Antonio Di Monaco

Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study

Objective: Impaired flow-mediated dilation (FMD) is associated with cardiovascular risk factors and provides prognostic information. Despite the noninvasive nature of this technique, a major limitation to its widespread use is low reproducibility. The aim of this study was to evaluate impact of methodological standardization among different investigation sites on brachial artery FMD reproducibility. Methods: Seven Italian centers recruited 135 healthy volunteers, aged 20–60 years. FMD was assessed by high-resolution ultrasound equipped with a stereotactic probe-holding device. Certified sonographers recorded brachial artery scans at baseline (day 1a), 1 h after (day 1b), and 1 month later (day 30). Endothelium-independent vasodilation (EIVD) to sublingual glyceril-trinitrate was recorded at day 1 and day 30. FMD and EIVD were blindly evaluated at the coordinating center by an automated edge detection system. The intra-session (day 1a versus 1b) and inter-session (day 1a versus 30) coefficients of variation were calculated. Results: FMD was not significantly (P = 0.91) different at day 1a, day 1b and day 30 (6.52 ± 2.9, 6.42 ± 3.1, 6.57 ± 2.8%, respectively). The FMD intra-session coefficient of variation was 9.9 ± 8.4% (from 7.6 to 11.9% across centers). The FMD inter-session coefficient of variation was 12.9 ± 11.6% (from 11.6 to 16.1% across centers). Inter-session coefficient of variation for EIDV was 19.7 ± 16.8%. Conclusions: This study shows a homogeneous coefficient of variation for FMD among different centers. The inter-session coefficient of variation was similar to the intra-session coefficient of variation, representing the intrinsic FMD variability. We demonstrate for the first time that rigorous and standardized procedure may provide reproducible FMD assessment to study endothelial function in multicenter clinical trials.

Effects of Ivabradine and Ranolazine in Patients With Microvascular Angina Pectoris

Patients with microvascular angina (MVA) often have persistence of symptoms despite full classical anti-ischemic therapy. In this study, we assessed the effect of ivabradine and ranolazine in MVA patients. We randomized 46 patients with stable MVA (effort angina, positive exercise stress test [EST], normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischemic therapy, to ivabradine (5 mg twice daily), ranolazine (375 mg twice daily), or placebo for 4 weeks. The Seattle Angina Questionnaire (SAQ), EuroQoL scale, and EST were assessed at baseline and after treatment. Coronary microvascular dilation in response to adenosine and to cold pressor test and peripheral endothelial function (by flow-mediated dilation) were also assessed. Both drugs improved SAQ items and EuroQoL scale compared with placebo (p <0.01 for all), with ranolazine showing some more significant effects compared with ivabradine, on some SAQ items and EuroQoL scale (p <0.05). Time to 1-mm ST-segment depression and EST duration were improved by ranolazine compared with placebo. No effects on coronary microvascular function and on flow-mediated dilation were observed with drugs or placebo. In conclusion, ranolazine and ivabradine may have a therapeutic role in MVA patients with inadequate control of symptoms in combination with usual anti-ischemic therapy.

Long-term prognosis of patients with cardiac syndrome X

BACKGROUND Previous follow-up studies of patients with cardiac syndrome X (CSX) reported good prognosis. However, some recent reports challenged this finding by showing appreciable mortality rates in patients with angina and normal coronary arteries admitted for acute coronary syndromes. METHODS We performed clinical follow-up of 155 patients (mean age 58.9+/-10 years, 40 men) with typical CSX. The occurrence of major cardiac events (cardiac death, acute myocardial infarction), readmission for chest pain, revascularization procedures, angina status, and non cardiac events during follow-up were collected for each patient. RESULTS At a mean follow-up time of 137+/-78 months (range 24-372) from the onset of symptoms, 4 patients died, 3 for cancers and 1 for acute pancreatitis. No patient died from cardiovascular causes or had any major cardiovascular event. Hospital readmission for recurrent chest pain was reported by 89 patients (58%), and 33 (22%) underwent at least one more coronary angiography. During follow-up, chest pain had remained unchanged in 33% of patients and had worsened in 14% of patients. CONCLUSION Our data show that patients with CSX have excellent long-term clinical prognosis. A significant number of patients, however, shows persistence or worsening of symptoms, as well as further recurrence to medical evaluation.

Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X

Background The causes of coronary microvascular dysfunction (CMVD) in patients with cardiac syndrome X (CSX) are largely unknown. Common cardiovascular risk factors (CVRFs) and increased markers of inflammation have been associated with CMVD in some studies, but their role in determining CMVD in CSX patients remains poorly known. Methods and results We studied 71 CSX patients (56 ± 9 years, 23 men) and 20 healthy volunteers (52 ± 7 years, nine men). Using transthoracic Doppler echocardiography, coronary microvascular vasodilator function was assessed in the left anterior descending coronary artery as the ratio of diastolic coronary blood flow (CBF) velocity at peak intravenous adenosine administration and during cold pressor test (CPT) to the respective basal CBF velocity values. Common CVRFs tended to be more frequent and C-reactive protein (CRP) levels were higher (P < 0.001) in CSX patients than in controls. Both CBF responses to adenosine (2.05 ± 0.6 vs. 2.92 ± 0.9, P < 0.001) and to CPT (1.71 ± 0.6 vs. 2.42 ± 0.7, P < 0.001) were lower in CSX patients than in controls. The differences between the two groups in CBF response to adenosine and in CBF response to CPT remained highly significant (P < 0.01 for both) after adjustment for all CVRFs, including serum CRP levels. Conclusion In CSX patients, both endothelium-dependent and endothelium-independent CMVD cannot be reliably predicted by CVRFs (including serum CRP levels), alone or in combination.

Methods to investigate coronary microvascular function in clinical practice.

