Effects of oral amino acid supplements on cardiac function and remodeling in patients with type 2 diabetes with mild-to-moderate left ventricular dysfunction.

The aim of this study was to evaluate the effects of an oral special mixture of amino acid (AA) supplements alongside angiotensin-converting enzyme (ACE) inhibitor therapy on left ventricular (LV) function and symptoms in patients with type 2 diabetes mellitus with mild-to-moderate LV dysfunction. It is established that the remodeling process is associated with late onset of heart failure and decreased survival. ACE inhibitor therapy reduces progressive increases in LV dimensions and significantly improves the clinical course of a broad spectrum of patients with LV dysfunction. Moreover, AA supplements prevent myocardial dysfunction caused by exercise in patients with type 2 diabetes. In addition to ACE inhibitor therapy, patients with diabetes were randomly assigned to receive AA supplements or placebo. LV function and dimensions were assessed with quantitative echocardiographic tests at intake into the study and after 6 months of follow-up. In patients with type 2 diabetes, LV end-diastolic index was reduced significantly during the 6-month period of AA consumption (89 +/- 9 mL/m2 vs 76 +/- 8 mL/m2; p <0.01), and LV ejection fraction (LVEF) improved (0.46 +/- 0.07 vs 0.52 +/- 0.05; p <0.001). No significant changes in LVEF or LV end-diastolic index occurred in the placebo group. These findings suggest that AA supplementation, together with ACE-inhibitor therapy, may have a beneficial effect on the LV remodeling process in patients with type 2 diabetes with mild-to-moderate LV dysfunction.

Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients.

OBJECTIVE: Postprandial glycemia is an independent risk factor for cardiovascular disease that is more powerful than fasting glycemia and determines myocardial perfusion defects in type 2 diabetes. We examined the efficacy of two different insulin regimes (regular insulin and insulin analog) in controlling postprandial hyperglycemia and in preventing myocardial perfusion abnormalities. RESEARCH DESIGN AND METHODS: A total of 20 consecutive type 2 diabetic patients and 20 control subjects were enrolled in this randomized, three-way, cross-over, placebo-controlled study. Myocardial perfusion was assessed by myocardial contrast echocardiography (MCE) in fasting and postprandial (120 min) state. RESULTS: Insulin analog was associated with lower, but not statistically significant, postprandial glycemia than regular insulin (glucose increase: 116 +/- 8 vs. 136 +/- 5%, P = NS). However, the area under the curve following insulin analog was significantly lower than regular insulin (18,354 +/- 702 vs. 20,757 +/- 738 mg per 120 min, P = 0.032). Fasting myocardial flow velocity (beta), myocardial blood volume (MBV), and myocardial blood flow (MBF) did not differ between control and type 2 diabetic subjects. Postprandial beta (0.67 +/- 0.24 vs. 0.92 +/- 0.25, P < 0.01), MBV (8.4 +/- 2 vs. 10.9 +/- 1.2, P < 0.01), and MBF (5.6 +/- 2 vs. 9.9 +/- 2.8, P < 0.01) increased significantly in control subjects. In type 2 diabetes, during placebo in the postprandial state, beta increased (0.65 +/- 0.27 vs. 0.89 +/- 0.24, P < 0.01), while MBV (8.34 +/- 1.2 vs. 4.3 +/- 1.3, P < 0.01) and MBF (5.4 +/- 1.5 vs. 3.4 +/- 0.9, P < 0.01) decreased. Similar changes in MCE variables were observed after regular insulin: beta increased (0.65 +/- 0.22 vs. 0.92 +/- 0.12, P < 0.01) and MBV (8.2 +/- 2 vs. 5.2 +/- 1.16, P < 0.01) and MBF (5.4 +/- 1.9 vs. 4.2 +/- 0.86, P < 0.01) were reduced. After insulin analog, postprandial beta (0.66 +/- 0.18 vs. 0.9 +/- 0.18, P < 0.01), MBV (8.2 +/- 1.6 vs. 9.6 +/- 1.2, P < 0.01), and MBF (5.4 +/- 2 vs. 7.2 +/- 1.9, P < 0.01) increased. Values of postprandial MBV and MBF were higher after insulin analog than regular insulin treatment. CONCLUSIONS: Insulin analog partially reversed myocardial perfusion abnormalities observed in postprandial state by improving glucose control.

Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients.

