Coronary flow responses to exercise training: further evidence of the benefit of an underutilized therapeutic modality

Inactivity is associated with endothelial dysfunction and the development of cardiovascular disease. Exercise training has a favourable effect in the management of hypertension, heart failure and ischaemic heart disease. These beneficial effects are probably mediated through improvements of vascular function and, in this issue of Clinical Science, Hagg and co-authors propose a coronary artery effect. The use of a Doppler technique for non-invasive assessment of coronary flow reserve in a small animal model is an exciting aspect of this study. If feasible in the hands of other investigators, the availability of sequential coronary flow measurements in animal models may help improve our understanding of the mechanisms of disorders of the coronary circulation.

Comparison of specificity of quantitative myocardial contrast echocardiography for diagnosis of coronary artery disease in patients with versus without diabetes mellitus

Impaired coronary flow reserve is widely reported in diabetes mellitus (DM) but its effect on myocardial contrast echocardiography (MCE) is unclear. We sought to identify whether DM influences the accuracy of qualitative and quantitative assessment of coronary artery disease (CAD) using MCE in 83 patients who underwent coronary angiography (60 men, 27 with DM; 56 +/- 11 years;). Destruction replenishment imaging was performed at rest and after combined dipyridamole-exercise stress testing. Ischemia was identified by the development of new wall motion abnormalities, qualitative MCE (new perfusion defects apparent 1 second after flash during hyperemia), and quantitative MCE (myocardial blood flow reserve < 2.0 in the anterior circulation). Qualitative and quantitative assessment of perfusion was feasible in 100% and 92% of patients, respectively. Significant left anterior descending coronary stenosis (> 50% by quantitative angiography) was present in 28 patients (including 8 with DM); 55 patients had no CAD (including 19 with DM). The myocardial blood flow reserve was reduced in patients with coronary stenosis compared with those with no CAD (1.6 +/- 1.1 vs 3.8 +/- 2.5, p < 0.001). Among patients with no CAD, those with DM had an impaired flow reserve compared with control patients without DM (2.4 +/- 1.0 vs 4.5 +/- 2.8, p = 0.003). In conclusion, DM significantly influenced the quantitative, but not the qualitative, assessment of MCE, with a marked reduction in specificity in patients with DM. (c) 2005 Elsevier Inc. All rights reserved.

Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.

Relationship between myocardial perfusion and dysfunction in diabetic cardiomyopathy: A study of quantitative contrast echocardiography and strain rate imaging

Objective: To use quantitative myocardial contrast echocardiography (MCE) and strain rate imaging (SRI) to assess the role of microvascular disease in subclinical diabetic cardiomyopathy. Methods: Stress MCE and SRI were performed in 48 patients (22 with type II diabetes mellitus (DM) and 26 controls), all with normal left ventricular systolic function and no obstructive coronary disease by quantitative coronary angiography. Real-time MCE was acquired in three apical views at rest and after combined dipyridamole-exercise stress. Myocardial blood flow (MBF) was quantified in the 10 mid- and apical cardiac segments at rest and after stress. Resting peak systolic strain rate (SR) and peak systolic strain (epsilon) were calculated in the same 10 myocardial segments. Results: The DM and control groups were matched for age, sex and other risk factors, including hypertension. The DM group had higher body mass index and left ventricular mass index. Quantitative SRI analysis was possible in all patients and quantitative MCE in 46 (96%). The mean e, SR and MBF reserve were all significantly lower in the DM group than in controls, with diabetes the only independent predictor of each parameter. No correlation was seen between MBF and SR (r = -0.01, p = 0.54) or between MBF and epsilon ( r = -0.20, p = 0.20). Conclusions: Quantitative MCE shows that patients with diabetes but no evidence of obstructive coronary artery disease have impaired MBF reserve, but abnormal transmural flow and subclinical longitudinal myocardial dysfunction are not related.

