Cees A. Visser

C-Reactive Protein as a Cardiovascular Risk Factor More Than an Epiphenomenon?

BACKGROUND Circulating levels of C-reactive protein (CRP) may constitute an independent risk factor for cardiovascular disease. How CRP as a risk factor is involved in cardiovascular disease is still unclear. METHODS AND RESULTS By reviewing available studies, we discuss explanations for the associations between CRP and cardiovascular disease. CRP levels within the upper quartile/quintile of the normal range constitute an increased risk for cardiovascular events, both in apparently healthy persons and in persons with preexisting angina pectoris. High CRP responses after acute myocardial infarction indicate an unfavorable outcome, even after correction for other risk factors. This link between CRP and cardiovascular disease has been considered to reflect the response of the body to the inflammatory reactions in the atherosclerotic (coronary) vessels and adjacent myocardium. However, because CRP localizes in infarcted myocardium (with colocalization of activated complement), we hypothesize that CRP may directly interact with atherosclerotic vessels or ischemic myocardium by activation of the complement system, thereby promoting inflammation and thrombosis. CONCLUSIONS CRP constitutes an independent cardiovascular risk factor. Unraveling the molecular background of this association may provide new directions for prevention of cardiovascular events.

Atrial Septal Aneurysm in Adult Patients A Multicenter Study Using Transthoracic and Transesophageal Echocardiography

BACKGROUND An atrial septal aneurysm (ASA) is a well-recognized abnormality of uncertain clinical relevance. We reevaluated the clinical significance of ASA in a large series of patients. The aims of the study were to define morphological characteristics of ASA by transesophageal echocardiography (TEE), to define the incidence of ASA-associated abnormalities, and to investigate whether certain morphological characteristics of ASA are different in patients with and without previous events compatible with cardiogenic embolism. METHODS AND RESULTS Patients with ASA were enrolled from 11 centers between May 1989 and October 1993. All patients had to undergo transthoracic and transesophageal echocardiography within 24 hours of each other; ASA was defined as a protrusion of the aneurysm > 10 mm beyond the plane of the atrial septum as measured by TEE. Patients with mitral stenosis or prosthesis or after cardiothoracic surgery involving the atrial septum were excluded. Based on these criteria, 195 patients 54.6 +/- 16.0 years old (mean +/- SD) were included in this study. Whereas TEE could visualize the region of the atrial septum and therefore diagnose ASA in all patients, ASA defined by TEE was missed by transthoracic echocardiography in 92 patients (47%). As judged from TEE, ASA involved the entire septum in 100 patients (51%) and was limited to the fossa ovalis in 95 (49%). ASA was an isolated structural defect in 62 patients (32%). In 106 patients (54%), ASA was associated with interatrial shunting (atrial septal defect, n = 38; patent foramen ovale, n = 65; sinus venosus defect, n = 3). In only 2 patients (1%), thrombi attached to the region of the ASA were noted. Prior clinical events compatible with cardiogenic embolism were associated with 87 patients (44%) with ASA; in 21 patients (24%) with prior presumed cardiogenic embolism, no other potential cardiac sources of embolism were present. Length of ASA, extent of bulging, and incidence of spontaneous oscillations were similar in patients with and without previous cardiogenic embolism; however, associated abnormalities such as atrial shunts were significantly more frequent in patients with possible embolism. CONCLUSIONS As shown previously, TEE is superior to the transthoracic approach in the diagnosis of ASA. The most common abnormalities associated with ASA are interatrial shunts, in particular patent foramen ovale. In this retrospective study, patients with ASA (especially with shunts) showed a high frequency of previous clinical events compatible with cardiogenic embolism; in a significant subgroup of patients, ASA appears to be the only source of embolism, as judged by TEE. Our data are consistent with the view that ASA is a risk factor for cardiogenic embolism, but thrombi attached to ASA as detected by TEE are apparently rare.

