René A. Tio

Angiotensin-(1–7) Attenuates the Development of Heart Failure After Myocardial Infarction in Rats

Background—The renin-angiotensin system (RAS) is a key player in the progression of heart failure. Angiotensin-(1–7) is thought to modulate the activity of the RAS. Furthermore, this peptide may play a part in the beneficial effects of angiotensin-converting enzyme inhibitors in cardiovascular disease. We assessed the effects of angiotensin-(1–7) on the progression of heart failure. Methods and Results—Male Sprague-Dawley rats underwent either coronary ligation or sham surgery. Two weeks after induction of myocardial infarction, intravenous infusion of angiotensin-(1–7) (24 &mgr;g/kg per hour) or saline was started by minipump. After 8 weeks of treatment, hemodynamic parameters were measured, endothelial function was assessed in isolated aortic rings, and plasma angiotensin-(1–7) levels were determined. Myocardial infarction resulted in a significant deterioration of left ventricular systolic and diastolic pressure, dP/dt, and coronary flow. Raising plasma levels 40-fold, angiotensin-(1–7) infusion attenuated this impairment to a nonsignificant level, markedly illustrated by a 40% reduction in left ventricular end-diastolic pressure. Furthermore, angiotensin-(1–7) completely preserved aortic endothelial function, whereas endothelium-dependent relaxation in aortas of saline-treated infarcted rats was significantly decreased. Conclusions—Angiotensin-(1–7) preserved cardiac function, coronary perfusion, and aortic endothelial function in a rat model for heart failure.

Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial

AIMS Previous trials that investigated cell therapy as an adjunctive therapy after acute myocardial infarction (AMI) have shown conflicting results. We designed a randomized controlled trial to determine the effect of intracoronary infusion of mononuclear cells from bone marrow (BM) or peripheral blood in patients with AMI. METHODS AND RESULTS In a multicentre trial, 200 patients with large first AMI treated with primary percutaneous coronary intervention were randomly assigned to either intracoronary infusion of mononuclear BM cells (n = 69), mononuclear peripheral blood cells (n = 66), or standard therapy (without placebo infusion) (n = 65). Mononuclear cells were delivered intracoronary between 3 and 8 days after AMI. Regional and global left ventricular myocardial function and volumes were assessed by magnetic resonance imaging before randomization and at 4 months, and clinical events were reported. The primary endpoint of the percentage of dysfunctional left ventricular segments that improved during follow-up did not differ significantly between either of the treatment groups and control: 38.6 ± 24.7% in the BM group, 36.8 ± 20.9% in the peripheral blood group, and 42.4 ± 18.7% in the control group (P = 0.33 and P = 0.14). Improvement of left ventricular ejection fraction was 3.8 ± 7.4% in the BM group, 4.2 ± 6.2% in the peripheral blood group when compared with 4.0 ± 5.8% in the control group (P = 0.94 and P = 0.90). Furthermore, the three groups did not differ significantly in changes in left ventricular volumes, mass, and infarct size and had similar rates of clinical events. CONCLUSION Intracoronary infusion of mononuclear cells from BM or peripheral blood following AMI does not improve regional or global systolic myocardial function in the HEBE trial. REGISTRATION The Netherlands Trial Register #NTR166 (www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).

Comparison Between the Prognostic Value of Left Ventricular Function and Myocardial Perfusion Reserve in Patients with Ischemic Heart Disease

