Pierpaolo Tarzia

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.

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.

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.

Relationship between cardiac autonomic function and sustained ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillators

AIMS Low left ventricular ejection fraction (LVEF) is the main indication of implantable cardioverter defibrillators (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death, but ICD therapy at follow-up occurs in a minority of patients. We investigated whether heart rate variability (HRV) may improve risk stratification in DCM patients. METHODS AND RESULTS We studied 42 patients (age 67.3 ± 3.5; 37 males) who had undergone ICD implant for either idiopathic or ischaemic DCM (LVEF <40%) 34.6 ± 19.7 months prior to the study (range 6-84). Patients underwent 24 h electrocardiographic Holter monitoring, and HRV was assessed over 2 hours in the afternoon showing stable sinus rhythm. Left ventricular ejection fraction was measured by two-dimensional echocardiography. The serum levels of C-reactive protein and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were also obtained. The primary endpoint was the occurrence of appropriate ICD shocks in the 6 months preceding the study. The occurrence of appropriate ICD discharge from ICD implant was considered as a secondary endpoint. In the last 6 months, appropriate ICD shocks had occurred in seven patients (17%). There were no differences between patients with and without ICD shocks in clinical variables, as well as in LVEF and in C-reactive protein and NT-proBNP serum levels. In contrast, most HRV parameters were significantly depressed in patients with, compared with those without, ICD shocks; the most significant difference was shown for the average of the standard deviations of RR intervals in all consecutive 5 min segments (n ¼ 12) within the 2 h (26.7 ± 9 vs. 39.7 ± 14 ms; P = 0.02) in the time domain and for LF amplitude (8.4 ± 3 vs. 14.8 ± 7 ms; P = 0.02) in the frequency domain. Implantable cardioverter defibrillator discharge had occurred in 11 patients (26%) since ICD implant (average 35 months). No clinical or laboratory variable showed significant differences between patients with or without ICD discharge, except very low-frequency (VLF) amplitude (23.8 ± 7 vs. 30.8 ± 10.6 ms, respectively; P = 0.049). CONCLUSION In ICD patients with reduced LVEF, several depressed HRV indices were significantly associated with appropriate ICD shocks in the previous 6 months, and VLF amplitude was the only variable significantly associated with ICD shocks recorded since ICD implant. These data suggest that full HRV analysis might be helpful for improving risk stratification for life-threatening ventricular arrhythmias and ICD indication in patients with DCM.

Evidence of increased platelet reactivity in the first six months after acute ST segment elevation myocardial infarction

INTRODUCTION Platelets play a crucial role in the pathogenesis of acute coronary syndromes. Accordingly, previous studies showed increased platelet reactivity on admission in these patients. In this study we assessed platelet reactivity at short-medium term follow-up in patients with ST-segment elevation acute myocardial infarction (STEMI). MATERIALS AND METHODS Fifty-nine patients (58 ± 11 years, 45 men), treated with primary angioplasty, were studied 1 month after STEMI. Thirty-five patients were retested at 6 months. Twenty matched patients with stable coronary artery disease served as controls. Platelet reactivity was assessed by flow cyometry at rest and at peak exercise, with and without adenosine diphosphate (ADP) stimulation, by measuring monocyte-platelet aggregates (MPAs) and glycoprotein IIb/IIIa (CD41) expression in the MPA gate, and CD41 and fibrinogen receptor (PAC-1) expression in the platelet gate. RESULTS Compared to controls, basal MPAs and CD41 in the MPA gate were higher in STEMI patients both at 1 month (p = 0.001 and p = 0.002, respectively) and at 6 months (p = 0.03 and p = 0.01, respectively). Basal CD41 and PAC-1 expression was also higher in STEMI patients at the two assessments compared to controls (P<0.001 for both). Exercise induced a similar increase in platelet reactivity in patients and controls. ADP induced a higher increase in CD41 platelet expression in STEMI patients compared to controls both at 1 and 6 months (P < 0.001). CONCLUSION Platelet reactivity is increased in the first 6 months after STEMI. The persistence of increased platelet reactivity in this time period may play a role in the early recurrence of coronary events after STEMI.

