Quantitative analysis of myocardial blood flow in surgically revascularized and not revascularized myocardial segments. A pilot PET study.

PURPOSE: To prospectively compare changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) in multivessel coronary artery disease (MVCAD) patients undergoing incomplete revascularization (IR) versus complete revascularization (CR) by coronary artery bypass grafting (CABG). METHODS: Seven male patients (age 68 ± 9 years) with MVCAD underwent myocardial perfusion PET/CT with [13N]ammonia before and at least 4 months after CABG. Segmental resting and stress MBF as well as MFR were measured. Resting and during stress left ventricle ejection fraction (LVEF) were also calculated. RESULTS: Three patients (43%) underwent CR and four (57%) IR. Among 119 myocardial segments, 101 (85%) were revascularized, and 18 (15%) were not. After CABG, stress MBF (mL/min/gr) and MFR are significantly increased in all myocardial segments, with a greater increase in the revascularized segments (p = 0.013). In both groups, LVEF significantly decreased during stress at baseline PET (p = 0.04), but not after CABG. CONCLUSION: Stress MBF and MFR significantly improve after CABG in both revascularized and not directly revascularized myocardial segments. IR strategy may be considered in patients with high surgical risk for CR.

Microvascular ischemia in patients with successful percutaneous coronary intervention: effects of ranolazine and isosorbide-5-mononitrate.

OBJECTIVE: About one-third of patients undergoing percutaneous coronary interventions (PCIs) for flow-limiting coronary stenosis continue to develop signs of myocardial ischemia (MI) during exercise stress test [EST], despite successful coronary revascularization. Coronary microvascular dysfunction is a likely major cause of the persistence of EST-induced MI in these patients. PATIENTS AND METHODS: We studied 15 patients (14 men, age 67±5 years) fulfilling the following strict inclusion criteria: (1) recent PCI (<6 months), with drug-eluting stent, of coronary artery stenoses for stable angina, with evidence of full success (no residual stenosis >20% in any vessel); (2) persistence of ST-segment depression induction during EST. After a basal investigation, patients received either ranolazine (375 mg bid) or isosorbide-5-mononitrate (ISMN, 20 mg bid) for 3 weeks in a single-blind, randomized crossover study. Clinical assessment, symptom-limited EST, echocardiographic color-Doppler, with tissue-Doppler examination, and coronary microvascular dilator response to adenosine (CFR-ADO) and cold pressor test (CFR-CPT), assessed by transthoracic echo-Doppler, were obtained at baseline and the end of the 3-week therapy with each drug. RESULTS: Compared to both baseline and ISMN, ranolazine showed a longer time to 1 mm ST-segment depression (404±116 s vs. 317±98 and 322±70 s, respectively; p<0.01). No differences were observed in coronary microvascular function and diastolic left ventricular function between the 2 drugs and compared to baseline. CONCLUSIONS: Our data show that ranolazine, but not ISMN, improved time to ischemia during EST. This effect, however, was independent of any effects on coronary microvascular and diastolic function.

Correlation between coronary microvascular function and angina status in patients with stable microvascular angina.

BACKGROUND: Classical anti-ischemic drugs are the first-line form of treatment in patients with microvascular angina (MVA), but they often fail to achieve a satisfactory control of angina symptoms. It is unknown whether there is any relation between improvement of angina status and changes in microvascular function induced by classical anti-ischemic drugs in MVA patients. AIM: To assess whether, in MVA patients, the effects of classical anti-ischemic drugs on symptoms and quality of life (QoL) are related to changes in coronary microvascular function. PATIENTS AND METHODS: We studied 51 patients (59±10 years; 15 men) with MVA. Coronary blood flow (CBF) response to adenosine (ADO) and to cold pressor test (CPT), Seattle Angina Questionnaire (SAQ) and EuroQoL scale were assessed at baseline, in pharmacological washout, and after 12 months under anti-ischemic therapy. Patients were divided into 2 groups: (1) Group 1 included patients with no improvement of QoL (EuroQoL score change < 10 points); (2) Group 2 included patients with QoL improvement (increase in EuroQoL score ≥ 10 points). RESULTS: At baseline, the 2 groups were similar in age, gender, cardiovascular risk factors, CBF response to ADO and to CPT, SAQ and EuroQoL scores. At follow-up the 2 groups differed only for beta blockers use (27% vs. 88% in group 1 and 2, respectively; p < 0.001). A significant improvement in SAQ score was observed only in group 2. CBF response to both ADO and CPT showed a similar improvement in the 2 groups. No relation was found between changes in coronary microvascular function and in angina status. CONCLUSIONS: In MVA patients beta-blockers are more effective than other anti-ischemic drugs in improving angina symptoms. The improvement of angina status does not seem to be mediated by changes in coronary microvascular function.

