Julian W. Sacre

Association of imaging markers of myocardial fibrosis with metabolic and functional disturbances in early diabetic cardiomyopathy

Background— Metabolic and vascular disturbances contribute to diabetic cardiomyopathy, but the role of interstitial fibrosis in early disease is unproven. We sought to assess the relationship between imaging markers of diffuse fibrosis and myocardial dysfunction and to link this to possible causes of early diabetic cardiomyopathy. Methods and Results— Hemodynamic and metabolic data were measured in 67 subjects with type 2 diabetes mellitus (age 60±10 years) with no cardiac symptoms. Myocardial function was evaluated with standard echocardiography and myocardial deformation; ischemia was excluded by exercise echocardiography. Calibrated integrated backscatter was calculated from parasternal long-axis views. T1 mapping was performed after contrast with a modified Look-Locker technique using saturation recovery images. Amino-terminal propeptides of procollagens type I and III, as well as the carboxy-terminal propeptide of procollagen type I, were assayed to determine collagen turnover. Subjects with abnormal early diastolic tissue velocity (Em) had shorter postcontrast T1 values (P=0.042) and higher calibrated integrated backscatter (P=0.007). They were heavier (P=0.003) and had worse exercise capacity (P<0.001), lower insulin sensitivity (P=0.003), and blunted systolic tissue velocity (P=0.05). Postcontrast T1 was associated with diastolic dysfunction (Em r=0.28, P=0.020; E/Em r=−0.24, P=0.049), impaired exercise capacity (r=0.30, P=0.016), central adiposity (r=−0.26, P=0.046), blood pressure (systolic r=−0.30, P=0.012; diastolic r=−0.49, P<0.001), and insulin sensitivity (r=0.30, P=0.037). The association of T1 with E/Em (&bgr;=−0.31, P=0.017) was independent of blood pressure and metabolic disturbance. Amino-terminal propeptide of procollagens type III was linked to diastolic dysfunction (Em r=−0.32, P=0.008) and calibrated integrated backscatter (r=0.30, P=0.015) but not T1 values. Conclusions— The association between myocardial diastolic dysfunction, postcontrast T1 values, and metabolic disturbance supports that diffuse myocardial fibrosis is an underlying contributor to early diabetic cardiomyopathy.

Association of cardiac autonomic neuropathy with subclinical myocardial dysfunction in Type 2 diabetes

OBJECTIVES The purpose of this study was to investigate the independent association between global cardiac autonomic neuropathy (CAN) and left ventricular (LV) dysfunction in addition to regional associations of LV dysinnervation and function, in patients with type 2 diabetes mellitus (T2DM). BACKGROUND CAN represents a potential mechanism in the etiology of nonischemic diabetic cardiomyopathy. METHODS Clinical measures of CAN based on total spectral power of heart rate variability and cardiac reflex testing and echocardiographic assessment of LV function were performed in 118 patients with type 2 diabetes mellitus. Systolic and diastolic function were defined at rest and peak exercise using peak systolic and peak early diastolic (Em) tissue velocities, calculated in 6 basal- and mid-segments using color tissue Doppler. Iodine 123-metaiodobenzylguanidine imaging was performed in 33 patients to directly quantify global (heart/mediastinum ratio) and regional LV sympathetic integrity. RESULTS Patients with CAN demonstrated higher resting heart rate, systolic and mean blood pressures, aortic stiffness, hemoglobin A(1c), and urine albumin/creatinine ratio, in addition to lower peak heart rate, chronotropic index, and exercise capacity. Diastolic function (Em) was associated with CAN, evidenced by total spectral power (r = 0.42, p < 0.001) and heart/mediastinum ratio (r = 0.41, p = 0.017). Diastolic function (Em) at rest and systolic function (peak systolic tissue velocity) at rest and exercise were significantly reduced in patients with CAN. Furthermore, total spectral power was associated with Em independent of age, hypertension, metabolic factors, and other relevant contributors to LV dysfunction (β = 0.20, p = 0.035). Relative regional tracer deficits indicative of local denervation were predominant in the anterior and lateral walls (p < 0.001). Associations with regional Em, independent of global iodine 123-metaiodobenzylguanidine uptake, were identified exclusively in mid-anterior (β = 0.45, p = 0.01) and mid-lateral walls (β = 0.34, p = 0.03). However, no association was found between regional denervation and systolic or diastolic dyssynchrony. CONCLUSIONS The diastolic dysfunction of type 2 diabetes mellitus shows associations with both regional markers of sympathetic integrity and clinical markers of autonomic neuropathy.