Peripheral Arterial Function and Coronary Microvascular Function in Patients with Variant Angina

Objectives: In this study, we assessed whether any abnormalities in coronary microvascular and peripheral vasodilator functions are present in patients with variant angina (VA) caused by epicardial coronary artery spasm (CAS). Methods: We studied 23 patients with VA (i.e. angina at rest, ST-segment elevation during angina attacks and documented occlusive CAS at angiography) and 18 matched healthy controls. Endothelium-dependent and -independent coronary microvascular function was assessed by measuring coronary blood flow (CBF) response to adenosine and the cold pressor test (CPT) in the left anterior descending artery by transthoracic Doppler echocardiography. Systemic endothelium-dependent and -independent arterial dilator function was assessed by measuring brachial flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD), respectively. Results: In VA patients, CBF responses to both adenosine (1.71 ± 0.25 vs. 2.97 ± 0.80, p < 0.01) and CPT (1.68 ± 0.23 vs. 2.58 ± 0.60, p < 0.01) were reduced compared to controls. Brachial FMD was also lower (3.87 ± 2.06 vs. 8.51 ± 2.95%, p < 0.01), but NMD was higher (16.7 ± 1.8 vs. 11.9 ± 1.4%, p < 0.01) in patients compared to controls. Differences were independent of the presence of coronary atherosclerotic lesions at angiography. Conclusions: Our data show that patients with VA have a generalized vascular dysfunction that involves both peripheral artery vessels and coronary microcirculation.

Coronary microvascular dysfunction after elective percutaneous coronary intervention: correlation with exercise stress test results

OBJECTIVES We assessed whether exercise stress test (EST) results are related to the presence of coronary microvascular dysfunction (CMVD) in patients undergoing elective percutaneous coronary intervention (PCI). BACKGROUND Previous studies showed that EST is poorly reliable in predicting restenosis after PCI; some studies also showed CMVD in the territory of the treated vessel. METHODS We studied 29 patients (age 64 ± 6, 23 M) with stable coronary artery disease and isolated stenosis (>75%) of the left anterior descending (LAD) coronary artery, undergoing successful PCI with stent implantation. EST and assessment of coronary microvascular function were performed 24h, 3 months and 6 months after PCI. Coronary blood flow (CBF) response to adenosine and to cold-pressor test (CPT) was assessed in the LAD coronary artery by transthoracic Doppler echocardiography. RESULTS Patients with ST-segment depression ≥ 1 mm at EST performed 24h after PCI (n=11, 38%) showed a lower CBF response to adenosine compared to those with negative EST (1.65 ± 0.4 vs. 2.11 ± 0.4, respectively, p=0.003), whereas the difference in CBF response to CPT was not significant (1.44 ± 0.4 vs. 1.64 ± 0.3, respectively; p=0.11). At 3-month and 6-month follow-up a positive EST was found in 12 (41%) and 13 (44%) patients, respectively; patients with positive EST also had lower CBF response to adenosine compared to those with negative EST (3 months: 1.69 ± 0.3 vs. 2.20 ± 0.3, respectively; 6 months: 1.66 ± 0.2 vs. 2.32 ± 0.3, respectively; p<0.001 for both). CONCLUSIONS Positive EST after elective successful PCI consistently reflects impairment of hyperemic CBF due to CMVD, which persists over a follow-up period of 6 months.

Usefulness of impairment of cardiac adrenergic nerve function to predict outcome in patients with cardiac syndrome X