BACKGROUND: In diabetic patients, postprandial hyperglycemia is a more powerful risk factor for cardiovascular disease than fasting hyperglycemia itself. A negative influence of acute hyperglycemia on systemic endothelial function (brachial artery) has been shown. However, myocardial perfusion during postprandial hyperglycemia has not been investigated. METHODS AND RESULTS: We evaluated the effects of a standardized mixed meal on myocardial perfusion in 20 healthy subjects and 20 consecutive patients with type 2 diabetes mellitus without macrovascular or microvascular complications. Myocardial perfusion was assessed in fasting and postprandial states by myocardial contrast echocardiography. Fasting myocardial flow velocity (beta, 0.65+/-0.27 versus 0.67+/-0.24; P=NS), myocardial blood volume (MBV; 8.3+/-1.2 versus 8.4+/-2; P=NS), and myocardial blood flow (5.4+/-1.5 versus 5.6+/-2; P=NS) did not differ between control subjects and diabetic patients. In the postprandial state, beta (0.67+/-0.24 versus 0.92+/-0.35; P<0.01), MBV (8.4+/-2 versus 10.9+/-2.7; P<0.01), and myocardial blood flow (5.6+/-2 versus 9.9+/-2.8; P<0.01) increased significantly in control subjects. In diabetic patients, beta increased (0.65+/-0.27 versus 0.8+/-0.24; P<0.01) but MBV (8.3+/-1.2 versus 4.3+/-1.3; P<0.01) and myocardial blood flow (5.4+/-1.5 versus 3.4+/-0.9; P<0.01) decreased significantly. Changes in MBV (expressed as [(MBV(postprandial)-MBV(fasting))/MBV(fasting)]x100) were significantly correlated with postprandial glycemia levels in diabetic patients. CONCLUSIONS: Postprandial hyperglycemia determines myocardial perfusion defects in type 2 diabetic patients. They are secondary to deterioration in microvascular function causing a decrease in MBV. In diabetic patients without microvascular or macrovascular complications, postprandial myocardial perfusion defects may represent an early marker of the atherogenic process in the coronary circulation; hence, its reversal constitutes a potential goal of treatment.

Long-term survival and functional results after aortic valve replacement in asymptomatic patients with chronic severe aortic regurgitation and left ventricular dysfunction.

OBJECTIVES: We examined the influence of medical treatment on the results of surgery in terms of long-term survival and functional results in patients with chronic, severe aortic regurgitation (AR). BACKGROUND: Asymptomatic patients with AR and a reduced left ventricular ejection fraction (LVEF) are at high risk because of a higher-than-expected long-term mortality. The influence of preoperative medical therapy on the outcome after aortic valve replacement (AVR) is not well known. METHODS: Surgery was indicated for the appearance of a reduced LVEF (<50%). At the time of AVR, there were 134 patients treated with nifedipine (group A), and 132 received no medication (group B). RESULTS: Operative mortality was similar in the two groups (0.75% vs. 0.76%, p = NS). The LVEF normalized in all of group A, whereas it remained abnormal in 36 group B patients (28%). At 10-year follow-up, LVEF persisted higher in group A (62 +/- 5% vs. 48 +/- 4%, p < 0.001). Five-year survival was similar in the two groups (94 +/- 2% vs. 94 +/- 3%, p = NS). Group A showed a 10-year survival not different from expected and significantly higher than that in group B (85 +/- 4% vs. 78 +/- 5%, p < 0.001), which had a worse survival than expected. CONCLUSIONS: Unloading treatment with nifedipine in AR allows one to indicate AVR at the appearance of a reduced LVEF with a low operative mortality and an optimal long-term outcome. The concept of surgical correction of AR indicated for reduced LVEF may not be applied to all patients. Indeed, in a large amount of untreated patients, a reduced LVEF preoperatively is not reversed by prompt surgery, indicating irreversible myocardial damage, and 10-year survival is worse than expected.

Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes.

In patients with diabetes and coronary artery disease, the potential negative role of sulfonylurea drugs is under intensive investigation. We assessed the effects of treatment with glibenclamide or insulin on the extension of left ventricular myocardial dysfunction induced by acute ischemia. Nineteen consecutive patients with type 2 diabetes and coronary artery disease entered the study. Each patient was randomly assigned to either insulin or glibenclamide therapy. Treatment was crossed over after 12 weeks and maintained for another 12 weeks. At the end of each treatment, left ventricular myocardial function at rest and during dipyridamole infusion was studied by two-dimensional echocardiography under the same conditions of metabolic control. Glibenclamide or insulin treatment did not influence the rest values of left ventricular dimensions, left ventricular ejection fraction (LVEF), or wall motion score index (WMSI). Dipyridamole infusion, in patients receiving glibenclamide treatment, decreased LVEF (43 +/- 7 vs. 37 +/- 12%, P < 0.005) and increased WMSI (1.4 +/- 0.28 vs. 1.98 +/- 0.24, P < 0.001) compared with baseline values; during insulin treatment, LVEF (46 +/- 8 vs. 45 +/- 11%, NS) and WMSI (1.4 +/- 0.29 vs. 1.6 +/- 0.4, NS) did not change significantly. Peak stress LVEF was higher (45 +/- 11 vs. 37 +/- 12%, P < 0.001) and WMSI lower (1.6 +/- 0.4 vs. 1.98 +/- 0.24, P < 0.001) in patients receiving insulin. The results indicate that in patients with type 2 diabetes and coronary artery disease, ischemic myocardial dysfunction induced by dipyridamole infusion is less severe during treatment with insulin than with glibenclamide. Restitution of a preconditioning mechanism in insulin-treated patients may be the potential beneficial mechanism.

