Raffaele Bugiardini

Endothelial Function Predicts Future Development of Coronary Artery Disease A Study of Women With Chest Pain and Normal Coronary Angiograms

Background—The prognosis for women with chest pain and angiographically normal coronary arteries is believed to be totally benign. Previous studies, however, did not account for the delay of a decade or so in the development of coronary artery disease that women may experience. Methods and Results—This study assessed long-term follow-up of 42 women with de novo angina, evidence of reversible myocardial perfusion defects on SPECT, and normal coronary angiograms. At recruitment, all women underwent endothelial function testing (intracoronary acetylcholine) during catheterization. Patients were followed up for >10 years. Angiography was repeated at the end of the follow-up in 37 patients. At recruitment, 22 patients developed diffuse vasoconstriction during acetylcholine in the absence of identifiable focal coronary spasm (acetylcholine-positive group). The remaining 20 patients showed vasodilation (acetylcholine-negative group). At the end of follow-up, in the acetylcholine-positive group, 1 patient developed cardiac death, 13 still complained of chest pain, and 8 had remission of symptoms. In the acetylcholine-negative group, all patients showed complete resolution of chest pain beginning 6 to 36 months after baseline assessment. Angiography showed development of coronary artery disease in the 13 symptomatic patients in the acetylcholine-positive group. Conclusions—In women with angiographically normal-appearing coronary arteries, persistence of chest pain over the years often relates to development of coronary artery disease. Endothelial dysfunction in a setting of normal coronary arteries is a sign of future development of atherosclerosis.

Angiotensin-Converting Enzyme Inhibitors and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Cardiac Syndrome X. Role of Superoxide Dismutase Activity

Background—Morbidity of patients with Syndrome X (SX; chest pain and normal coronary angiograms) is high and is associated with continuing episodes of chest pain and hospitalization. Impairment of microvascular endothelial function caused by increased oxidative stress has been suggested to be a mechanism of the disease. Superoxide dismutase (SOD) is the major antioxidant enzyme system of the vascular wall. This study sought to establish whether combination treatment with ACE inhibitors and statins reduces oxidative stress and improves quality of life of patients with cardiac SX. Methods and Results—Forty-five patients with SX were randomly assigned to receive either a combination of ramipril (10 mg/d) and atorvastatin (40 mg/d) or placebo for 6 months. We determined the activity of extracellular SOD and its relation to flow-dependent endothelium-mediated dilation (FMD) and quality of life (exercise capacity and score with Seattle Angina Questionnaire [SAQ]) before and after treatment. After 6 months, patients with SX who received atorvastatin and ramipril had significantly reduced (P =0.001) SOD levels (188.1±29.6 U/mL). No significant changes were seen on placebo (262.9±48.8 U/mL). Reduction of SOD after therapy was negatively correlated with FMD (r =0.38; P =0.01) and positively with total cholesterol (r =−0.56; P <0.001). At follow-up, patients taking atorvastatin and ramipril improved their quality of life both in terms of exercise duration (by 23.46%) and SAQ (by 64.1%). Conclusions—Six months of therapy with atorvastatin and ramipril improves endothelial function and quality of life of patients with SX. Reduced SOD activity may reflect low superoxide anion production. Benefits of these drugs may be related to reduction of oxidative stress.

A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings

Obstructive disease of the large coronary arteries is the prominent cause for angina pectoris. However, angina may also occur in the absence of significant coronary atherosclerosis or coronary artery spasm, especially in women. Myocardial ischaemia in these patients is often associated with abnormalities of the coronary microcirculation and may thus represent a manifestation of coronary microvascular disease (CMD). Elucidation of the role of the microvasculature in the genesis of myocardial ischaemia and cardiac damage-in the presence or absence of obstructive coronary atherosclerosis-will certainly result in more rational diagnostic and therapeutic interventions for patients with ischaemic heart disease. Specifically targeted research based on improved assessment modalities is needed to improve the diagnosis of CMD and to translate current molecular, cellular, and physiological knowledge into new therapeutic options.

Gender Bias in Acute Coronary Syndromes

The major aim of this review was to ascertain whether effective evidence-based treatments for acute coronary syndromes (ACS) are underutilized in women in various geographic areas compared with men. The focus of our review was the relative use of effective treatments in patients with coronary angiographic evidence of obstructive coronary disease, defined as a lumen stenosis >50% of the adjacent non-diseased arterial diameter. We searched MEDLINE, and the Cochrane Database between January 1998 and May 2008. Only a few of the published clinical registries on ACS provide data on treatments dichotomized by confirmed coronary angiographic disease. Consequently, we also accessed individual patient-level data from 3 established ACS registries: the Finnish TACOS (Tampere Acute COronary Syndrome), the British EMMACE 2 (Evaluation of Methods and Management of Acute Coronary Events) and the Argentine PACS-ITALSIA (Prognosis in Acute Coronary Syndromes and the ITALian hospital Sindrome Isquemico Agudo). Despite presenting with higher risk characteristics and having higher in-hospital and 6 months risk of death, women with ACS and obstructive coronary artery disease were apparently treated less aggressively with secondary preventive drugs than were men, being less likely to receive aspirin, beta-blockers and statins at discharge. Overall, coronary revascularization appears to be performed in a similar proportion of women and men - once angiography has been performed and the coronary anatomy is known. However, substantial geographic variation exists in the relative rate of coronary angiography in men and women. In United Kingdom coronary revascularization tends to be done less frequently in women. Our study, therefore, demonstrates a gender bias in the delivery of secondary drug treatments for ACS, even for patients with documented significant coronary disease.