C-Reactive Protein Colocalizes With Complement in Human Hearts During Acute Myocardial Infarction

BACKGROUND Rises in circulating C-reactive protein (CRP), the prototypical acute-phase protein in humans, correlate with clinical outcome in patients with myocardial ischemia and infarction. We hypothesized that these correlations might reflect active participation of CRP in the local inflammatory response ensuing in the jeopardized myocardium because on binding to a ligand, CRP is able to activate the classic pathway of complement, and in addition, complement activation has been shown to occur locally in infarcted myocardium. METHODS AND RESULTS To verify our hypothesis, we investigated localization of CRP in relation to deposition of complement in tissue specimens of infarcted and healthy heart tissue obtained from 17 patients who had died after acute myocardial infarction. CRP was found to be deposited only in infarcted regions and not in normal-appearing areas of the myocardium, being colocalized with depositions of C4 and C3 activation fragments of the complement system. Deposition of CRP and complement in infarcted myocardium appeared to be time dependent, because it was found in all infarctions except for one of young age (< 12 hours old) and two of greater age (> 1 year old), whereas another tissue specimen of an infarct < 12 hours old showed only moderate but positive staining for both CRP and complement in comparison with older infarctions. CONCLUSIONS We conclude that in humans, CRP may localize in infarcted heart tissue and suggest that this acute-phase protein promotes local complement activation, and hence tissue damage, in acute myocardial infarction.

Magnetic Resonance Angiography of Anomalous Coronary Arteries A New Gold Standard for Delineating the Proximal Course

BACKGROUND The clinical significance of anomalously originating coronary arteries depends on their proximal course. Diagnosis of this course by conventional x-ray coronary angiography alone may be equivocal. We postulated that with fast magnetic resonance (MR) angiography, accurate detection of anomalous coronary arteries and unambiguous delineation of their proximal course is feasible. METHODS AND RESULTS In a selected group of 38 patients, 19 of them having an anomalously originating coronary artery, a fast MR angiographic technique was used to study the proximal coronary anatomy. Blinded analysis of randomly ordered MR studies was performed independently by two observers. Both origin and proximal course of the coronary arteries were defined. Two cardiologists reviewed all x-ray coronary angiograms. After the separate analyses, a final consensus result was defined for each patient. In 37 patients, successful MR coronary angiography could be performed. Interobserver agreement for determining both origin and proximal course was 100%. An x-ray coronary angiogram was available in 36 patients. In 3 patients (all with an anomalous left main coronary artery originating from the right aortic sinus), there was disagreement about the proximal course between the results of MR and x-ray coronary angiography. Review of these cases demonstrated that MR angiography had unambiguously visualized the proximal coronary artery course, whereas the results of x-ray angiography had been equivocal. Thus, sensitivity and specificity for detecting anomalous coronary arteries and delineating their proximal course were 100%. CONCLUSIONS These data suggest that fast MR angiography is highly accurate in determining the origin and delineating the proximal course of anomalous coronary arteries, even in those cases in which x-ray coronary angiographic diagnosis is difficult or even erroneous.

Delayed contrast-enhanced magnetic resonance imaging for the prediction of regional functional improvement after acute myocardial infarction.

OBJECTIVES We evaluated whether delayed contrast-enhanced magnetic resonance imaging (DCE-MRI) using an extracellular contrast agent could predict improvement of dysfunctional but viable myocardium after acute reperfused myocardial infarction (MI). BACKGROUND The transmural extent of hyperenhancement at DCE-MRI has been related to improvement of function in reperfused MI. However, evidence is still limited, and earlier reports have produced conflicting results regarding the significance of contrast patterns after infarction. METHODS Thirty patients (mean age 59 +/- 11 years, 27 males) underwent cine MRI and DCE-MRI 7 +/- 3 days after a first reperfused acute MI and follow-up cine MRI at 13 +/- 3 weeks. Segmental wall thickening and segmental extent of hyperenhancement were scored in 1,689 segments. RESULTS Of 500 dysfunctional segments, 273 (55%) improved at follow-up. There was no difference in likelihood of improvement or complete functional recovery between segments with 0% and 1% to 25% hyperenhancement. The likelihood of improvement of segments without hyperenhancement was 2.9, 14.3, and 20 times higher than that of segments with 26% to 50%, 51% to 75%, and >75% hyperenhancement, respectively (p < 0.001). The likelihood of complete functional recovery of segments without hyperenhancement was 3.8, 11.1, and 50 times higher than that of segments with 26% to 50%, 51% to 75%, and >75% hyperenhancement, respectively (p < 0.001). CONCLUSIONS In patients with recent reperfused MI, functional improvement of stunned myocardium is predicted by DCE-MRI.

