John F. Beltrame

Major Racial Differences in Coronary Constrictor Response Between Japanese and Caucasians With Recent Myocardial Infarction

BACKGROUND Enhanced coronary vasomotion may contribute to acute coronary occlusion during the acute phase of myocardial infarction (AMI). Japanese have a higher incidence of variant angina than Caucasian patients, but racial differences in vasomotor reactivity early after AMI are controversial. METHODS AND RESULTS The same team studied 15 Japanese and 19 Caucasian patients within 14 days of AMI by acetylcholine injection into non-infarct-related (NIRA) and infarct-related (IRA) coronary arteries followed by nitroglycerin. Incidence of vasodilation, vasoconstriction, spasm, and basal tone were assessed in proximal, middle, and distal segments after each drug bolus by quantitative angiography. Japanese patients had much lower cholesterol levels than Caucasians (183+/-59 versus 247+/-53 mg/dL, P<0.006) but showed a lower incidence of vasodilation (2% versus 9% of coronary segments) and a greater incidence of spasm after acetylcholine (47% versus 15% of arteries, P<0.00001). Incidence of spasm was higher in IRAs than in NIRAs in both populations (67% versus 39% and 23% versus 11%, respectively). Multivessel spasm was more common (64% versus 17%, P<0.02) and vasoconstriction of nonspastic segments was greater in Japanese patients (-23.4+/-14.9% versus -20.1+/-15.7%, P<0.02) in the presence of similar average basal coronary tone with respect to post-nitroglycerin dilation and of nonsignificant differences of coronary atherosclerotic score. CONCLUSIONS Soon after AMI, Japanese patients exhibited a 3-fold-greater incidence of spasm and greater vasoconstriction of nonspastic segments after acetylcholine than Caucasians. The causes of such differences warrant further investigation because they may have relevant pathophysiological and therapeutic implications.

Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial

BACKGROUND Cardiac transplantation is associated with oxidant stress, which may contribute to the development of accelerated coronary arteriosclerosis. We postulated that treatment with antioxidant vitamins C and E would retard the progression of transplant-associated arteriosclerosis. METHODS In a double-blind prospective study, 40 patients (0-2 years after cardiac transplantation) were randomly assigned vitamin C 500 mg plus vitamin E 400 IU, each twice daily (n=19), or placebo (n=21) for 1 year. The primary endpoint was the change in average intimal index (plaque area divided by vessel area) measured by intravascular ultrasonography (IVUS). Coronary endothelium-dependent vasoreactivity was assessed with intracoronary acetylcholine infusions. IVUS, coronary vasoreactivity, and vitamin C and E plasma concentrations were assessed at baseline and at 1 year follow-up. All patients received pravastatin. Analyses were by intention to treat. FINDINGS Vitamin C and E concentrations increased in the vitamin group (vitamin C 43 [SD 21] to 103 [43] mmol/L; vitamin E 24 [14] to 65 [27] mmol/L) but did not change in the placebo group (vitamin C 45 [15] vs 43 [16] mmol/L; vitamin E 27 [14] vs 27 [9] mmol/L; p<0.0001 for difference between groups). During 1 year of treatment, the intimal index increased in the placebo group by 8% (SE 2) but did not change significantly in the treatment group (0.8% [1]; p=0.008). Coronary endothelial function remained stable in both groups. INTERPRETATION Supplementation with antioxidant vitamins C and E retards the early progression of transplant-associated coronary arteriosclerosis.

Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and caucasian patients

Japanese investigators have provided a substantial contribution in the understanding of coronary vasomotor reactivity. On occasions, their findings have been at variance with those undertaken on caucasian patients, raising speculation that vasomotor differences between races may exist. In a comparative review of the published literature, we evaluated the vasoreactive differences among Japanese and caucasian patients with variant angina or myocardial infarction. In variant angina, Japanese patients appear to have diffusely hyperreactive coronary arteries compared with caucasian people, manifested by their segmental rather than focal spasm, hyperreactive nonspastic vessels and multivessel spasm. These differences may reflect the increased basal tone among Japanese variant angina patients and may relate to controversial differences in endothelial nitric oxide production or autonomic nervous system activity. Provocative vasomotor studies of Japanese patients with a recent myocardial infarction report a higher incidence of inducible spasm than caucasian studies, an observation recently supported by a controlled study. Furthermore, the hyperreactivity was diffuse, occurring in both non-infarct- and infarct-related vessels. These observations support the existence of racial coronary vasomotor reactivity differences but require confirmation in further prospectively conducted studies.

