Waist-to-height ratio and metabolic phenotype compared to the Matsuda index for the prediction of insulin resistance.

Current screening algorithms for type 2 diabetes (T2D) rely on fasting plasma glucose (FPG) and/or HbA1c. This fails to identify a sizeable subgroup of individuals in early stages of metabolic dysregulation who are at high risk for developing diabetes or cardiovascular disease. The Matsuda index, a combination of parameters derived from a fasting and postprandial insulin assay, is an early biomarker for metabolic dysregulation (i.e. insulin resistance/compensatory hyperinsulinemia). The aim of this analysis was to compare four widely available anthropometric and biochemical markers indicative of this condition [waist-to-height ratio (WHtR), hypertriglyceridemic-waist phenotype (HTW), triglycerides-to-HDL-C ratio (TG/HDL-C) and FPG] to the Matsuda index. This cross-sectional analysis included 2231 individuals with normal fasting glucose (NFG, n = 1333), impaired fasting glucose (IFG, n = 599) and T2D (n = 299) from an outpatient diabetes clinic in Germany and thus extended a prior analysis from our group done on the first two subgroups. We analyzed correlations of the Matsuda index with WHtR, HTW, TG/HDL-C and FPG and their predictive accuracies by correlation and logistic regression analyses and receiver operating characteristics. In the entire group and in NFG, IFG and T2D, the best associations were observed between the Matsuda index and the WHtR (r = - 0.458), followed by HTW phenotype (r = - 0.438). As for prediction accuracy, WHtR was superior to HTW, TG/HDL-C and FPG in the entire group (AUC 0.801) and NFG, IFG and T2D. A multivariable risk score for the prediction of insulin resistance was tested and demonstrated an area under the ROC curve of 0.765 for WHtR and its interaction with sex as predictor controlled by age and sex. The predictive power increased to 0.845 when FPG and TG/HDL-C were included. Using as a comparator the Matsuda index, WHtR, compared to HTW, TG/HDL-C and FPG, showed the best predictive value for detecting metabolic dysregulation. We conclude that WHtR, a widely available anthropometric index, could refine phenotypic screening for insulin resistance/hyperinsulinemia. This may ameliorate early identification of individuals who are candidates for appropriate therapeutic interventions aimed at addressing the twin epidemic of metabolic and cardiovascular disease in settings where more extended testing such as insulin assays are not feasible.

Impact of the Triglyceride/High-Density Lipoprotein Cholesterol Ratio and the Hypertriglyceremic-Waist Phenotype to Predict the Metabolic Syndrome and Insulin Resistance.

Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations.

Dietary therapy in heart failure with preserved ejection fraction and/or left ventricular diastolic dysfunction in patients with metabolic syndrome.

BACKGROUND: Heart failure is an ongoing epidemic of left ventricular (LV) dilatation and/or dysfunction due to the increasing prevalence of predisposing risk factors such as age, physical inactivity, (abdominal) obesity, and type-2-diabetes. Approximately half of these patients have diastolic heart failure (HFpEF). The prognosis of HFpEF is comparable to that of systolic heart failure, but without any known effective treatment. DIASTOLIC DYSFUNCTION: A biomathematically corrected diagnostic approach is presented that quantifies diastolic dysfunction via the predominant age dependency of LV diastolic function and unmasks (metabolic) risk factors, that are independent of age and, therefore, potential targets for therapy. Patients with HFpEF have reduced cardiac energy reserve that is frequently caused by insulin resistance. Consequently, HFpEF and/or LV diastolic dysfunction may be regarded as a cardiac manifestation of the metabolic syndrome (MetS). DIETARY THERAPY: Accordingly, a causal therapy for metabolically induced dysfunction aims at normalizing insulin sensitivity by improving postprandial glucose and lipid metabolism. The respective treatments include 1) weight loss induced by dietary energy restriction that is often not sustained long-term and 2) independent of weight loss, focus on carbohydrate modification in exchange for an increase in protein and fat, ideally combined with an aerobic exercise program. Hence, beneficial effects of different macronutrient compositions in the dietary therapy of the underlying MetS are discussed together with the most recently available publications and meta-analyses. CONCLUSION: Modulation/restriction of carbohydrate intake normalizes postprandial hyperglycemic and insulinemic peaks and has been shown to improve all manifestations of the MetS and also to reduce cardiovascular risk.

Cardiometabolic Syndrome and Increased Risk of Heart Failure.