A growing amount of data is increasingly showing the relevance of coronary microvascular dysfunction (CMVD) in several clinical contexts. This article reviews techniques and clinical investigations of the main noninvasive and invasive methods proposed to study coronary microcirculation and to identify CMVD in the presence of normal coronary arteries, also trying to provide indications for their application in clinical practice.

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

Objective: To assess whether abnormalities in cardiac uptake of 123I-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.

Effect of Vagal Nerve Stimulation on Systemic Inflammation and Cardiac Autonomic Function in Patients with Refractory Epilepsy

Objective: Recent data suggest that vagus nerve stimulation (VNS) can inhibit cytokine release by inflammatory cells. Accordingly, an association between impaired cardiac parasympathetic function, as assessed by heart rate variability (HRV), and increased markers of inflammation has recently been reported. In this study we assessed the effect of direct left VNS on inflammatory markers and HRV in patients with refractory epilepsy. Methods: A 24-hour electrocardiogram Holter recording was performed both at baseline and after 3 months of left VNS in 8 patients (age 32 ± 24 years, 2 men) who underwent implantation of a VNS device because of refractory epilepsy. Tumor necrosis factor-α, interleukin-6 and C-reactive protein serum levels were measured, as markers of inflammation, at the same times. Results: No significant changes were found after 3 months of left VNS, compared to baseline, both for HRV variables and inflammatory markers. Also, no consistent correlation could be demonstrated between HRV parameters and inflammatory markers in these patients. Conclusions: Our data in epileptic patients without cardiovascular disease failed to show a significant effect of left VNS on cardiac autonomic function and on systemic inflammation at short-term follow-up.

Clinical Correlates and Prognostic Value of Flow Mediated Dilation in Patients With Non-ST Segment Elevation Acute Coronary Syndromes

Endothelial dysfunction can predict cardiovascular outcomes in several populations of patients. The aim of this study was to assess the severity, time course, and clinical implications of endothelial dysfunction in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Sixty patients with NSTE ACS (mean age 62 ± 8 years, 44 men) and 40 controls with stable coronary artery disease (CAD) (mean age 63 ± 10 years, 27 men) were studied. In patients with NSTE ACS and in those with stable CAD, endothelial function was assessed <12 hours after admission and at 3-month follow-up by measuring right brachial artery dilation after 5 minutes of forearm ischemia (flow-mediated dilation [FMD]). Clinical outcomes were assessed after a median follow-up period of 32 months (range 14 to 36). The primary end point was a combination of cardiac death or readmission for new ACS or recurrence of angina pectoris. FMD on admission was significantly lower in patients with NSTE ACS compared to those with stable CAD (2.1 ± 1.2% vs 4.8 ± 1.9%, p <0.001). FMD improved significantly at 3-month follow-up in patients with NSTE ACS, becoming comparable to that in patients with stable CAD (5.7 ± 2.6% vs 5.5 ± 1.7%, p = 0.93). During follow-up, 14 cardiac events (23%) occurred in patients with NSTE ACS. On multivariate analysis, only diabetes (hazard ratio 18.1, 95% confidence interval 3.9 to 83.9, p <0.001) and FMD at 3 months (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, p = 0.04) were independent predictors of the primary end point in patients with NSTE ACS. In conclusion, endothelial function is markedly impaired in the acute phase of NSTE ACS but improves significantly at 3-month follow-up. In patients with NSTE ACS, FMD at 3 months after the acute event is a significant independent predictor of cardiac outcomes.

Effect of Spinal Cord Stimulation in Patients With Refractory Angina: Evidence From Observational Studies

Objectives:  To review the evidence in observational studies of the effect of spinal cord stimulation (SCS) in patients with refractory angina pectoris (RAP) due to obstructive coronary artery disease. The effect of SCS in patients with refractory microvascular angina (MVA) also was assessed.

Cardiac adrenergic nerve function in patients with cardiac syndrome X.

Background We previously found a severe impairment of cardiac uptake of 123I-metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, on myocardial scintigraphy in a small group of patients with cardiac syndrome X (CSX), suggesting a dysfunction of cardiac adrenergic nerve fibres. In this study, we assessed the consistency of these previous findings in a larger group of these patients. Methods Planar and single-photon emission computed tomography MIBG myocardial scintigraphy was performed in 40 CSX patients (58 ± 7 years, 17 men). Cardiac MIBG uptake was measured by the heart/mediastinum ratio and by a single-photon emission computed tomography regional cardiac MIBG uptake defect score (higher values = lower uptake). As a control group, we studied 20 healthy individuals (56 ± 6 years, nine men). An exercise stress 99mTc-SestaMIBI myocardial scintigraphy was performed in 34 CSX patients (85%). Results Cardiac MIBG defects were observed in 30 patients (75%), with nine (22.5%) showing no cardiac MIBG uptake at all. Compared with controls, CSX patients showed a significantly lower heart/mediastinum ratio (1.70 ± 0.35 vs. 2.1 ± 0.22, P < 0.001) and a higher cardiac MIBG defect score (27 ± 25 vs. 4.4 ± 2.5, P < 0.001). No differences were found in lung MIBG uptake between the two groups. Reversible perfusion defects on stress myocardial scintigraphy were found in 17 out of 34 CSX patients (50%), all of whom also had abnormal cardiac MIBG uptake; cardiac MIBG uptake abnormalities were also present in nine of 17 patients with normal perfusion scintigraphic images. Cardiac MIBG uptake findings were similar in our first 12 patients and in the 28 patients studied subsequently. Conclusion Our data show a relevant impairment of cardiac MIBG uptake in patients with CSX, suggesting that functional abnormalities in cardiac adrenergic nerve function may play a significant role in the mechanisms responsible for the syndrome.