The Coronary Slow Flow Phenomenon – A New Coronary Microvascular Disorder

The coronary slow flow phenomenon is an angiographic finding characterized by delayed distal vessel opacification in the absence of significant epicardial coronary disease. Case-control and observational studies of patients with this phenomenon were conducted to determine the associated clinical features and prognosis. Patients with coronary slow flow (n = 47) differed from controls (n = 47), more often being current smokers (32 vs. 9%; p < 0.01) and presenting with rest pain requiring urgent admission (74 vs. 21%; p < 0.001), usually to the coronary care unit (66 vs. 17%; p < 0.01). During a median 21-month follow-up of 64 slow flow patients, 84% had recurrent chest pain. Based upon these findings and those of previous investigators, it is speculated that coronary slow flow is a new disease entity characterized by acute but recurrent perturbations of microvascular function.

Systematic Review of Patients Presenting With Suspected Myocardial Infarction and Nonobstructive Coronary Arteries

Background— Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a puzzling clinical entity with no previous evaluation of the literature. This systematic review aims to (1) quantify the prevalence, risk factors, and 12-month prognosis in patients with MINOCA, and (2) evaluate potential pathophysiological mechanisms underlying this disorder. Methods and Results— Quantitative assessment of 28 publications using a meta-analytic approach evaluated the prevalence, clinical features, and prognosis of MINOCA. The prevalence of MINOCA was 6% [95% confidence interval, 5%–7%] with a median patient age of 55 years (95% confidence interval, 51–59 years) and 40% women. However, in comparison with those with myocardial infarction associated with obstructive coronary artery disease, the patients with MINOCA were more likely to be younger and female but less likely to have hyperlipidemia, although other cardiovascular risk factors were similar. All-cause mortality at 12 months was lower in MINOCA (4.7%; 95% confidence interval, 2.6%–6.9%) compared with myocardial infarction associated with obstructive coronary artery disease (6.7%, 95% confidence interval, 4.3%–9.0%). Qualitative assessment of 46 publications evaluating the underlying pathophysiology responsible for MINOCA revealed the presence of a typical myocardial infarct on cardiac magnetic resonance imaging in only 24% of patients, with myocarditis occurring in 33% and no significant abnormality in 26%. Coronary artery spasm was inducible in 27% of MINOCA patients, and thrombophilia disorders were detected in 14%. Conclusions— MINOCA should be considered as a working diagnosis with multiple potential causes that require evaluation so that directed therapies may improve its guarded prognosis.

Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon

BACKGROUND The coronary slow flow phenomenon (CSFP) is an angiographic finding characterized by Thrombolysis in Myocardial Infarction (TIMI)-2 flow in the absence of significant large vessel coronary disease. Although clinical and pathological features have been previously described, the underlying pathophysiology has not been fully elucidated. This study investigates the persistence of the phenomenon on serial angiographic studies, coronary hemodynamic findings at rest and during provocative stimuli, and biochemical evidence of inducible myocardial ischemia. METHODS Twelve patients with CSFP underwent repeat angiography and coronary sinus canulation that allowed for the assessment of coronary blood flow, transmyocardial lactate, and oxygen extraction. Parameters were assessed at rest and during rapid atrial pacing, cold pressor stimulation, and acetylcholine infusion. Angiographic and coronary hemodynamic findings were compared with 47 patients who underwent angiography and 8 patients who were hemodynamic control subjects, respectively. RESULTS Persistent TIMI-2 flow was demonstrated with repeat angiography in only 4 of the patients. However, the corrected TIMI frame count remained delayed compared with that in control subjects. Furthermore, resting coronary sinus oxygen saturation was low compared with control subjects (23% +/- 4% vs 31% +/- 4%; P <.01), reflecting an increased basal coronary vasomotor tone. The coronary vasodilatory response to atrial pacing was similar to that in control subjects; however, several patients exhibited abnormal vasomotor responsiveness to cold pressor and acetylcholine stimuli. There was no evidence of nett myocardial lactate production with atrial pacing. CONCLUSION The CSFP is associated with a chronically elevated resting coronary microvascular tone, even when symptoms are relatively quiescent.

ESC working group position paper on myocardial infarction with non-obstructive coronary arteries

The management of acute myocardial infarction (AMI)1 has evolved over the past century and particularly in the past 50 years. Important milestones include the development of the electrocardiogram, coronary care units, coronary angiography, reperfusion therapies, and troponin assays. These innovations are the foundation of contemporary AMI management strategies that include a diagnosis centred on elevated troponin values associated with corroborative clinical evidence,1 early use of coronary angiography, and reperfusion therapies.2–4 Pivotal in the evolution of these contemporary strategies were the early AMI coronary angiography studies undertaken by DeWood et al. These pioneering studies demonstrated that, in patients presenting with ST elevation myocardial infarction (STEMI), almost 90% had an occluded coronary artery provided that angiography was undertaken within 4 h of chest pain onset.5 In contrast, in AMI patients who did not present with ST elevation (non-ST elevation myocardial infarction or NSTEMI), only 26% had an occluded coronary artery when angiography was performed within 24 h of symptom onset.6 In both of these landmark studies,5,6 >90% of the acute MI patients had angiographic evidence of obstructive coronary artery disease (CAD), underscoring the importance of the atherosclerotic process in the pathogenesis of AMI. Although DeWoods studies underscore the importance of obstructive CAD in AMI, it is fascinating that ∼10% had no significant CAD on coronary angiography. This is confirmed in several large AMI registries7–9 where 1–13% of AMIs occurred in the absence of obstructive CAD thereby eliciting an important set of questions—what is the mechanism of the myocardial damage in these patients? Do these patients differ from those with obstructive CAD? Should they be …