Effect of bariatric surgery on peripheral flow-mediated dilation and coronary microvascular function.

BACKGROUND AND AIMS: To assess the effects of bariatric surgery (BS) on peripheral endothelial function and on coronary microvascular dilator function. METHODS AND RESULTS: We studied 50 morbidly obese patients (age 38 ± 9, 13 M) who underwent BS and 20 comparable obese controls (age 41 ± 11, 6 M) without any evidence of cardiovascular disease. Peripheral vascular dilator function was assessed by brachial artery diameter changes in response to post-ischemic forearm hyperaemia (flow-mediated dilation, FMD). Coronary microvascular function was assessed by measuring coronary blood flow (CBF) velocity response to i.v. adenosine and to cold pressor test (CPT) in the left anterior descending coronary artery by transthoracic Doppler echocardiography. The tests were performed at baseline and at 3-month follow-up. At baseline, FMD and CBF response to adenosine and CPT were similar in the 2 groups. Compared to baseline, FMD at follow-up improved significantly in BS patients (5.9 ± 2.7% to 8.8 ± 2.4%, p < 0.01), but not in controls (6.3 ± 3.2% vs. 6.4 ± 3.1%, p = 0.41). Similarly, a significant improvement of CBF response to adenosine (1.63 ± 0.47 to 2.45 ± 0.57, p < 0.01) and to CPT (1.43 ± 0.26 to 2.13 ± 0.55, p < 0.01) was observed in BS patients but not in controls (1.55 ± 0.38 vs. 1.53 ± 0.37, p = 0.85; and 1.37 ± 0.26 vs. 1.34 ± 0.21, p = 0.48, respectively). The favourable vascular effects of BS were similar independently of the presence and changes of other known cardiovascular risk factors and of basal values and changes of serum C-reactive protein levels. CONCLUSIONS: Our data show that, in morbidly obese patients, together with peripheral endothelial function, BS also improves coronary microvascular function. These effects suggest global improvement of vascular function which can contribute significantly to the reduction of cardiovascular risk by BS reported in previous studies.

Cardiac adrenergic nerve function and microvascular dysfunction in patients with cardiac syndrome X.

OBJECTIVE: To assess whether abnormalities in cardiac uptake of (123)I-metaiodobenzylguanidine (MIBG) correlate with coronary microvascular dysfunction in patients with cardiac syndrome X (CSX). SETTING: University hospital. PATIENTS: 29 patients (aged 59 (SD 7) years, 11 men) with typical CSX and a matched group of 20 healthy subjects (aged 56 (7) years, 8 men) were studied. INTERVENTIONS: Planar and single photon emission computed tomography (SPECT) MIBG myocardial scintigraphy was performed in all subjects. Coronary flow response (CFR) to adenosine and to cold pressor test (CPT) in the left anterior descending (LAD) coronary artery was assessed in all CSX patients and in 12 controls by transthoracic Doppler echocardiography. MAIN OUTCOME MEASURES: Abnormalities in cardiac MIBG scintigraphy were observed in 25 CSX patients (86.2%), but in no healthy control (p<0.001). Compared to controls, CSX patients showed a lower heart/mediastinum (H/M) ratio of MIBG uptake (1.69 (0.24) vs 2.2 (0.3), p<0.001) and a higher cardiac MIBG defect score (25 (22) vs 4 (2), p = 0.002). Both CFR to adenosine (3.31 (1.1) vs 1.94 (0.6), p<0.001) and CFR to CPT (2.35 (0.5) vs 1.63 (0.4), p<0.001) were lower in CSX patients than in controls. In CSX patients, however, no correlation was found between MIBG H/M ratio and CFR to adenosine (r = 0.17; p = 0.38) and to CPT (r = -0.28; p = 0.13), as well as between MIBG uptake score in the LAD territory and CFR to adenosine (r = 0.14; p = 0.47) and to CPT (r = 0.06; p = 0.73). CONCLUSION: Our data show striking abnormalities in cardiac adrenergic nerve function and in coronary microvascular function in CSX patients. However, no significant relation between the two abnormalities was found. Further studies are needed to clarify the mechanisms and the role of MIBG defects in CSX patients.

Platelet aggregability in cardiac syndrome X.