Assessment of Myocardial Reperfusion by Intravenous Myocardial Contrast Echocardiography and Coronary Flow Reserve After Primary Percutaneous Transluminal Coronary Angiography in Patients With Acute Myocardial Infarction

Background—This study investigated whether the extent of perfusion defect determined by intravenous myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction (AMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) relates to coronary flow reserve (CRF) for assessment of myocardial reperfusion and is predictive for left ventricular recovery. Methods and Results—Twenty-five patients with first AMI underwent intravenous MCE with NC100100 with intermittent harmonic imaging before PTCA and after 24 hours. MCE before PTCA defined the risk region and MCE at 24 hours the “no-reflow” region. The no-reflow region divided by the risk region determined the ratio to the risk region. CFR was assessed immediately after PTCA and 24 hours later. Left ventricular wall motion score indexes were calculated before PTCA and after 4 weeks. CFR at 24 hours defined a recovery (CFR ≥1.6; n=17) and a nonrecovery group (CFR <1.6; n=8). Baseline CFR did not differ between groups. M...

Prognostic Implications of Restrictive Left Ventricular Filling in Acute Myocardial Infarction: A Serial Doppler Echocardiographic Study

OBJECTIVES This study was designed to evaluate the relative prognostic significance of restrictive left ventricular (LV) filling after acute myocardial infarction. BACKGROUND Data regarding the contribution of diastolic dysfunction to prognosis after myocardial infarction are limited, and the additional value over the assessment of systolic dysfunction is not known. METHODS Serial Doppler echocardiography was performed in 95 patients on days 1, 3 and 7 and 3 months after acute myocardial infarction. Patients were classified into two groups: a restrictive group (n = 12) with a peak velocity of early diastolic filling wave (E)/peak velocity of late filling wave (A) ratio > or = 2 or between 1 and 2 and a deceleration time (DT) < or = 140 ms during at least one echocardiographic study; and a nonrestrictive group (n = 83) with an E/A ratio < or = 1 or between 1 and 2 and a DT > 140 ms at all examinations. RESULTS Cardiac death occurred in 10 patients during a mean follow-up interval of 32 +/- 17 months. The survival rate at 1 year was 100% in the nonrestrictive group and only 50% in the restrictive group. After 1 year there was a continuing divergence of mortality, resulting in a 3-year survival rate of 100% and 22%, respectively. Univariate Cox analysis revealed that restrictive LV filling, wall motion score index, ejection fraction and end-systolic and end-diastolic volume indexes, as well as peak creatine kinase, peak MB fraction and heart failure during the hospital course were significant predictors of cardiac death, although restrictive filling was the single best predictor (p < 0.0001). Multivariate analysis showed that restrictive filling adds prognostic information to clinical and echocardiographic variables of systolic dysfunction. CONCLUSIONS Restrictive LV filling after acute myocardial infarction is the single best predictor of cardiac death and adds significantly to clinical and echocardiographic markers of systolic dysfunction.

Prediction of recovery of myocardial dysfunction after revascularization comparison of fluorine-18 fluorodeoxyglucose/thallium-201 SPECT, thallium-201 stress-reinjection SPECT and dobutamine echocardiography

OBJECTIVES We compared three techniques to predict functional recovery after revascularization. BACKGROUND Recently, fluorine-18 (F-18) fluorodeoxyglucose in combination with single-photon emission computed tomography (SPECT) has been proposed to identify viable myocardium, Thallium-201 reinjection and low dose dobutamine echocardiography are used routinely for this purpose. METHODS Seventeen patients (mean [+/- SD] left ventricular ejection fraction 36 +/- 11%) were studied. Regional and global ventricular function were evaluated before and 3 months after revascularization by echocardiography and radionuclide ventriculography, respectively. Myocardial F-18 fluorodeoxyglucose uptake (during hyperinsulinemic glucose clamping) was compared with rest perfusion assessed with early thallium-201 SPECT. On a separate day, low dose dobutamine echocardiography and post-stress thallium-201 reinjection SPECT were simultaneously performed. RESULTS The sensitivities for F-18 fluorodeoxyglucose/thallium-201, thallium-201 reinjection and low dose dobutamine echocardiography to assess recovery were 89%, 93% and 85%, respectively; specificities were 77%, 43% and 63%, respectively. Stepwise logistic regression indicated that F-18 fluorodeoxyglucose/ thallium-201 was the best predictor. In hypokinetic segments, the combination of F-18 fluorodeoxyglucose/thallium-201 and low dose dobutamine echocardiography was the best predictor. Global function improved (left ventricular ejection fraction increased > 5%) in 6 patients and remained unchanged in 11. All three techniques correctly identified five of six patients with improvement. Fluorine-18 fluorodeoxyglucose/thallium-201 identified all patients without improvement; low dose dobutamine echocardiography identified 9 of 11 without improvement; and thallium-201 reinjection identified 6 of 11 patients without improvement. CONCLUSIONS Fluorine-18 fluorodeoxyglucose/thallium-201 SPECT was superior to the other techniques in assessing functional recovery. Integration of metabolic and functional data is necessary, particularly in hypokinesia, for optimal prediction of improvement of regional function.