Pulse Wave Analysis Is a Reproducible Technique for Measuring Central Blood Pressure During Hemodynamic Perturbations Induced by Exercise

BACKGROUND Central blood pressure (BP) and markers of wave reflection (augmentation index; AIx) measured by radial tonometry have prognostic value independent from brachial BP. The measurement of the central waveform is increasingly used during altered hemodynamics, including exercise, but reliability of the test has not been reported under changed loading conditions. This study aimed to test the techniques reproducibility during major hemodynamic perturbations induced by exercise. METHODS Radial waveforms were recorded (SphygmoCor) in 28 healthy subjects (aged 53 +/- 11 years) at rest, during submaximal exercise (cycling at 50, 60, and 70% of maximal age-predicted heart rate (HR)) and immediately after maximal treadmill exercise on two occasions separated by 9 +/- 5 days. Data were compared between testing days. Waveforms were calibrated with brachial BP measured using a mercury sphygmomanometer. Pulse pressure amplification (PPAmp) was defined as the ratio of brachial to central pulse pressure. RESULTS There was very good reproducibility between visits at all exercise intensities for all waveform measures, including AIx, central pulse pressure, and PPAmp (intraclass correlations at 50% exercise were 0.93, 0.89, and 0.89, respectively; P < 0.001). The mean difference between tests at this intensity was 0 +/- 4% for AIx, 4 +/- 6 mm Hg for central pulse pressure, and -0.02 +/- 0.09 for PPAmp. There were no significant differences between visits for HR, PPAmp, or AIx at rest or with exercise (P > 0.05 for all). CONCLUSIONS Radial tonometry is a reproducible technique for measurement of central waveform indices during perturbations induced by exercise. It should, therefore, be suitable for use in intervention studies in which hemodynamics are altered.

Benefits for Type 2 Diabetes of Interrupting Prolonged Sitting With Brief Bouts of Light Walking or Simple Resistance Activities

OBJECTIVE To determine whether interrupting prolonged sitting with brief bouts of light-intensity walking (LW) or simple resistance activities (SRA) improves postprandial cardiometabolic risk markers in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men 62 ± 6 years old) underwent the following 8-h conditions on three separate days (with 6–14 days washout): uninterrupted sitting (control) (SIT), sitting plus 3-min bouts of LW (3.2 km · h−1) every 30 min, and sitting plus 3-min bouts of SRA (half-squats, calf raises, gluteal contractions, and knee raises) every 30 min. Standardized meals were consumed during each condition. Incremental areas under the curve (iAUCs) for glucose, insulin, C-peptide, and triglycerides were compared between conditions. RESULTS Compared with SIT, both activity-break conditions significantly attenuated iAUCs for glucose (SIT mean 24.2 mmol · h · L−1 [95% CI 20.4–28.0] vs. LW 14.8 [11.0–18.6] and SRA 14.7 [10.9–18.5]), insulin (SIT 3,293 pmol · h · L−1 [2,887–3,700] vs. LW 2,104 [1,696–2,511] and SRA 2,066 [1,660–2,473]), and C-peptide (SIT 15,641 pmol · h · L−1 [14,353–16,929] vs. LW 11,504 [10,209–12,799] and SRA 11,012 [9,723–12,301]) (all P < 0.001). The iAUC for triglycerides was significantly attenuated for SRA (P < 0.001) but not for LW (SIT 4.8 mmol · h · L−1 [3.6–6.0] vs. LW 4.0 [2.8–5.1] and SRA 2.9 [1.7–4.1]). CONCLUSIONS Interrupting prolonged sitting with brief bouts of LW or SRA attenuates acute postprandial glucose, insulin, C-peptide, and triglyceride responses in adults with T2D. With poor adherence to structured exercise, this approach is potentially beneficial and practical.