The purpose of this study was to compare the prognostic value of left ventricular ejection fraction (LVEF) and myocardial perfusion reserve (MPR) assessed with PET in patients with ischemic heart disease (IHD). Myocardial perfusion is the main determinant of left ventricular function in patients with IHD. The prognostic value of LVEF has been widely established. In addition, MPR determines survival in patients with hypertrophic and dilated cardiomyopathies. In the present study, we evaluated whether MPR also determines survival in patients with IHD. Methods: Between 1995 and 2003, 480 consecutive patients with chronic IHD underwent dipyridamole stress and rest 13N-ammonia PET to determine MPR. Additionally, 18F-FDG PET was performed for viability (mismatching defects), infarction (matching defects), and left ventricular function assessment. Patients were followed for all causes of mortality and major cardiovascular events. Results: In 463 of the 480 patients, valid MPR could be measured (368 men; mean age, 66 ± 11 y; LVEF, 35% ± 15%). One hundred nineteen patients underwent a PET-driven revascularization (67 through percutaneous coronary intervention and 52 through coronary artery bypass grafting). The remaining 344 patients were the subject of this study. The overall MPR was 1.71 ± 0.50 (intertertile boundaries, 1.49 and 1.84). After adjustment for age and sex, MPR was associated with a hazard ratio for cardiac death of 4.11 (95% confidence interval, 2.98–5.67) per SD decrease, whereas the risk for LVEF was 2.76 (2.00–3.82) per SD decrease. Conclusion: Patients with IHD with a low MPR are at high risk of cardiac death. MPR is a more sensitive predictor for cardiac death than is LVEF.

A single dose of erythropoietin in ST-elevation myocardial infarction

AIMS Cardioprotective effects of erythropoietin (EPO) have been shown in experimental and smaller clinical studies. We performed a prospective, multicentre, randomized trial to assess the effects of a single high dose of EPO after primary coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods and results Patients with a successful PCI for a first STEMI were randomized to receive either standard medical care alone, or in combination with a single bolus with 60,000 IU i.v. of epoetin alfa within 3 h after PCI. Primary endpoint was left ventricular ejection fraction (LVEF) after 6 weeks, assessed by planar radionuclide ventriculography. Pre-specified secondary endpoints included enzymatic infarct size and major adverse cardiovascular events. A total of 529 patients were enrolled (EPO n = 263, control n = 266). At baseline (before EPO administration), groups were well-matched for all relevant characteristics. After a mean of 6.5 (± 2.0) weeks, LVEF was 0.53 (± 0.10) in the EPO group and 0.52 (± 0.11) in the control group (P = 0.41). Median area under the curve (inter-quartile range) after 72 h for creatinine kinase was 50 136 (28 212-76 664)U/L per 72 h in the EPO group and 53 510 (33 973-90 486)U/L per 72 h in the control group (P = 0.058). More major adverse cardiac events occurred in the control than in the EPO group (19 vs. 8; P = 0.032). Conclusion A single high dose of EPO after a successful PCI for a STEMI did not improve LVEF after 6 weeks. However, the use of EPO was related to less major adverse cardiovascular events and a favourable clinical safety profile. CLINICAL TRIAL REGISTRATION INFORMATION NCT00449488; http://www.clinicaltrials.gov/ct2/show/NCT00449488?term=voors&rank=2.

Usefulness of fractional flow reserve for risk stratification of patients with multivessel coronary artery disease and an intermediate stenosis

Intracoronary-derived, pressure-based fractional flow reserve (FFR) is important for clinical decision-making in patients with 1-vessel coronary artery disease (CAD). In the present study, we investigated the prognostic value of FFR in patients with intermediate stenoses and multivessel CAD. Therefore, we analyzed 107 patients with stable angina pectoris who underwent myocardial perfusion scintigraphy and showed no perfusion defects in the region of the intermediate lesion. At angiography, FFR was determined distal to the intermediate lesion. FFR was abnormal (i.e., <0.75) in 15 of 107 stenoses (14%). Angioplasty of the intermediate stenosis was deferred based on the absence of a perfusion defect. Patients were followed for 1 year to document major cardiac events related to the intermediate lesion. At 1-year follow-up, a total of 12 (11%: no deaths, 3 myocardial infarctions, 2 coronary bypass operations, 7 coronary angioplasties) events occurred in the entire group that were related to the intermediate lesion. The event rate was significantly higher when angioplasty was deferred despite FFR <0.75 compared with the group with FFR > or = 0.75 (4 of 15 [27%] vs 8 of 92 [9%]; p <0.041). The relative risk of FFR for predicting cardiac events (mainly revascularization procedures) was 3.1 (95% confidence interval 1.1 to 8.9; p <0.05). In conclusion, deferral of angioplasty of intermediate coronary narrowings is safe based on FFR > or = 0.75 in this patient cohort; this coincides with previous reports in patients with 1-vessel CAD. Furthermore, these results suggest that FFR is more useful than single-photon emission computed tomography for clinical decision-making and risk stratification in patients with multivessel CAD.