AIMS: To assess platelet aggregability at rest and in response to exercise in patients with cardiac syndrome X (anginal chest pain, ST-segment depression on exercise, angiographically normal coronary arteries). METHODS AND RESULTS: We performed a symptom/sign-limited exercise test in 31 patients with syndrome X, 25 patients with coronary artery disease and 29 healthy subjects. Platelet aggregability was measured in flowing whole blood at baseline, at peak exercise, and after 30 and 120 min, as the time to occlude a collagen/adenosine diphosphate coated ring (aggregation time). Resting aggregation time was shorter in syndrome X patients (83.2+/-12 s), compared to patients with coronary disease (94.0+/-18 s, P<0.01) and to healthy subjects (96.4+/-21 s, P<0.01). With exercise, aggregation time did not change in healthy controls, decreased in patients with coronary disease (-13.8 s at peak; 95% CI, -10.2, -17.3 s;P<0.001), but increased in syndrome X (+17.4 s 30 min after exercise; 95% CI, +10.4, +24.4 s;P<0.0001). The intravenous administration of an adenosine antagonist (theophylline) prevented the exercise-induced prolongation of aggregation time in syndrome X patients (n=11), but had no effect in healthy controls (n=11). CONCLUSION: Platelet aggregability at rest was increased in syndrome X patients, compared to patients with coronary artery disease and healthy subjects. In contrast to patients with coronary disease, however, platelet aggregability was reduced by exercise. This response was prevented by theophylline, strongly suggesting the involvement of adenosine.

Low-grade exercise enhances platelet aggregability in patients with obstructive coronary disease independently of myocardial ischemia.

Moderate and strenuous exercise is known to enhance platelet aggregability in patients with obstructive coronary artery disease (CAD), but the effect of low-grade exercise is not known. We assessed shear-induced platelet aggregability before and after mild exercise (less than or equal to stage III of the modified Bruce protocol) in 27 patients with documented CAD who were receiving aspirin and in 12 subjects without CAD (controls). Ex vivo platelet aggregability was assessed in flowing whole blood as the time to occlude a collagen and adenosine diphosphate-coated ring; shorter times indicated greater aggregability. Aggregability, plasma von Willebrand factor (vWF) antigen, platelet and white cell counts, and hematocrit were measured at baseline, immediately after exercise (peak), and at 30 and 180 minutes after exercise. Exercise of similar workloads induced myocardial ischemia in 14 patients (group 1), but not in the other 13 (group 2) nor in controls. Both patient groups showed a reduction in aggregation time at peak exercise compared with baseline (group 1: 84+/-17 seconds at peak vs 96+/-22 seconds at baseline; group 2: 84+/-20 seconds at peak vs 99+/-20 seconds at baseline; p <0.03 for both comparisons), with a return to baseline values within 180 minutes. No significant variation occurred in controls (89+/-18 seconds at peak vs 85+/-21 second at baseline). Changes in vWF antigen did not differ significantly among groups. Aggregation times did not correlate with hematocrit or platelet and white cell counts. Thus, even low-grade exercise transiently enhances whole blood platelet aggregability in patients with obstructive CAD, but not in controls. The effect is independent of myocardial ischemia, occurs despite aspirin, and is likely dependent on hemodynamic factors interacting with coronary obstructions or dysfunctional endothelium.

A simple assay for platelet-mediated hemostasis in flowing whole blood (PFA-100): reproducibility and effects of sex and age.

BACKGROUND: A simple assay for platelet-mediated hemostasis in flowing blood (PFA-100) has become available. Whole blood is aspirated through the central opening of a membrane coated with platelet agonists; the time required for a platelet thrombus to occlude the opening is defined as closure time; the shorter the closure time the greater the platelet aggregability. There are limited data on the normal range of values for this test, and the effects of sex and age are not known. The aim of this study was to determine the effects of sex and age on closure time in normal volunteers and to assess the reproducibility of the test in our laboratory. METHODS: Closure time using collagen/adenosine-5'-diphosphate was measured in 62 apparently healthy individuals 35 to 75 years of age (11 men and 17 women < 55 years and 22 men and 12 women > 55 years). RESULTS: Closure time was 96.6 +/- 24 s in men and 93.1 +/- 16 s in women (p = 0.20). In the entire group, closure time did not significantly correlate with age (r = -0.17, p = 0.18). However, men < 55 years tended to have a longer closure time than men > 55 years (109.7 +/- 23 vs 90.0 +/- 22 s, p = 0.08), whereas in women closure time was similar in those younger or older than 55 years (93.1 +/- 16 vs 93.3 +/- 18 s, respectively). In 20 samples tested in duplicate, the mean closure time was 80.9 +/- 10 s on the first determination and 81.5 +/- 12 s on the second (r = 0.89, p < 0.001). There was no significant correlation between closure time and hematocrit, platelet number, mean platelet volume, or leukocyte count. CONCLUSIONS: The platelet function analyzer PFA-100 showed a good reproducibility in apparently healthy subjects. No significant difference in closure time was found between men and women, nor between subjects younger or older than 55 years, although a tendency towards shorter values was found in older compared with younger men.