Reliability of heart rate variability in patients with Type 2 diabetes mellitus

Diabet. Med. 29, e33–e40 (2012)

Diagnostic accuracy of heart‐rate recovery after exercise in the assessment of diabetic cardiac autonomic neuropathy

Diabet. Med. 29, e312–e320 (2012)

Interrupting prolonged sitting with brief bouts of light walking or simple resistance activities reduces resting blood pressure and plasma noradrenaline in type 2 diabetes

Objective: Prolonged sitting is increasingly recognized as a ubiquitous cardiometabolic risk factor, possibly distinct from lack of physical exercise. We examined whether interrupting prolonged sitting with brief bouts of light-intensity activity reduced blood pressure (BP) and plasma noradrenaline in type 2 diabetes (T2D). Methods: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men; mean ± SD; 62 ± 6 years) consumed standardized meals during 3 × 8 h conditions: uninterrupted sitting (SIT); sitting + half-hourly bouts of walking (3.2 km/h for 3-min) (light-intensity walking); and sitting + half-hourly bouts of simple resistance activities for 3 min (SRAs), each separated by 6–14 days washout. Resting seated BP was measured hourly (mean of three recordings, ≥20-min postactivity). Plasma noradrenaline was measured at 30-min intervals for the first hour after meals and hourly thereafter. Results: Compared with SIT, mean resting SBP and DBP were significantly reduced (P < 0.001) for both light-intensity walking (mean ± SEM; −14 ± 1/−8 ± 1 mmHg) and SRA (−16 ± 1/−10 ± 1 mmHg), with a more pronounced effect for SRA (P < 0.05 versus light-intensity walking). Similarly, mean plasma noradrenaline was significantly reduced for both light-intensity walking (−0.3 ± 0.1 nmol/l) and SRA (−0.6 ± 0.1 nmol/l) versus SIT, with SRA lower than light-intensity walking (P < 0.05). Mean resting heart rate was lowered by light-intensity walking (−3 ± 1 bpm; P < 0.05), but not SRA (−1 ± 1 bpm). Conclusion: Interrupting prolonged sitting with brief bouts of light-intensity walking or SRA reduces resting BP and plasma noradrenaline in adults with T2D, with SRA being more effective. Given the ubiquity of sedentary behaviors and poor adherence to structured exercise, this approach may have important implications for BP management in patients with T2D.

A six-month exercise intervention in subclinical diabetic heart disease: Effects on exercise capacity, autonomic and myocardial function ☆

OBJECTIVE Autonomic dysfunction may contribute to the etiology and exercise intolerance of subclinical diabetic heart disease. This study sought the efficacy of exercise training for improvement of peak oxygen uptake (VO₂(peak)) and cardiac autonomic function in type 2 diabetic patients with non-ischemic subclinical left-ventricular (LV) dysfunction. MATERIALS/METHODS Forty-nine type 2 diabetic patients with early diastolic tissue Doppler velocity >1 standard deviation below the age-based mean entered an exercise intervention (n=24) or usual care (n=25) for 6-months (controlled, pre-/post- design). Co-primary endpoints were treadmill VO₂(peak) and 5-min heart-rate variability (by the coefficient of variation of normal RR intervals [CVNN]). Autonomic function was additionally assessed by resting heart-rate (for sympathovagal balance estimation), baroreflex sensitivity, cardiac reflexes, and exercise/recovery heart-rate profiles. Echocardiography was performed for LV function (systolic/diastolic tissue velocities, myocardial deformation) and myocardial fibrosis (calibrated integrated backscatter). RESULTS VO₂(peak) increased by 11% during the exercise intervention (p=0.001 vs. -1% in controls), but CVNN did not change (p=0.23). Reduction of resting heart-rate in the intervention group (p<0.05) was associated with an improvement in the secondary endpoint of heart-rate variability total spectral power (p<0.05). However, baroreflex sensitivity, cardiac reflexes, and exercise/recovery heart-rate profiles showed no significant benefit. No effects on LV function were observed despite favorable reduction of calibrated integrated backscatter in the intervention group (p<0.05). CONCLUSIONS The exercise intolerance of subclinical diabetic heart disease was amenable to improvement by exercise training. Despite a reduction in resting heart-rate and potential attenuation of myocardial fibrosis, no other cardiac autonomic or LV functional adaptations were detected.