Embolic Potential of Left Ventricular Thrombus After Myocardial Infarction: A Two-Dimensional Echocardiographic Study of 119 Patients

Left ventricular thrombus complicating myocardial infarction was diagnosed by two-dimensional echocardiography in 119 patients. The infarct site was anterior in 98 patients and inferior in 11. Systemic embolism occurred in 26 patients (stroke in 18, lower limb embolism in 7 and mesenteric embolism in 1). A protruding configuration of the thrombus was more common in the patients with embolism than in those without (23 [88%] of 26 versus 17 [18%] of 93) (p less than 0.01). Free mobility of the thrombus was found in 15 (58%) of 26 and 3 (3%) of 93 cases, respectively (p less than 0.01). In predicting embolism, protruding thrombus configuration had a sensitivity of 88% and a specificity of 82%, and positive and negative predictive accuracy was 57 and 96%, respectively. For free mobility of the thrombus, sensitivity was 58%, specificity 97%, positive predictive accuracy 85% and negative predictive accuracy 89%. In the 46 patients whose echocardiogram was obtained during the hospital admission for the index infarct, repeat echocardiograms were obtained during oral anticoagulant therapy. Twelve of these 46 patients had embolism and 2 of the 12 died. In seven of these patients, full dose oral anticoagulant therapy had been given before embolism occurred and in five it was started after an embolic event. The thrombus decreased in size or disappeared in six patients; in four the thrombus showed no change, and in two of these four emboli recurred despite anticoagulation. It is concluded that two-dimensional echocardiography may help delineate the embolic potential of left ventricular thrombus complicating myocardial infarction and may be of value in weighing the benefits and disadvantages of oral anticoagulant therapy.

Myocardial viability in chronic ischemic heart disease: Comparison of contrast-enhanced magnetic resonance imaging with 18F-fluorodeoxyglucose positron emission tomography

OBJECTIVES We sought to compare contrast-enhanced magnetic resonance imaging (ceMRI) with nuclear metabolic imaging for the assessment of myocardial viability in patients with chronic ischemic heart disease and left ventricular (LV) dysfunction. BACKGROUND Contrast-enhanced MRI has been shown to identify scar tissue in ischemically damaged myocardium. METHODS Twenty-six patients with chronic coronary artery disease and LV dysfunction (mean ejection fraction 31 +/- 11%) underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET), technetium-99m tetrofosmin single-photon emission computed tomography (SPECT), and ceMRI. In a 17-segment model, the segmental extent of hyperenhancement (SEH) by ceMRI, defined as the relative amount of contrast-enhanced tissue per myocardial segment, was compared with segmental FDG and tetrofosmin uptake by PET and SPECT. RESULTS In severely dysfunctional segments (n = 165), SEH was 9 +/- 14%, 33 +/- 25% (p < 0.05), and 80 +/- 23% (p < 0.05) in segments with normal metabolism/perfusion, metabolism/perfusion mismatch, and matched defects, respectively. Segmental glucose uptake by PET was inversely correlated to SEH (r = -0.86, p < 0.001). By receiver operator characteristic curve analysis, the area under the curve was 0.95 for the differentiation between viable and non-viable segments. At a cutoff value of 37%, SEH optimally differentiated viable from non-viable segments defined by PET. Using this threshold, the sensitivity and specificity of ceMRI to detect non-viable myocardium as defined by PET were 96% and 84%, respectively. CONCLUSIONS Contrast-enhanced MRI allows assessment of myocardial viability with a high accuracy, compared with FDG-PET, in patients with chronic ischemic heart disease and LV dysfunction.