Approximately 50 % of patients with heart failure have diastolic heart failure (HFPEF) with the major predisposing risk factors age, inactivity, obesity, insulin resistance (IR), type-2 diabetes, and hypertension. The prognosis of HFPEF is comparable to that of systolic heart failure, but without any specific or effective treatment. This review presents a biomathematically corrected diagnostic approach for quantification of diastolic dysfunction (DD) via the age dependency of diastolic function. Pathophysiological mechanisms for DD in the cardiometabolic syndrome (CMS) are mainly based on downstream effects of IR including insufficient myocardial energy supply. The second section discusses therapeutic strategies for the control and therapy of CMS, IR, and the associated DD/HFPEF with a focus on dietary therapy that is independent of weight loss but improves all manifestations of the CMS and reduces cardiovascular risk.

Effects of analogue insulin in multiple daily injection therapy of type 2 diabetes on postprandial glucose control and cardiac function compared to human insulin: a randomized controlled long-term study.

BACKGROUND: The prevention of cardiovascular disease, including diastolic cardiac dysfunction with its high prevalence and ominous prognosis, is a therapeutic challenge for patients with type 2 diabetes. Both short and long-acting insulin analogues (AI) have been shown to reduce glucose variability and provide potential benefit for cardiovascular disease although the effects on cardiac function have not yet been evaluated. This long-term, prospective, randomized controlled trial in patients with type 2 diabetes (T2D) tested the hypothesis that a multiple daily injection regimen (MDI) with AI improves postmeal glucose excursions in comparison to human insulin (HI) and that the effects of AI improve diastolic cardiac function. METHODS: For 36 months, MDI treatment in 109 T2D patients was adapted every 3 months (targets: fasting glucose ≤ 110 mg/dl, postmeal glucose ≤ 150 mg/dl) in both groups: AI (insulin detemir and insulin aspart, n = 61) and HI (NPH-insulin and regular HI, n = 48). Diastolic cardiac function (myocardial velocity E' using tissue Doppler imaging and the mitral inflow ratio E/A) and vascular function were assessed before and 2 h after a standardized breakfast (48 g carbohydrates). At baseline, both groups were comparable with regards to demographic, cardiac and metabolic data. Analysis of data included traditional statistics as well as the use of a multiple imputation technique shown in brackets [ ]. RESULTS: At 36 months, the primary endpoint, postmeal glucose, decreased by 20 ± 62 mg/dl, p = 0.038 [p = 0.021] with AI and increased insignificantly with HI (inter-group p = 0.032 [p = 0.047]) to postmeal glucose levels of 161 ± 39 with AI vs. 195 ± 54 mg/dl with HI (inter-group p = 0.002 [p = 0.010]) whereas the levels of fasting glucose and HbA1c were comparable. With AI, postmeal E' improved by 0.6 ± 1.4 cm/s, p = 0.009 [p = 0.002] and fasting E' by 0.4 ± 1.4 cm/s, p = 0.069 [p = 0.013], however, E' remained unchanged with HI. These changes were consistent with those of the traditional parameter E/A. CONCLUSIONS: MDI with AI results in better postmeal glucose control compared to HI. The treatment with AI is associated with improved diastolic cardiac function. ClinicalTrials.gov (NTC00747409).

[Diastolic heart failure treated by diet]. / Diastolische Herzinsuffizienz bei Typ-2-Diabetes--diätetisch therapiert.

History and admission findings | An obese patient with type 2 diabetes (on 90 IU insulin daily) and exertional dyspnoea (NYHA II-III) for 3 weeks presented in a rehabilitation clinic hoping to reduce his weight. Clinical and laboratory findings excluded any inflammatory or systemic disease apart from diabetes mellitus. Blood pressure and serum lipid levels were normal. Investigations | An unremarkable ECG stress test and echocardiogram excluded ischemic and hypertensive heart disease and primary cardiomyopathy. Pulsed tissue Doppler revealed diastolic cardiac dysfunction. Unremarkable were also chest X-ray, pulmonary function testing and 24-hour ECG. Treatment and Course | The findings supported the diagnosis of HFpEF and diabetic/insulin resistance cardiomyopathy. Insulin resistance was treated for three weeks by low-carbohydrate nutrition and moderate exercise. At discharge, weight was reduced by 2 kg, exercise capacity and diastolic function were normalized, as were insulin resistance and postprandial glucose levels, whilst antidiabetic therapy was reduced to low-carbohydrate nutrition. Conclusion | HFpEF due to insulin resistance cardiomyopathy is often not recognized, especially in obese individuals, and may be further aggravated by the traditional recommendation of low-fat nutrition. Due to the high reversibility of metabolically dysregulated cardiovascular mechanisms, a causal, i.e. metabolic therapeutic strategy that normalizes insulin resistance by low-carbohydrate nutrition is a promising option.

L-Arginine and vascular health. / Bedeutung von L-Arginin für die Gefäßgesundheit.