N-Terminal Pro-Brain Natriuretic Protein Levels in Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular (LV) systolic dysfunction independent of fixed coronary disease or coronary spastic pathogenesis. A number of investigators have documented marked elevation of natriuretic peptide levels at presentation in such patients. We sought to determine the pattern, extent, and determinants of the release of N-terminal pro-B type natriuretic peptide/B type natriuretic peptide (NT-proBNP/BNP) in patients with TTC. We evaluated NT-proBNP/BNP release acutely and during the first 3 months in 56 patients with TTC (96% women, mean age 69 ± 11 years). The peak plasma NT-proBNP levels were compared to the pulmonary capillary wedge pressure and measures of regional and global LV systolic dysfunction (systolic wall stress, wall motion score index, and LV ejection fraction) as potential determinants of NT-proBNP/BNP release. In patients with TTC, the plasma concentrations of NT-proBNP (median 4,382 pg/ml, interquartile range 2,440 to 9,019) and BNP (median 617 pg/ml, interquartile range 426 to 1,026) were substantially elevated and increased significantly during the first 24 hours after the onset of symptoms (p = 0.001), with slow and incomplete resolution during the 3 months thereafter. The peak NT-proBNP levels exhibited no significant correlation with either pulmonary capillary wedge pressure or systolic wall stress. However, the peak NT-proBNP level correlated significantly with the simultaneous plasma normetanephrine concentrations (r = 0.53, p = 0.001) and the extent of impairment of LV systolic function, as measured by the wall motion score index (r = 0.37, p = 0.008) and LV ejection fraction (r = -0.39, p = 0.008). In conclusion, TTC is associated with marked and persistent elevation of NT-proBNP/BNP levels, which correlated with both the extent of catecholamine increase and the severity of LV systolic dysfunction.

Interval training versus continuous exercise in patients with coronary artery disease: a meta-analysis.

BACKGROUND High aerobic capacity is inversely related to cardiovascular disease morbidity and mortality. Recent studies suggest greater improvements in aerobic capacity with high-intensity interval training (interval) compared to moderate-intensity continuous aerobic exercise (continuous). Therefore we perform a meta-analysis of randomised controlled trials comparing the effectiveness of INTERVAL versus CONTINUOUS in aerobic capacity, amongst patients with stable coronary artery disease (CAD) and preserved ejection fraction METHODS We searched PubMed, EMBASE, CINAHL, the Australia and New Zealand Clinical Trials Register, clinicaltrials.gov and TROVE for randomised controlled trials comparing INTERVAL with CONTINUOUS in patients with CAD. Studies published in the English language up to December 2013 were eligible for inclusion. Aerobic capacity, quantified by peak oxygen consumption (VO2peak) post exercise training was extracted and compared post-intervention between INTERVAL and CONTINUOUS by way of a fixed model meta-analysis. Secondary outcomes including anaerobic threshold, blood pressure and high-density lipoproteins (HDL) were also analysed. RESULTS Six independent studies with 229 patients (n=99 randomised to INTERVAL) were included in the meta-analysis. There was a significantly higher increase in VO2peak following INTERVAL compared to CONTINUOUS (Weighted Mean Difference=1.53 ml•kg(-1)min(-1), 95% CI 0.84 to 2.23) with homogeneity displayed between studies (Chi Squared=2.69; P=0.7). Significant effects of INTERVAL compared to CONTINUOUS were also found for anaerobic threshold but not systolic blood pressure. CONCLUSION In patients with CAD, INTERVAL appears more effective than CONTINUOUS for the improvement of aerobic capacity in patients with CAD. However, long-term studies assessing morbidity and mortality following INTERVAL are required before this approach can be more widely adopted.

International standardization of diagnostic criteria for vasospastic angina

The Coronary Vasomotion Disorders International Study Group (COVADIS) was established to develop international standards for the diagnostic criteria of coronary vasomotor disorders. The first symposium held on the 4-5 September 2013 addressed the criteria for vasospastic angina, which included the following (i) nitrate-responsive angina, (ii) transient ischaemic electrocardiogram changes, and (iii) documented coronary artery spasm. Adoption of these diagnostic criteria will improve the clinical diagnosis of this condition and facilitate research in this field.