Effects of bamiphylline on exercise testing in patients with syndrome X.

An abnormal stimulation of adenosine A1-receptors has been suggested to play a role in the pathogenesis of both chest pain and ischemia-like electrocardiographic changes in patients with syndrome X and a nonselective adenosine antagonist (theophylline) has been reported to be beneficial in these patients. In this study we investigated the acute effects of bamiphylline, a specific A1-receptor antagonist, in 16 patients with syndrome X (14 women, age 57 +/- 6 years), with both angina and ST-segment depression inducible during exercise testing. All patients underwent two treadmill exercise tests (Bruce modified protocol) on 2 separate days, 5 minutes after the end of randomized intravenous infusion of either placebo (saline solution) or bamiphylline (300 mg). Severity of chest pain was assessed by a 100 mm visual analogic scale. There were no significant differences in resting heart rate and blood pressure after bamiphylline or placebo. Rate-pressure product (20 600 +/- 5000 vs 20 200 +/- 5200 bpm.mmHg), time to 1 mm ST depression (549 +/- 196 vs 581 +/- 201 sec), time to angina (519 +/- 209 vs 571 +/- 196 sec), and exercise duration (717 +/- 134 vs 676 +/- 166 sec) were also not significantly different after bamiphylline or placebo, but there was a mild reduction of the severity of exercise-induced chest pain (30 +/- 22 vs 39 +/- 20 mm, p < 0.05) with the active drug. Thus, in patients with syndrome X, bamiphylline does not improve exercise-induced ST changes, suggesting that A1-receptors are not significantly involved in their appearance. In addition, bamiphylline had little effect on anginal pain, suggesting that this cannot be mediated exclusively by A1-receptor stimulation in these patients.

Microvascular angina in patients with normal coronary arteries and with other ischaemic syndromes.

In this paper we review the evidence that angina and 'ischaemic' ST depression can be caused by inappropriate constriction of small coronary artery vessels in patients with microvascular angina (i.e. anginal chest pain with angiographically normal coronary arteries). Although the mechanisms responsible for microvascular dysfunction remain unknown, it is conceivable that the constrictor stimuli may involve vessels which are proximal to those involved in metabolically induced dilation, so that the effect cannot be opposed, at the same site, by the dilator effect caused by ischaemic metabolites. Furthermore, in this review we also present evidence that myocardial ischaemia may result mainly from inappropriate constriction of small coronary vessels, rather than by obstruction of major epicardial coronary arteries. In addition, there are those prone to the condition, such as specific groups of patients with atherosclerotic ischaemic syndromes, including patients with single isolated coronary artery occlusion and no evidence of previous myocardial infarction, patients with single-vessel coronary stenosis who underwent successful balloon angioplasty, and patients with single-vessel disease with detectable abnormal vasomotor responses in non-stenotic coronary arteries.

Differences in vasodilatory response to dipyridamole between patients with angina and normal coronary arteries and patients with successful coronary angioplasty.

BACKGROUND: Previous studies reported a reduced coronary blood flow reserve, assessed by the intravenous administration of dipyridamole, in patients with angina and normal coronary arteries, and early after successful coronary angioplasty, which suggests the presence of small coronary vessel dysfunction. This study aimed to establish whether the mechanisms of small coronary vessel disease in these two groups of patients are similar. METHODS: The effects of the intracoronary infusion of adenosine and dipyridamole (maximum dose 2.7 and 7.5 mg/min, respectively) on coronary blood flow velocity were assessed in 11 patients with angina and normal coronary arteries (group A) and in 12 patients immediately after successful coronary angioplasty (group B) using a 0.018" Doppler wire. RESULTS: Baseline coronary blood flow velocity was significantly higher in group B than group A (34 +/- 14 versus 19 +/- 8 cm/s; P = 0.001). In group A, coronary blood flow velocity was higher during adenosine than dipyridamole infusion (74 +/- 17 versus 58 +/- 21 cm/s; P < 0.001), whereas in group B velocities were similar (85 +/- 30 versus 78 +/- 32 cm/s; NS). CONCLUSIONS: In patients with angina and normal coronary arteries, a maximal dose of adenosine causes a greater coronary dilation than that of dipyridamole. Given that dipyridamole operates mainly through an inhibition of adenosine re-uptake, it can only dilate the arteriolar segments exposed to endogenous adenosine. Therefore, the lower response to dipyridamole than to exogenous adenosine observed in patients with angina and normal coronary arteries suggests an impairment of the pre-arterioles that are not influenced by endogenous adenosine, resulting in a limited flow-mediated dilation in response to arteriolar dilation. Such an impairment is not apparent immediately after successful coronary angioplasty, where the most obvious abnormality is an increase of baseline coronary blood flow velocity.