Normal coronary arteries: clinical implications and further classification.

The term “chest pain with normal coronary arteries” encompasses a large number of different cardiac pathophysiological abnormalities, including impairment of coronary flow reserve, endothelial dysfunction, and early atherosclerosis that, in most cases, cannot be readily differentiated one from the other.To study early coronary atherosclerosis, physicians must look beyond contrast filled arteries (so called lumenology). Angiograms cannot evaluate the vessel wall, plaque distribution and composition or other morphology. Plaques are often angiographically not visible due to their small size and compensatory enlargement (outward remodeling) of the coronary arteries. As a result, the search for an underlying atherosclerotic process remains ongoing. Available clinical studies showed that many patients with chest pain and normal angiography have early atherosclerosis as documented by intravascular ultrasound imaging, reduced coronary flow reserve and coronary endothelial dysfunction. Additional studies showed that patients presenting with normal coronary angiography have recurrent coronary events at long-term follow up.Research to determine if improved diagnosis and treatment of quantitatively low degrees of atherosclerosis lead to improved outcomes of patients with normal angiography should be undertaken.ZusammenfassungDer Begriff „Brustschmerz mit normalem Koronarogramm“ umfasst eine große Zahl von verschiedenen kardialen pathophysiologischen Anomalien, z. B. eine Einschränkung der koronaren Flussreserve, eine endotheliale Dysfunktion und frühe Zeichen der Atherosklerose, die in vielen Fällen nicht voneinander differenziert werden können. Um die frühen Zeichen der koronaren Arteriosklerose zu erkennen, müssen weitergehende Untersuchungen zur reinen Kontrastangiographie (Konturmethode) durchgeführt werden. Die Angiographie kann die Gefäßwand, die Plaqueverteilung und die Plaquekomposition nicht darstellen. Plaques sind häufig angiographisch nicht sichtbar, weil sie umschrieben, klein und durch kompensatorische Gefäßerweiterungen (auswärts Remodeling) verdeckt werden. Deshalb muss die Suche nach einer möglicherweise vorhandenen arteriosklerotischen Erkrankung ausgedehnt werden. Verfügbare klinische Studien zeigen, dass viele Patienten mit Brustschmerz und normalen Koronararterien frühe Zeichen der Arteriosklerose aufweisen, die mittels intravaskulärem Ultraschall auch an einer reduzierten koronaren Flussreserve und einer gestörten Endothelfunktion erkannt werden können. Studien zeigen, dass bei Patienten mit normalem Koronarogramm wiederholte Koronarereignisse im Langzeitverlauf auftreten können. Studien müssen durchgeführt werden, um zu zeigen, ob Patienten mit einem Frühstadium der Arteriosklerose einen günstigen Verlauf zeigen, wenn frühzeitig die Diagnose gestellt und eine entsprechende Behandlung eingeleitet wird.

In-hospital case fatality rates for acute myocardial infarction in Romania

Background: We describe the clinical characteristics, treatments and in-hospital case-fatality rates in an unselected population of patients admitted for acute myocardial infarction. Methods: From January 2000 to June 2007, we tracked consecutive patients who were admitted to 7 tertiary referral and 21 county hospitals in Romania for medical treatment of ST-segment elevation acute myocardial infarction. These patients were enrolled in the Romanian Registry for ST-segment Elevation Myocardial Infarction. For this prospective study, we collected data on demographic characteristics, cardiovascular risk factors, various aspects of treatment for myocardial infarction, and in-hospital death. Results: The 9186 patients in the study group had a mean age of 63.8 years. The median time from onset of symptoms to thrombolysis was 230 (interquartile range 120–510) minutes. Of the 9186 patients, 4986 (54.3%) had hypertension, 1974 (21.5%) had diabetes mellitus, 3545 (38.6%) had lipid disorders and 4653 (50.7%) were smokers. The in-hospital mortality rate was 12.7% (1170 deaths). The study group consisted of 2893 women and 6293 men. The women were older than the men and had higher rates of hypertension and diabetes mellitus but were less likely to be smokers. A smaller proportion of women than men presented within 2 hours after onset of symptoms (23.1% v. 34.4%, p < 0.001). Smaller proportions of women received thrombolytics (40.8% v. 53.5%, p < 0.001), anticoagulants (93.4% v. 95.2%; p = 0.001), antiplatelet agents (88.3% v. 91.2%, p < 0.001) and primary percutaneous coronary interventions (1.5% v. 2.2%, p = 0.030). The risk of in-hospital death was greater for women, even after adjustment for confounders (odds ratio 1.33, 95% confidence interval 1.13–1.56; p < 0.001). Interpretation: The rates of reperfusion therapy for patients with acute myocardial infarction were low, and in-hospital case-fatality rates were high in this study. Excess in-hospital mortality was more pronounced among women.