Exercise and Dietary Influences on Arterial Stiffness in Cardiometabolic Disease

The association of aortic and proximal arterial stiffness with cardiovascular and all-cause mortality is independent of conventional risk factors and strongest in the setting of elevated cardiometabolic risk (including hypertensive, metabolic, atherosclerotic, and renal disease).1 These associations are consistent with the physiological consequences of proximal arterial stiffening.1 In particular, widening of central (ie, aortic) pulse pressure through elevation in systolic and a reduction in diastolic blood pressure (BP). Higher central systolic BP increases cardiac afterload, whereas lower diastolic BP reduces myocardial perfusion. Elevation in central pressure pulsatility has also been linked to peripheral vascular dysfunction2 and impaired blood flow to the brain, kidneys, and other organs,3,4 which may in turn promote cognitive decline, renal impairment, and other adverse outcomes.4,5 Physical activity and diet habits are well-known determinants of the rate of arterial stiffening in healthy aging.6–12 However, it is controversial whether such lifestyle measures represent clinically useful interventions to modulate arterial biomechanical properties beyond their impact on BP and other conventional risk factors, as may be achieved with some pharmacological therapies.13,14 This review examines the arterial destiffening and central systolic unloading capacity of exercise and dietary interventions in the contexts of healthy aging, elevated cardiometabolic risk, and established disease. The evidence presented integrates our 2006 review11 with a PubMed search for subsequent literature that combined title/abstract terms pertaining to arterial properties1,15–17 with those relevant to physical activity/exercise18 and dietary approaches19,20 and the PubMed dietary supplement subset. Clinical randomized, controlled trials (RCTs) reporting on markers of proximal arterial stiffness were prioritized. A review of this field necessarily encompasses a wide variety of methods to characterize both arterial stiffness (eg, systemic estimates derived from Windkessel models and …

The effect of a high-fat meal on postprandial arterial stiffness in men with obesity and Type 2 diabetes

CONTEXT Postprandial dysmetabolism is emerging as an important cardiovascular risk factor. Augmentation index (AIx) is a measure of systemic arterial stiffness and independently predicts cardiovascular outcome. OBJECTIVE The objective of this study was to assess the effect of a standardized high-fat meal on metabolic parameters and AIx in 1) lean, 2) obese nondiabetic, and 3) subjects with type 2 diabetes mellitus (T2DM). DESIGN AND SETTING Male subjects (lean, n = 8; obese, n = 10; and T2DM, n = 10) were studied for 6 h after a high-fat meal and water control. Glucose, insulin, triglycerides, and AIx (radial applanation tonometry) were measured serially to determine the incremental area under the curve (iAUC). RESULTS AIx decreased in all three groups after a high-fat meal. A greater overall postprandial reduction in AIx was seen in lean and T2DM compared with obese subjects (iAUC, 2251 +/- 1204, 2764 +/- 1102, and 1187 +/- 429% . min, respectively; P < 0.05). The time to return to baseline AIx was significantly delayed in subjects with T2DM (297 +/- 68 min) compared with lean subjects (161 +/- 88 min; P < 0.05). There was a significant correlation between iAUC AIx and iAUC triglycerides (r = 0.50; P < 0.05). CONCLUSIONS Obesity is associated with an attenuated overall postprandial decrease in AIx. Subjects with T2DM have a preserved, but significantly prolonged, reduction in AIx after a high-fat meal. The correlation between AIx and triglycerides suggests that postprandial dysmetabolism may impact on vascular dynamics. The markedly different response observed in the obese subjects compared with those with T2DM was unexpected and warrants additional evaluation.