Abnormal myocardial perfusion and contractile recruitment during exercise in type 1 diabetic patients.

BACKGROUND: No data are available on the relationship between myocardial perfusion and left ventricular (LV) function in type 1 diabetes mellitus (T1DM), which may constitute a factor explaining the progressive contractile dysfunction to the overt phase of diabetic cardiomyopathy. HYPOTHESIS: This study was undertaken to test whether myocardial perfusion abnormalities are present at rest and during exercise and whether they are related to contractile dysfunction in T1DM. METHODS: Twenty-two patients with T1DM, aged 32 +/- 8.3 years, without macro- or microvascular complications, and 10 controls, aged 31 +/- 3 years, were studied. Left ventricular function and myocardial perfusion were assessed by two-dimensional and myocardial contrast echocardiography at rest and during handgrip (HG). RESULTS: Fourteen patients with T1DM showed a decline in LV ejection fraction (LVEF) during HG (Group 1) while 8 had a normal response (Group 2). Both basal myocardial blood volume (MBV) and velocity (beta) were normal in T1DM. During exercise, MBV and beta increased and were associated with an increase in myocardial blood flow (MBF) in controls. In T1DM, beta did not change and MBV increased only in Group 2, while this increase was not observed in Group 1 (controls: 14.9 +/- 2.3 vs. Group 1: 7.6 +/- 1.6, p < 0.001; and vs. Group 2: 10.2 +/- 2.8, p < 0.001), beta (0.86 +/- 0.12 vs. 0.68 +/- 0.14, p < 0.001; and vs. 0.67 +/- 0.15, p < 0.001). A correlation between the ratio exercise MBF/resting MBF and LVEF at peak exercise in T1DM was observed (r = 0.805, p < 0.001). CONCLUSIONS: A large proportion of patients with T1DM exhibit abnormalities in myocardial adaptable capacity to match an acute overload, which are related to a defective increase in myocardial perfusion.

Effects of oral amino acid supplementation on myocardial function in patients with type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus is associated with an increased rate of cardiac amino acid catabolism that could interfere with cardiac function. METHODS: We assessed the effects of an oral amino acids mixture (AAM) on myocardial function in patients with type 2 diabetes mellitus (DM2). We studied 65 consecutive patients with DM2 who had normal resting left ventricular ejection fraction (LVEF) and did not have obstructive coronary artery disease (CAD). After baseline evaluations, patients were randomized to receive, in a single-blinded fashion, AAM (12 grams/day) or placebo for 12 weeks, after which, treatment was crossed over for another similar period. At baseline and at the end of each treatment, 2-dimensional ecocardiography at rest and during isometric exercise (handgrip) was performed, as were biochemical assays. Twenty adults, matched for age, sex, and body mass index served as control subjects. RESULTS: At baseline and during AAM or placebo treatment, resting left ventricular dimensions and LVEF in patients with DM2 did not differ from those of control subjects. In patients with DM2, at baseline and during placebo treatment, peak handgrip LVEF decreased significantly in comparison with the resting value (63% +/- 9% vs 56% +/- 9%, P <.001; and 62% +/- 6% vs 55% +/- 8%, P <.001). During AAM treatment, peak handgrip LVEF did not differ from resting value (66% +/- 11% vs 64% +/- 9%, P = not significant). Thus, exercise LVEF was higher during AAM treatment than both baseline and placebo treatment (66% +/- 11% vs 56% +/- 9% and vs 55% +/- 8%, P <.001). In contrast to placebo treatment, after the AAM supply, a decreased glycated hemoglobin level was observed (7.0% +/- 1.3% vs 7.6% +/- 1.8%, P <.05). CONCLUSIONS: Myocardial dysfunction is easily inducible with isometric exercise in patients with DM2 who have normal resting LV function and do not have CAD. An increased amino acid supply prevents this phenomenon and improves metabolic control.