Haemodialysis is associated with a pronounced fall in myocardial perfusion

BACKGROUND Whereas haemodialysis (HD) is lifesaving by replacement of renal function, there are data to suggest that the HD procedure itself may contribute to the high cardiac risk in dialysis patients. The HD procedure is associated with an increased risk of sudden death, and there is accumulating evidence that HD can elicit myocardial ischaemia. In this study, we evaluated the effect of HD on global and regional myocardial blood flow (MBF) and left ventricular (LV) function in non-diabetic, non-cardiac compromised patients. METHODS (13)N-NH(3) positron emission tomography (PET) was used to quantify changes in MBF, LV wall motion, cardiac output (CO), LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) in seven non-diabetic patients with uneventful cardiac histories. PET scans were performed before and at 30 and 220 min of HD. RESULTS In all patients global MBF fell during HD. At 30 min of HD without ultrafiltration (UF), global MBF had fallen 13.5 +/- 11.5% (P < 0.05) while CO, LVEDV and LVESV were 4.6 +/- 5.3% (NS), 5.6 +/- 4.2% (P < 0.05) and 6.9 +/- 7.2% (P < 0.05) lower, respectively. At 220 min of HD, after UF of 2.5 +/- 0.9 l, global MBF had fallen 26.6 +/- 13.9% (P < 0.05) from baseline while CO, LVEDV and LVESV were 21.0 +/- 19.7%, 31.1 +/- 12.7% and 36.4 +/- 17.5% (all P < 0.05) lower, respectively. In two patients, new LV regional wall motion abnormalities (RWMA) developed at 220 min of HD. MBF was reduced to a greater extent in regions that developed LV RWMA compared to those that did not. CONCLUSIONS Haemodialysis induced a pronounced fall in MBF. Since MBF fell already early during HD not only hypovolaemia but also acute dialysis-associated factors seem to play a role. Haemodialysis-associated reductions in MBF may contribute to the high cardiac event rate of dialysis patients.

Coronary blood flow dynamics during transcutaneous electrical nerve stimulation for stable angina pectoris associated with severe narrowing of one major coronary artery

To study the effect of transcutaneous electrical nerve stimulation (TENS) on coronary vasomotion, patients with New York Heart Association class III angina pectoris and significant single-vessel left coronary artery disease and who were also scheduled for elective percutaneous transluminal coronary angioplasty, were allocated to a study group (precordial actual TENS, n = 10) and a control group (precordial simulated TENS, n = 5, and TENS on the back, n = 3). Coronary volumetric flow was assessed in the stenotic and nonstenotic coronary artery before and after neurostimulation. The diameter (in millimeters) of the stenotic coronary artery was reduced in the study group after actual TENS (from 2.73 +/- 0.55 by 0.12 +/- 0.11; p = 0.008). In the nonstenotic coronary artery, the diameter increased in the study group (from 2.64 +/- 0.43 by 0.24 +/- 0.15; p = 0.01). In both the stenotic and nonstenotic coronary arteries, no effect was shown on the average peak velocity (centimeters per second) in the study group. The coronary volumetric flow (milliliters per minute) was reduced in the stenotic artery of the study group (from 62 +/- 18 by 8 +/- 7; p = 0.007). In the nonstenotic coronary artery, volumetric flow increased in the study group (from 57 +/- 18 by 11 +/- 10; p = 0.007). In the control group, simulated TENS and TENS on the back had no effect on the diameter of the artery, average peak velocity, or volumetric flow. In addition, in all patients, TENS had no effect on the total volumetric flow of the left coronary artery and hemodynamic variables during the study period. This observation suggests that TENS modulates regional coronary vasomotion in patients with coronary artery disease.

