conflict, left ventricular myocardial contractility was measured using the same expressions for the force-velocity relationship in all subjects. Studies were performed in five normal human subjects, six patients with cardiomyopathy, eight normal mongrel dogs, and six dogs with ischemic myocardial scarring, before and during angiotensin infusions in dosages producing 15--20-mm Hg increases of aortic diastolic pressure. Contractile element velocity at peak, dP/dt (Vce) and the Frank-Levinson contractility index (CyIx), which normalizes Vce for diastolic fiber length, decreased during angiotensin infusion in all groups. The mean decreases (11 to 19) per cent in Vce, 15 to 23 per cent in CyIx, SEM's 4-5 per cent) were significant (P values ranging from smaller than 0.05 to smaller 0.005) in the normal hearts of dogs and man and in the scarred canine hearts, in which preangiotensin Vce and CyIx were normal. In the cardiomyopathy group, in which contractility was depressed before angiotensin, the drug elicited a further decrease in Vce (mean fall 17 plus or minus 7 per cent, P smaller than 0.1) and CyIx (26 plus or minus 8 per cent, P smaller than 0.02). We conclude that, in the intact organism, with a normal myocardium or a diffuse or segmental myocardial disease, the administration of angiotensin results in a depression of contractility.

Gilbert E. Levinson

Papers

Evidence for Cardiomyopathy in Familial Diabetes Mellitus

Systolic time intervals as measures of the contractile state of the left ventricular myocardium in man.

Depression of myocardial contractility with low doses of ethanol in normal man.

The effect of angiotensin on myocardial contractility.

Cardiomyopathy and regional scar in diabetes mellitus.