Further insights into syndrome X

Chest pain with normal coronary angiograms is a relatively common syndrome. The mode of presentation of this syndrome includes patients with ‘syndrome X’ and patients with an acute myocardial infarction and angiographically normal coronary arteries. Several authors have attempted to categorise ‘chest pain with normal coronary arteries’ into distinct syndromes: cardiac syndrome X (CSX), vasotonic angina and ‘the sensitive heart’.1 Other authors preferred to label these patients simply as: ‘patients with normal angiography’.2 Yet, these terms are often used to describe a different situation for each group of authors. In the study of Chimenti et al ( see page 1926 ) the definition of CSX is ‘patients with chest pain, positive exercise test for myocardial ischaemia and angiographically smooth coronary arteries in multiple angiographic views’.3 Lanza et al defined CSX as a form of stable effort angina, which, according to careful diagnostic investigation, can reasonably be attributed to abnormalities in the coronary microvascular circulation even in the presence of near normal (<20% luminal narrowing) coronary arteries at angiography.4 Clearly, with this definition, patients with normal angiography are diluted with those with mild coronary artery disease in whom development of subsequent coronary events may simply reflect complication of coronary artery disease that was already present. Acknowledging that mild coronary artery disease is equivalent to normal coronary arteries is an assumption that is contradicted by recent data on the prognosis of those patients presenting acute coronary syndromes without angiographically visible lumen narrowing.5nnAbnormalities of pain perception have been reported in patients with CSX.1 In situ thrombosis or embolisation with subsequent clot lysis and recanalisation, coronary artery spasm, cocaine abuse and viral myocarditis have been reported as potential mechanisms responsible for an acute coronary syndrome in patients with angiographically normal coronary arteries.6 Recent data suggest that both microvascular …

Effect of Percutaneous Coronary Intervention on Coronary Blood Flow at Rest in Myocardial Sites Remote from the Intervention Site in Patients With Stable Angina Pectoris

Little is known about changes in myocardial perfusion of myocardial regions supplied by angiographically normal or near-normal coronary arteries after percutaneous coronary intervention (PCI) of the target lesion. The purpose of this study was to assess the effect of PCI on coronary blood flow at rest in sites remote from the PCI. We studied 85 patients who underwent successful elective PCI for stable angina. We used the Thrombolysis In Myocardial Infarction frame count to provide a simple continuous index of coronary flow and myocardial perfusion in the target and nontarget arteries. Coronary artery diameters of nontarget vessels did not significantly differ before and after PCI and at 6 months follow-up. At baseline, the greater the percent diameter stenosis in the target artery, the slower the flow in the target (r = 0.22, p <0.01) and nontarget arteries (r = 0.28, p <0.01). Relief of stenosis using PCI did not account for simultaneous changes in epicardial coronary blood flow of the nontarget artery. After 6 months, coronary blood flow improved in both the target (p <0.05) and nontarget arteries (p = 0.007). In conclusion, this study provided evidence of a functional link between coronary blood flow in diseased and nondiseased arteries. Relief of a significant stenosis using PCI globally improved regional and global myocardial blood flow at rest in patients with stable angina. Flow improvement was not apparent at the time of revascularization, but at 6 months follow-up. Late upturn of the microcirculation may account for delayed recovery of myocardial perfusion.

Diagnosis and Treatment of Heart Disease: Are Women Different From Men?

Key questions concerning strategies for diagnosis, prevention, and treatment of heart disease in women remain unanswered. Thrombolytic therapy has been shown to reduce mortality similarly in men and women. In addition, percutaneous coronary intervention for acute coronary syndromes is as effective in women as in men. However, after hospital discharge, medical treatment carries different benefits in men and women. Aspirin has not been definitively proven to prevent cardiovascular events in women. Men and women respond differently to statins. Men may experience a greater benefit than women from angiotensin-converting enzyme inhibitors. β-Blockers substantially improve survival in women, with possibly a greater benefit than in men. Clopidogrel appears to be equally effective in reducing cardiovascular events in both men and women. Our report will review current knowledge supporting sex differences in the diagnosis and treatment of ischemic heart disease. A clear definition of the state of the science, with recognition of the shortcomings of current data, is necessary to guide future research and move the field forward.