Patients with cardiac syndrome X (CSX) have an excellent long-term prognosis, but a significant number show worsening angina over time. Previous studies have found a significant impairment of cardiac uptake of iodine-123-meta-iodobenzylguanidine (MIBG) on myocardial scintigraphy, indicating abnormal function of cardiac adrenergic nerve fibers. The aim of this study was to assess whether cardiac MIBG results can predict symptomatic outcome in patients with CSX. Cardiac MIBG scintigraphy was performed in 40 patients with CSX (mean age 58 ± 5 years, 14 men). Cardiac MIBG uptake was measured by the heart/mediastinum uptake ratio and a single photon-emission computed tomographic regional uptake score (higher values reflected lower uptake). Clinical findings, exercise stress test parameters, sestamibi stress myocardial scintigraphy, and C-reactive protein serum levels were also assessed. At an average follow-up of 79 months (range 36 to 144), no patient had died or developed acute myocardial infarction. Cardiac MIBG defect score was significantly lower in patients with worsening versus those without worsening of angina status (13 ± 7 vs 38 ± 28, p = 0.001), in those with versus those without hospital readmission because of recurrent chest pain (15 ± 9 vs 35 ± 29, p = 0.01), and in those who underwent versus those who did not undergo repeat coronary angiography (11 ± 7 vs 36 ± 27, p = 0.001). Significant correlations were found between quality of life (as assessed by the EuroQoL scale) and heart/mediastinum ratio (r = 0.48, p = 0.002) and cardiac MIBG uptake score (r = -0.69, p <0.001). No other clinical or laboratory variable showed a significant association with clinical end points. In conclusion, in patients with CSX, abnormal function of cardiac adrenergic nerve fibers, as assessed by an impairment of cardiac MIBG uptake, identifies those with worse symptomatic clinical outcomes.

Effect of shift work on endothelial function in young cardiology trainees

Background: Long-term shift work (SW) is associated with an increase in cardiovascular disease (CVD). Previous studies have shown that prolonged SW is associated with endothelial dysfunction, suggesting that this abnormality may contribute to the SW-related increase in cardiovascular risk. The immediate effect of SW on endothelial function in healthy subjects, however, is unknown. Design: We studied endothelial function and endothelium-independent function in 20 healthy specialty trainees in cardiology at our Institute, without any cardiovascular risk factor (27.3±1.9 years, nine males), at two different times: (1) after a working night (WN), and (2) after a restful night (RN). The two test sessions were performed in a random sequence. Methods: Endothelial function was assessed by measuring brachial artery dilation during post-ischaemic forearm hyperaemia (flow-mediated dilation, FMD). Endothelium-independent function in response to 25 µg of sublingual glyceryl trinitrate (nitrate-mediated dilation, NMD) was also assessed. Results: FMD was 8.02 ± 1.4% and 8.56 ± 1.7% after WN and RN, respectively (p = 0.025), whereas NMD was 10.5 ± 2.1% and 10.4 ± 2.0% after WN and RN, respectively (p = 0.48). The difference in FMD between WN and RN was not influenced by the numbers of hours slept during WN (<4 vs >4 hours) and by the duration of involvement of specialty trainees in nocturnal work (<12 vs >12 months). Conclusions: Our study shows that in healthy medical residents, without any cardiovascular risk factor, FMD is slightly impaired after WN compared to RN. Disruption of physiological circadian neuro-humoral rhythm is likely to be responsible for this adverse vascular effect.

Coronary microvascular dysfunction. An update

Several studies in the last years have shown that a dysfunction of coronary microcirculation may be responsible for abnormalities in coronary blood flow and some clinical pictures. Coronary microvascular dysfunction, in absence of other coronary artery abnormalities, can cause anginal symptoms, resulting in a condition named microvascular angina (MVA). MVA can occur in a chronic form, predominantly related to effort (stable MVA), more frequently referred as cardiac syndrome X, or in an acute form, most frequently ensuing at rest, which simulates an acute coronary syndrome (unstable MVA). The main abnormalities characterizing these two forms of MVA consist of an impaired vasodilation and an increased vasoconstriction of small resistive coronary arteries, respectively. The mechanisms responsible for stable MVA are still unclear, but seem to include, together with the known traditional cardiovascular risk factors, an abnormally increased cardiac adrenergic activity. The prognosis of stable MVA is good, but some patients have progressive worsening of symptoms. Clinical outcome of patients with unstable MVA is substantially unknown, as there are no specific studies about this population. Treatment of stable MVA includes traditional anti-ischemic drugs as first step; in case of persisting symptoms several other drugs have been proposed, including xanthine derivatives, ACE-inhibitors, statins and, in women, estrogens. Severe forms of intense constriction (or spasm) of small coronary arteries may cause transmural myocardial ischemia, as the microvascular form of variant angina and the tako-tsubo syndrome.