Early myocardial dysfunction in the diabetic heart: current research and clinical applications.

Patients with diabetes mellitus have a high incidence of heart failure, which contributes significantly to their increased cardiovascular morbidity and mortality. One of the major complications of diabetes is the development of cardiomyopathy, a condition characterized by defects of contractile function in the absence of significant coronary artery disease or systemic hypertension. Experimental data in animal models show that contractile depression begins as early as 1 week after induction of diabetes, and the dysfunction is related to an isomyosin distribution shift from V(1) with high adenosine triphosphatase (ATPase) to V(3) with low ATPase activity. Moreover, diabetes is associated with an increased or poorly regulated rate of amino acid catabolism at the cardiac level. Abnormal responses to acute left ventricular (LV) overload induced by exercise (isometric or isotonic) have been demonstrated in patients with diabetes. Impaired augmentation of LV ejection fraction occurs in up to 40% of patients with diabetes. Analysis of the LV afterload-pump function (LV circumferential wall stress-ejection fraction) relationship shows that defective contractile recruitment is the main cause of this anomaly. Exercise-induced LV dysfunction may be the first manifestation of cardiac involvement in patients with diabetes. Increasing the supply of amino acids in addition to conventional therapy significantly attenuates this phenomenon. Although the precise underlying pathophysiologic mechanism is not completely known, these observations may eventually be important in designing an optimal dietary or supplemental approach for patients with diabetes in order to prevent progressive myocardial dysfunction.

Diabetic cardiomyopathy: a metabolic perspective.

Patients with diabetes mellitus have a >3-fold increased risk of coronary ischemic events and congestive heart failure. Several hypotheses have been provided to explain the increased cardiac vulnerability in individuals with diabetes; among these are the metabolic abnormalities. Diabetes is associated with profound changes in cardiac metabolism, characterized by diminished glucose utilization, diminished rates of lactate oxidation, and increased use of fatty acids. Very few investigations have focused on amino acid disturbances at the level of the heart. This area of research is potentially relevant because cardiac amino acid alterations may not only result in a reduced energy reserve but could also lead to quantitative and qualitative abnormalities of contractile protein present in the diabetic heart.

Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus.

UNLABELLED: In type 2 diabetes mellitus (DM2) patients, coronary artery disease (CAD) generally is detected in an advanced stage, whereas an asymptomatic stage is commonly missed. Abnormal myocardial perfusion during stress myocardial contrast echocardiography (MCE) and significant CAD were similar, irrespective of risk factor (RF) profile in our patients, but coronary anatomy differed. An "aggressive" diagnostic approach, requiring coronary angiography in asymptomatic DM2 patients with < or = 1 associated RF for CAD and abnormal MCE, identified silent CAD, characterized by a more favorable angiographic anatomy. The criterion of > or = 2 RFs did not help to identify patients with a higher prevalence of CAD and is only related to a more severe coronary atherosclerosis with unfavorable anatomy. OBJECTIVES: We sought to verify the effectiveness of current American Diabetes Association screening guidelines in identifying asymptomatic patients with coronary artery disease (CAD) in type 2 diabetes mellitus (DM2). BACKGROUND: In DM2 patients, CAD generally is detected in an advanced stage with an extensive atherosclerosis and poor outcome, whereas CAD in an asymptomatic stage is commonly missed. METHODS: This study included 1,899 asymptomatic DM2 patients (age < or = 60 years). Of these, 1,121 had > or = 2 associated risk factors (RFs), group A, and the remaining 778 had < or = 1 RF, group B, for CAD. All patients underwent dipyridamole myocardial contrast echocardiography (MCE), and in those with myocardial perfusion defects, the anatomy of coronary vessels was analyzed by selective coronary angiography. RESULTS: In the two study groups, the prevalence of abnormal MCE (59.4% vs. 60%, p = 0.96) and of a significant CAD (64.6% vs. 65.5%, p = 0.92) was similar, irrespective of RF profile. But coronary anatomy differed: group B had a lower prevalence of three-vessel disease (7.6% vs. 33.3%, p < 0.001), of diffuse disease (18.0% vs. 54.9%, p < 0.001), and of vessel occlusion (3.8% vs. 31.2%, p < 0.001), whereas one-vessel disease was more frequent (70.6% vs. 46.3%, p < 0.001). Coronary anatomy did not allow any revascularization procedure in 45% of group A patients. CONCLUSIONS: An "aggressive" diagnostic approach, requiring coronary angiography in asymptomatic DM2 patients with < or =1 associated RF for CAD and abnormal MCE, identified patients with a subclinical CAD characterized by a more favorable angiographic anatomy. The criterion of > or =2 RFs did not help to identify asymptomatic patients with a higher prevalence of CAD and is only related to a more severe CAD with unfavorable coronary anatomy.