Myocardial blood volume and perfusion reserve responses to combined dipyridamole and exercise stress: A quantitative approach to contrast stress echocardiography

Background: Qualitative interpretation of myocardial contrast echocardiography (MCE) improves the accuracy of wall-motion analysis for assessment of coronary artery disease (CAD). We examined the feasibility and accuracy of quantitative MCE for diagnosis of CAD. Methods: Dipyridamole/exercise stress MCE (destruction-replenishment protocol with real-time imaging) was performed in 90 patients undergoing quantitative coronary angiography, 48 of whom had significant (> 50%) stenoses. MCE was repeated with exercise alone in 18 patients. Myocardial blood flow (A*beta) was obtained from blood volume (A) and time to refill (beta). Results: Quantification of flow reserve was feasible in 88%. The mean A*beta reserve in the anterior wall was significantly impaired for patients with left anterior descending coronary artery disease (n = 28) compared with those with no disease (1.6 +/- 1.2 vs; 4.0 +/- 2.5, P <=.001). This reflected impaired beta reserve, with no difference in the A reserve. Applying a receiver operating characteristic curve derived cutoff of 2.0 for A*beta reserve, quantitative MCE was 76% sensitive and 71% specific for the diagnosis of significant left anterior descending coronary artery stenosis. Posterior circulation results were similar, with 78% sensitivity and 59% specificity for detection of posterior CAD. Overall, quantitative MCE was similarly sensitive to qualitative approach for diagnosis of CAD (88% vs 93%), but with lower specificity (52% vs 65%, P =.07). In 18 patients restudied with pure exercise stress, the mean myocardial blood flow reserve was less than after combined stress (2.1 +/- 1.6 vs 3.7 +/- 1.9, P =.01). Conclusion: Quantitative MCE is feasible for the diagnosis of CAD with dipyridamole/exercise stress. Dipyridamole prolongs postexercise hyperemia, augmenting the degree of hyperemia at the time of imaging.

Can myocardial contrast echo provide incremental benefit to exercise echo? Implications of the intensity and duration of hyperaemia

Background. Stress myocardial contrast echo (MCE) is technically challenging with exercise (Ex) because of cardiacmovementandshort duration ofhyperemia.Vasodilators solve these limitations, but are less potent for inducing abnormal wall motion (WM). We sought whether a combined dipyridamole (DI; 0.56 mg/kg i.v. 4 min) and Ex stress protocol would enable MCE to provide incremental benefit toWManalysis for detection of CAD. Methods. Standard echo images were followed by real time MCE at rest and following stress in 85 pts, 70 undergoing quantitative coronary angiography and 15 low risk pts.WMAfrom standard and LVopacification images, and then myocardial perfusion were assessed sequentially in a blinded fashion. A subgroup of 13 pts also underwent Ex alone, to assess the contribution of DI to quantitative myocardial flow reserve (MFR). Results. Significant (>50%) stenoses were present in 43 pts, involving 69 territories. Addition of MCE improved SE sensitivity for detection of CAD (91% versus 74%, P = 0.02) and better appreciation of disease extent (87% versus 65%territories, P=0.003), with a non-significant reduction in specificity. In 55 territories subtended by a significant stenosis, but with no resting WM abnormality, ability to identify ischemia was also significantly increased by MCE (82% versus 60%, P = 0.002). MFR was less with Ex alone than with DIEx stress (2.4 ± 1.6 versus 4.0 ± 1.9, P = 0.05), suggesting prolongation of hyperaemia with DI may be essential to the results. Conclusions. Dipyridamole-exercise MCE adds significant incremental benefit to standard SE, with improved diagnostic sensitivity and more accurate estimation of extent of CAD.

Coronary revascularization can improve regional left ventricular volumes in non-transmural scars without contractile reserve