[Mechanisms of coronary microvascular dysfunction]. / Meccanismi della disfunzione microvascolare coronarica.

Abnormal constriction of coronary resistive vessels can induce angina and myocardial ischemia. The possibility that a microvascular vasomotor dysfunction could cause ischemia is in contrast with the well-known traditional notion that a metabolically induced vasodilation could compensate for the effect of an epicardial coronary stenosis. Vasoconstrictor stimuli can plausibly act on vessels situated immediately proximal (prearterioles) to those that can be dilated by ischemia metabolites (arterioles). This functional 2-compartment model of resistive vessels is based on the ability of different substances to cause opposite actions on resistive vessels with different sizes. The possible mechanisms of prearteriolar dysfunction, observed in patients with syndrome X, single vessel disease after a successful PTCA and in a subset of chronic stable patients include: an organic reduction of total vascular section; vascular smooth muscle hyperreactivity to heterogeneous constrictor stimuli; an impaired flow-mediated endothelium-dependent vasodilation (possibly due to a reduced NO and/or EDHF synthesis). The first and third hypothesis can only account for anginal episodes at effort while the second model could explain episodes occurring at rest and without an increase in heart rate. Those mechanisms causing an imbalance between myocardial oxygen supply and demand, induce an increased release of adenosine in order to promote a compensating vasodilation. Adenosine can possibly avoid the occurrence of ischemia but, being a powerful algogenic stimulus, causes pain. It is worth noting that the presence of patchy prearteriolar dysfunction induces areas with excessive release of adenosine. Since total vascular section is extremely large a massive adenosine spill-over can occur with a consequential boosting of algogenic and vasodilatory effect.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapy of microvascular angina]. / Terapia dell'angina microvascolare.

The treatment of microvascular angina (anginal pain resulting from myocardial ischemia due to dysfunction of small coronary arteries) is empiric and often ineffective at present. The poor knowledge of the pathophysiologic mechanisms responsible for the microvascular dysfunction and the possible heterogeneous nature of the disease limit the possibility of a rational therapeutic approach to these patients. The failure of traditional antiischemic therapy is confirmed by the frequent unresponsiveness of angina and by the reduced exercise tolerance with administration of sublingual nitrates. Despite that, beta-blockers and calcium-antagonists, when given either alone or in combination, are beneficial in the control of symptoms in some patients. Alternative forms of treatment, based on some pathophysiological hypotheses and clinical observations, include xanthine derivatives, ACE-inhibitors, alpha-blocking agents, imipramine and, in women, oestrogens. The actual clinical usefulness of these drugs, however, is questionable at present, as their efficacy should be evaluated with more adequate studies in the future.

[Results of surgical treatment in supraventricular tachycardias]. / Risultati del trattamento chirurgico delle tachicardie sopraventricolari.

From May 1989 to May 1992, 44 patients (mean age 41 years, range 15-66) underwent surgery for supraventricular tachycardias: in 35 patients with atrioventricular reentrant tachycardia or atrial fibrillation associated with accessory pathway and refractory to medical treatment, the epicardial approach was used; in 8 with atrioventricular nodal reentrant tachycardia, a perinodal cryosurgery of the atrioventricular node was used, and in 1 patient with atrial flutter a cryosurgical ablation around the orifice of the coronary sinus and surrounding tissues was performed. All 38 accessory pathways were successfully ablated in 35 patients and no recurrences of delta wave or tachycardia were observed during a mean follow-up of 17 +/- 10 months. Atrial perforation during surgery and pericarditis were the only complications observed. All 8 patients with atrioventricular nodal reentrant tachycardia were successfully treated: in 2 patients dual pathways persisted after surgery but tachycardia was no longer inducible. No recurrences were observed during a mean follow-up of 15 +/- 4 months. Since surgery (15 months), the patient with atrial flutter has been free of recurrent episodes of atrial flutter. In conclusion, surgical treatment of supraventricular tachycardias is highly successful, with no mortality and very low morbidity. Should transcatheter ablation fail, surgery should be the treatment of choice in patients with frequent and symptomatic supraventricular tachycardias.