Endothelial dysfunction, characterized by a disturbed vascular NO metabolism, represents a key point in atherogenesis. Modern antiatherogenic therapies improve NO availability within the endothelium. As L-arginine acts as the substrate of endothelial nitric oxide synthase (eNOS), arginine supplementation can enhance NO formation. Actually, L-arginine at appropriate dosage (6­8 g/day) improves endothelial function and lowers blood pressure. However, beneficial effects can only be expected in individuals with pronounced endothelial dysfunction and/or individuals with an absolute (patients with hemodialysis) or relative (patients with elevated ADMA levels) arginine deficiency. Whether L-arginine delays progression of atherosclerotic lesions and lowers cardiovascular morbidity and mortality is unknown.

Impact of diabetes on postinfarction heart failure and left ventricular remodeling.

Diabetes mellitus, the metabolic syndrome, and the underlying insulin resistance are increasingly associated with diastolic dysfunction and reduced stress tolerance. The poor prognosis associated with heart failure in patients with diabetes after myocardial infarction is likely attributable to many factors, important among which is the metabolic impact from insulin resistance and hyperglycemia on the regulation of microvascular perfusion and energy generation in the cardiac myocyte. This review summarizes epidemiologic, pathophysiologic, diagnostic, and therapeutic data related to diabetes and heart failure in acute myocardial infarction and discusses novel perceptions and strategies that hold promise for the future and deserve further investigation.

Rosiglitazone, but not glimepiride, improves myocardial diastolic function in association with reduction in oxidative stress in type 2 diabetic patients without overt heart disease.

The effects of thiazolidinediones on cardiac function are controversial in humans with type 2 diabetes (T2DM) and in animals. Given the high prevalence and prognostic relevance of diastolic myocardial dysfunction in T2DM, we tested the hypothesis that by reducing oxidative stress rosiglitazone, but not glimepiride, may improve diastolic function. This randomised cross-over study investigated 12 metformin-treated T2DM patients without cardiovascular disease before and after 16 weeks of additional therapy with rosiglitazone (8 mg daily) or glimepiride (3 mg daily). Systolic and diastolic myocardial velocity (E') were assessed with tissue Doppler. In spite of similar non-significant lowering of glycosylated haemoglobin (HbA1C), rosiglitazone, but not glimepiride, significantly improved E' (p=0.04), reduced malondialdehyde (p=0.028), lowered high-sensitivity C-reactive protein (hsCRP) (p=0.019), and increased adiponectin (p=0.002). For rosiglitazone, multivariate regression analysis revealed malondialdehyde reduction as an independent determinant of treatment-induced improvement in E'. The rosiglitazone-induced improvements of diastolic function and oxidative stress may be of prognostic relevance in choosing therapy for T2DM patients without overt heart disease.

Tissue Doppler imaging for the detection and quantitation of myocardial dysfunction in patients with type 2 diabetes mellitus.

UNLABELLED: The prevalence of type 2 diabetes mellitus is rapidly increasing. Myocardial dysfunction may be a consequence of diabetic cardiomyopathy and it contributes to the poor prognosis of diabetic patients. AIMS: This study was designed to test whether tissue Doppler imaging might be a suitable tool for early detection of myocardial dysfunction in diabetic patients. METHODS: Forty-three diabetic patients and 33 non-diabetic controls, including age-matched subgroups without evidence of coronary artery disease (n=12), were recruited if they had normal LV-function by standard 2-D echocardiography and no clinical signs of heart failure. They were investigated with tissue Doppler imaging at rest and during pharmacological stress with dipyridamole and/or dobutamine. Myocardial function was calculated as the mean value from six basal myocardial segments for peak velocity at systole (Vs), early diastole (Ve) and atrial contraction (Va). RESULTS: Compared to controls, diabetic patients had compromised Ve at rest (8.5 +/- 1.7 vs. 9.6 +/- 1.9 cm/sec, p < 0.02), as did the subgroups without coronary artery disease (9.3 +/- 1.7 vs. 10.7 +/- 1.5 cm/sec, p < 0.05). Dobutamine stress resulted in lower Vs (10.7 +/- 2.7 vs. 13.6 +/- 3.4 cm/sec, p < 0.05) and Ve (10.0 +/- 2.1 vs. 13.1 +/- 3.8 cm/sec, p < 0.05) in the diabetic patients, demonstrating an impaired increase of Vs, Vd and Va (p < 0.05, p < 0.0003 and p < 0.03, respectively). An inverse correlation was observed between Ve and age in both control and diabetic individuals. Thus, abnormal values were defined in relation to age. CONCLUSIONS: Diastolic and systolic myocardial dysfunction in patients with type 2 diabetes may be identified by quantitative tissue Doppler imaging before the onset of clinical signs of heart failure and before the appearance of traditional echocardiographic indices of systolic myocardial dysfunction.