Revascularization (RVS) of scar segts does not lead to recovery of left ventricular (LV) function, but its effect on post-infarct remodeling is unclear. We examined the impact of RVS on regional remodeling in different transmural extents of scar (TME). Dobutamine echo (DbE) and contrast enhanced magnetic resonance imaging (ce- MRI) were performed in 72 pts post MI (age 63±10, EF 49±12%). Pts were selected for RVS (n = 31) or medical treatment (n = 41). Segts were classified as scar if there were no contractile reserve during lowdose DbE.TMEwas measured by ce-MRI; a cutoff of 75% was used to differentiate transmural (TM) from non-transmural (NT) scars. Regional end systolic (ESV) and end diastolic volumes (EDV) were measured at baseline and 12 months follow up.Of 218 segts identified as scar on DbE, 164wereNTand 54 were TM on ce-MRI. Revascularization was performed to 62 NT and 11 TM segts. In the RVS group, there was reverse remodeling with significant reduction in LV volumes in NT (ESV, 6.8±3.2 ml versus 5.8±3.7 ml, p = 0.002; EDV, 10.9±4.9 ml versus 9.8±5.6 ml, p = 0.02), but no significant change in volumes in TM (ESV, 6.9±3.7 ml versus 5.4±2.1 ml, p = 0.09; EDV, 10.2±4.4 ml versus 9.4±4.3 ml, p = 0.5). In the medically treated group, there were no changes in LV volumes in both NT (ESV, 12.0±11.9 ml versus 12.7±13.8 ml, p = 0.3; EDV, 12.5±7.8 ml versus 12.6±9.7 ml, p = 0.8) and TM (ESV, 8.0±3.8 ml versus 7.9±4.6 ml, p = 0.8; EDV, 10.3±4.8 ml versus 10.4±5.4 ml, p = 0.9). Despite absence of contractile reserve on DbE, NT benefit from coronary revascularization with regional reverse LV remodeling.

Use of cyclic variation of integrated backscatter to assess contractile reserve and myocardial viability in chronic ischemic left ventricular dysfunction

The detection of viable myocardium has important implications for management, but use of stress echocardiography to detect this is subjective and requires exposure to dobutamine. We investigated whether cyclic variation (CV) of integrated backscatter (IB) from the apical views could provide a resting study for detection of contractile reserve (CR) and prediction of myocardial viability in 27 patients with chronic ischemic left ventricular (LV) dysfunction. Repeat echocardiography was performed after 6.7 +/- 3.8 months of follow-up; 14 patients underwent revascularization and 13 were treated medically. Using a standardized dobutamine echocardiography (DbE) protocol, images from three apical views were acquired at 80-120 frames/sec at rest and during stress. CR was identified if improvement of wall motion was observed at low dose (5 or 10 mug/kg/min) DbE. Myocardial viability was characterized by improvement at follow-up echocardiography in patients with revascularization. CVIB at rest and low dose dobutamine were assessed in 194 segments with resting asynergy (severe hypokinesis or akinesis), of which 88 (45%) were in patients who underwent revascularization. Of these, CVIB could be measured in 190 (98%) segments at rest and 185 (95%) at low dose dobutamine. Sixty-two (33%) segments had CR during low dose DbE and 50 (57%) segments showed wall-motion recovery (myocardial viability) at follow-up echocardiography. Segments with CR had significantly higher CVIB at rest (P < 0.001) and low dose dobutamine (P = 0.005) than segments without CR. Using optimal thresholds of CVIB (> 8.2 dB) at rest, the accuracy of CVIB for detecting CR was 70%. Compared with nonviable segments, viable segments had significantly higher CVIB at rest (P < 0.001) and low dose dobutamine (P < 0.001). Using optimal thresholds of CVIB (> 5.3 dB) at rest, the accuracy of CVIB for detecting myocardial viability was 85%, which was higher than that in conventional DbE (62%, P < 0.01). Thus, assessment of CV.TB from the apical views is a feasible and accurate tool for detecting CR and predicting myocardial viability in chronic LV dysfunction.

A randomized trial of aggressive lipid reduction for improvement of myocardial ischemia, symptom status, and vascular function in patients with coronary artery disease not amenable to intervention

PURPOSE: To determine the effects of aggressive lipid lowering on markers of ischemia, resistance vessel function, atherosclerotic burden, and Symptom status in patients with symptomatic coronary artery disease. METHODS: Sixty consecutive patients with coronary artery disease that was unsuitable for revascularization were assigned randomly to either usual therapy of lipids for patients with a low-density lipoprotein (LDL) cholesterol target level <116 mg/dL, or to a, more aggressive lipid-lowering strategy involving up to 80 mg/d of atorvastatin, with a target LDL cholesterol level <77 mg/dL. The extent and severity of inducible ischemia (by dobutamine echocardiography), vascular function.(brachial artery reactivity), atheroma burden (carotid intima-media thickness), and symptom status were evaluated blindly at baseline and after 12 weeks of treatment. RESULTS: After 12 weeks of treatment, patients in the aggressive therapy group had a significantly greater decrease in mean (+/- SD) LDL cholesterol level than those in the usual care group (29 +/- 38 mg/dL vs. 7 +/- 24 mg/dL, P = 0.03). Patients in the aggressive therapy group had a reduction in the number of ischemic wall segments (mean between-group difference of 1.3; 95% confidence interval: 0.1 to 2.0; P = 0.04), flow-mediated dilatation (mean between-group difference of 5.9%; 95% confidence interval: 2.5% to 9.4%; P = 0.001), and angina score after 12 weeks. There were no significant changes in atherosclerotic burden in either group. CONCLUSION: Patients with symptomatic coronary artery disease who are treated with aggressive lipid lowering have improvement of symptom status and ischemia that appears to reflect improved vascular function but not atheroma burden. Am J Med. 2003;114:445-453. (C) 2003 by Excerpta Medica Inc.