Prognostic value of coronary blood flow velocity and myocardial perfusion in intermediate coronary Narrowings and multivessel disease

OBJECTIVES This study aimed to investigate the roles of intracoronary derived coronary flow velocity reserve (CFVR) and myocardial perfusion scintigraphy (single photon emission computed tomography, or SPECT) for management of an intermediate lesion in patients with multivessel coronary artery disease. BACKGROUND Evaluation of the functional significance of intermediate coronary narrowings (40% to 70% diameter stenosis) is important for clinical decision making and risk stratification. METHODS In a prospective, multicenter study, SPECT was performed in 191 patients with stable angina and multivessel disease and scheduled for angioplasty (percutaneous transluminal coronary angioplasty, or PTCA) of a severe coronary narrowing. Coronary flow velocity reserve was determined selectively distal to an intermediate lesion in another artery using a Doppler guidewire. Percutaneous transluminal coronary angioplasty of the intermediate lesion was deferred when SPECT was negative or CFVR greater-than-or-equal 2.0. Patients were followed for one year to document major cardiac events (death, infarction, revascularization), related to the intermediate lesion. RESULTS Reversible perfusion defects were documented in the area of the intermediate lesion in 30 (16%) patients; CFVR was positive in 46 (24%) patients. Percutaneous transluminal coronary angioplasty of the intermediate lesion was deferred in 182 patients. During follow-up, 19 events occurred (3 myocardial infarctions, 16 revascularizations). Coronary flow velocity reserve was a more accurate predictor of cardiac events than was SPECT; relative risk: CFVR 3.9 (1.7 to 9.1), p < 0.05; SPECT 0.5 (0.1 to 3.2), p = NS. Multivariate analysis revealed CFVR as the only significant predictor for cardiac events. CONCLUSIONS Deferral of PTCA of intermediate lesions in multivessel disease is safe when CFVR greater-than-or-equal 2.0 (event rate 6%). This selective evaluation of coronary lesion severity during cardiac catheterization allows a more accurate risk stratification than does SPECT, which is important for clinical decision making in this patient cohort.

Myocardial bridging in a survivor of sudden cardiac near-death: role of intracoronary doppler flow measurements and angiography during dobutamine stress in the clinical evaluation.

Extensive myocardial bridging in the left anterior descending coronary artery was found in a 46 year old survivor of sudden cardiac near-death. Positron emission tomography and dobutamine stress echocardiography revealed ischaemia in the myocardium distal to the bridging. Spasm was excluded as cause of the ischaemia by intracoronary infusion of acetylcholine. Further evaluation of the haemodynamic importance of the bridging using intracoronary Doppler flow velocity measurements revealed an abnormal flow reserve. Dobutamine stress during coronary angiography caused increased mechanical compression during diastole. This was accompanied by multiple premature ventricular contractions. After a debridging operation the flow velocity reserve was normal. The abnormalities found during dobutamine stress had disappeared. Unexpectedly, a spasm was inducible. This may have been due to local oedema or scar formation after the operation. For the evaluation of the haemodynamic importance of myocardial bridging, intracoronary Doppler flow velocity measurements and angiography during dobutamine stress may be helpful in clinical decision making.

Carotid plaque formation and serum biomarkers

Treatment of carotid artery stenosis by endarterectomy or stenting can significantly reduce stroke risk, but is also associated with surgery related mortality and morbidity. At present it is neither possible to assess whether a carotid plaque will become symptomatic or not, nor to define the time when symptoms will occur. Identification of carotid plaques which confer excess risk of neurologic events is fundamental in the selection of patients for vascular intervention. Molecular processes such as inflammation, lipid accumulation, apoptosis, proteolysis, thrombosis and angiogenesis have shown to be highly related with plaque vulnerability. Serum biomarkers reflecting these processes may distinguish unstable from stable carotid artery stenosis and thus be a powerful tool in the selection of patients for carotid surgery. Until now, no serum biomarker has qualified for regular clinical use in carotid artery disease. However, several biomarkers, especially markers of inflammatory or proteolytic activity seem to be promising in the identification of vulnerable carotid plaques. Therefore, it is anticipated that non-invasive risk assessment in carotid artery disease by determination of serum biomarker levels may play an important future role in clinical practice improving better selection criteria for vascular intervention.