Effects of trimetazidine on left ventricular function in patients with type 2 diabetes and heart failure.

UNLABELLED: Congestive heart failure and type 2 diabetes have a deleterious prognosis when combined. Trimetazidine, a metabolic agent with anti-ischemic properties, reduces fatty acid beta-oxidation via decreased 3-ketoacyl-coenzyme-A thiolase activity thereby facilitating energy production via the glycolytic pathway. OBJECTIVES: To assess myocardial function by Tissue Doppler Imaging (TDI) after one month of trimetazidine (Vastarel) added-on conventional treatment in patients with type 2 diabetes and heart failure. METHODS: Twenty diabetic patients with ischemic heart failure (mean age 66 years; NYHA class II-III) were randomized to trimetazidine (60 mg daily) or placebo in a double-blind crossover design. Exercise tolerance, 2-dimensional echocardiograms, and TDI (rest and exercise) were studied before and during treatment. RESULTS: Changes in exercise tolerance did not differ in the two groups. Ejection fraction at rest and moderate exercise only improved significantly with trimetazidine when analyzed for the first treatment period. TDI velocities did not change significantly during treatment periods. CONCLUSION: In this early pilot investigation of the effects of trimetazidine in patients with diabetes and heart failure there were only weak signs of improved systolic myocardial function at rest and exercise. The present observations indicate the need of further research to explore the effect of trimetazidine during longer treatment period or with more selected patient population.

C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes.

Myocardial dysfunction, perfusion abnormalities, and the extent to which these abnormalities may be reversed by C-peptide administration was assessed in type 1 diabetic patients. Eight patients were studied before and during a 0.84-mg/kg dipyridamole administration using a randomized double-blind crossover protocol with infusion of C-peptide (6 pmol x kg(-1) x min(-1)) or saline during 60 min on two different days. Myocardial function was measured as peak myocardial velocity during systole (Vs) and early diastole (Vd) by pulsed tissue Doppler imaging. Myocardial contrast echocardiography was used for assessment of myocardial blood volume (SI(max)) and myocardial blood flow index (MBFI) calculated from the relation between trigger interval and signal intensity. Eight age-matched healthy volunteers served as control subjects. In the basal state, Vd (13.8 +/- 0.6 vs. 15.6 +/- 0.5 cm/s, P < 0.04) and SI(max) (6.6 +/- 0.6 vs. 8.2 +/- 0.6 a.u. P < 0.04) were reduced in patients compared with control subjects. Dipyridamole administration significantly increased indexes of myocardial function and blood flow to a similar extent in patients and control subjects. During C-peptide administration, Vs and Vd increased by 12% (P = 0.03), SI(max) increased from 6.6 +/- 0.6 to 8.1 +/- 0.7 a.u. (P < 0.02), and MBFI increased from 3.3 +/- 0.4 to 5.3 +/- 0.9 (P < 0.05). The results demonstrate that type 1 diabetic patients have impaired myocardial function and perfusion in the basal state that can be improved by short-term replacement of C-peptide.

Interaction of Microbubbles with Ultrasound.

The clinical need for bedside myocardial perfusion studies is obvious in the present era of revascularization. Animal and first clinical studies suggest that microbubbles can be used as intravascular tracers of perfusion in conjunction with echocardiography as an imaging modality. In order to fully appreciate the potential and limitations of this approach, the complex interactions of microbubbles within an acoustic field need to be elucidated. Most importantly, there is a strong dependence of bubble effects on the acoustic pressure. At low pressures, linear backscatter yields low signal intensities; at medium range of pressures, bubble resonance causes the reflection of nonlinear signals with harmonic frequencies; and at high pressures, spontaneous acoustic emission with high signal intensity occurs as a final signal of the bubble in its process of disintegration. Thus, in order to allow sufficient replenishment of bubbles to the imaging plane, triggered imaging should be used with one frame every second to eighth cardiac cycle. Traditional gray scale echocardiography was not successful as an imaging modality because of the similarity of gray shades between the myocardium and the contrast effect. Subsequently, second harmonic imaging was developed and was fairly successful in contrast detection, although inherent problems persisted due to the overlap of fundamental and harmonic frequencies in the filtered signals. Harmonic power Doppler imaging turned out as the most sensitive acquisition method, however, with an early dropout at medium range attenuation. In theory, the new technique of pulse inversion may be most promising as this bubble specific imaging modality should combine high sensitivity of detection with great tolerance for attenuation effects in humans. First in vitro studies have confirmed its superiority over harmonic power Doppler in combination with stabilized microbubbles such as SonoVuetrade mark. Thus, we will have to accomplish a lot more work and comparative studies in humans before myocardial contrast echocardiography can emerge as a reproducible technique for evaluating myocardial perfusion with high diagnostic accuracy.