Oral amino acids in elderly subjects: effect on myocardial function and walking capacity.

BACKGROUND: With advancing age the risk of developing serious nutritional deficiencies increases, and disturbances to the actions of insulin and insulin-like growth factor, coupled with reduced protein/amino acid (AA) intake, impair protein synthesis in muscles. OBJECTIVE: To assess the effects of administering oral AAs on walking capacity and perceived walking impairment, isometric muscular strength, and myocardial function at rest and during isometric exercise. METHODS: One hundred elderly subjects (aged >65 years) with reduced physical activity were randomized to receive an oral AA mixture (12 g/day) or placebo for 3 months. At baseline and after 3 months of therapy we assessed physical capacity with the 6-min walk test, and perceived physical impairment with the walking impairment questionnaire (WIQ); we assessed maximal isometric muscular strength of the right hand with a handgrip dynamometer, and left ventricular ejection fraction (LVEF) using quantitative two-dimensional echocardiography at rest and during acute overload. RESULTS: Three months of AA treatment resulted in significant increases in 6-min walk distance (268.8 +/- 34.9 vs. 212 +/- 40 m, p < 0.001), WIQ scores (distance: 68.3 +/- 12 vs. 53 +/- 14.8%, p < 0.001; speed: 72.2 +/- 14.4 vs. 52.8 +/- 12%, p < 0.001; stairs: 98.2 +/- 24 vs. 72.4 +/- 22%, p < 0.001), and in maximal muscular isometric strength (20.2 +/- 2 vs. 14 +/- 2.8 kg, p < 0.001). Moreover, peak stress LVEF was higher during AA administration when compared to placebo administration (67 +/- 7 vs. 56 +/- 9%, p < 0.01). Left ventricular response to exercise normalized during AA administration in 24 out of 32 (75%) patients with abnormal LV response at baseline, whereas it remained unchanged in the placebo group. CONCLUSION: An oral AA supply such as that used in this study improves ambulatory capacity, maximal isometric muscle strength and myocardial ability to match an acute overload in elderly subjects without affecting the main metabolic parameters. These functional gains may translate into increased perceived walking capacity.

The effects of oral amino acid intake on ambulatory capacity in elderly subjects.

BACKGROUND AND AIMS: The combination of high prevalence of inactivity in the older population, and high risk of ill-health and disability associated with inactivity, suggests that interventions that are successful in increasing levels of activity may have a great impact on population health in later life. With advancing age, the risk of developing serious nutritional deficiencies also increases. This study was designed to assess the effects of dietary amino acid supplementation on effort tolerance in healthy elderly subjects with reduced physical activity. METHODS: Forty-four subjects (age > 65 years) with sedentary life-style and lower health-related quality of life were studied. Subjects, in an open-label fashion, received an oral amino acid mixture (AAM, 12 g/day) containing essential and non-essential amino acids for a 3-month period. Ambulatory dysfunction resulting in sedentary life-style was assessed by a 6-min walk test. A walking impairment questionnaire (WIQ) was used to evaluate self-perceived ambulatory dysfunction. Maximal isometric muscular strength of the right hand was measured during isometric exercise by a handgrip dynamometer. RESULTS: The 6-min walk distance increased from 214.5 +/- 32 to 262.8 +/- 34.8 m (p < 0.001) after AAM treatment. The baseline scores on the three subscales of WIQ changed significantly during treatment: WIQ distance increased from 56.2 +/- 12.9 to 66.3 +/- 12.8% (p < 0.001); WIQ speed from 52 +/- 12.6 to 69.2 +/- 14.8% (p < 0.001) and WIQ stairs from 74.4 +/- 22.6 to 94.2 +/- 25% (p < 0.001), as did maximal isometric muscular strength (16.6 +/- 2.4 vs 19.2 +/- 2.2 kg, p < 0.001). Changes in plasma glucose (+11 +/- 11 mg/dL), total cholesterol (0 +/- 39 mg/dL), HDL cholesterol (0 +/- 17 mg/dL), and triglycerides (-11 +/- 58 mg/dL) were not significant between baseline and AAM. CONCLUSIONS: An oral amino acid supplement, as used in this pilot study, improves ambulatory capacity and maximal isometric muscle strength in elderly subjects without affecting the main metabolic parameters. Amino acid supplementation may thus represent useful non-pharmacological intervention to maintain physical fitness in these subjects.