Effects of revascularisation and contractile reserve on left ventricular remodelling in patients with impaired left ventricular function

Objective: We sought to define the influence of revascularisation and contractile reserve on left ventricular (LV) remodelling in patients with LV dysfunction after myocardial infarction. Revascularisation of viable myocardium is associated with improved regional function, but the effect on remodelling is undefined. Methods: We studied 70 patients with coronary artery disease and LV dysfunction, 31 of whom underwent revascularisation. A standard dobutamine stress echocardiogram (DbE) was carried out. All patients underwent standard medical treatment; the decision to revascularise was made clinically, independent of this study. LV volumes and ejection fraction were measured by 3D echocardiography at baseline and after an average of 40 weeks. Results: There was no significant difference in baseline ejection fraction or volumes between patients who underwent revascularisation and the remainder. Compared to medically treated patients, revascularised patients had significant improvements in ejection fraction and end-systolic volume in follow-up. The impact of baseline variables on remodelling was assessed by dividing patients into tertiles of LV ejection fraction and volumes. Revascularised patients in the lowest tertile of ejection fraction at baseline (<38%) had a significant improvement in end-systolic volume and ejection fraction, larger than obtained in medically treated patients with low ejection fraction. Revascularised patients with an ejection fraction >38% did not show significant improvement in volumes compared to baseline. Revascularised patients in the largest tertiles of end-systolic (>88 ml) or end-diastolic volume (>149 ml) at baseline had a significant improvement in end-systolic volume. Conclusion: Remodeling appears to occur independent of the presence of regional contractile reserve but does correlate with the volume response to low-dose dobutamine. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Increased platelet-derived microparticles in the coronary circulation of percutaneous transluminal coronary angioplasty patients

Platelet-derived microparticles that are produced during platelet activation are capable of adhesion and aggregation. Endothelial trauma that occurs during percutaneous transluminal coronary angioplasty (PTCA) may support platelet-derived microparticle adhesion and contribute to development of restenosis. We have previously reported an increase in platelet-derived microparticles in peripheral arterial blood with angioplasty. This finding raised concerns regarding the role of platelet-derived microparticles in restenosis, and therefore the aim of this study was to monitor levels in the coronary circulation. The study population consisted of 19 angioplasty patients. Paired coronary artery and sinus samples were obtained following heparinization, following contrast administration, and subsequent to all vessel manipulation. Platelet-derived microparticles were identified with an anti-CD61 (glycoprotein IIIa) fluorescence-conjugated antibody using flow cytometry. There was a significant decrease in arterial platelet-derived microparticles from heparinization to contrast administration (P=0.001), followed by a significant increase to the end of angioplasty (P=0.004). However, there was no significant change throughout the venous samples. These results indicate that the higher level of platelet-derived microparticles after angioplasty in arterial blood remained in the coronary circulation. Interestingly, levels of thrombin-antithrombin complexes did not rise during PTCA. This may have implications for the development of coronary restenosis post-PTCA, although this remains to be determined.

Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease

Background: Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease. Methods: We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a, and C1-Inhibitor (C1 inh.) were measured enzymatically. Results: Patients with IJAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r = 0.27, p < 0.02), C3a (r = 0.32, p < 0.001) and C1 INH.(r = 0.41, p < 0.003), but not with flow mediated dilatation (r = 0.09, P = 0.41). Hs-CRP and C1 INH.were found to be independant predictors of IJAP in a backward stepwise logistic regression model. Conclusions: We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP. (c) 2005 Elsevier B.V. All rights reserved.