C-reactive protein, lung hyperinflation and heart rate variability in chronic obstructive pulmonary disease --a pilot study.

Chronic obstructive pulmonary disease (COPD) is associated to cardiovascular morbidity and mortality, and abnormalities of the autonomic nervous system have been described in subjects with severe disease. We studied heart rate variability (HRV) in COPD patients at rest and during the 6-minute Walk Test (6mWT) and the association with lung function impairment taking into account systemic inflammation. Thirty outpatients with stable COPD underwent lung function measurements, blood gas analysis, ECG Holter and transcutaneous pulse oximetry during 6mWT and then they were classified by BODE index. Also C-reactive protein (CRP) was measured. At rest, we observed a significant reduction of HRV for increasing BODE index. During the 6mWT, HRV tended to decrease in BODE 1 subjects whereas an increase was observed in BODE 2 and BODE 3-4 subjects. Subjects with elevated CRP values had a significant reduction in Standard Deviation of all normal RR intervals at rest (SDNN: p = 0.013), Total Power (TFA: p = 0.04) and Very Low Frequency band (VLF: p = 0.041). At rest, subjects with Inspiratory Capacity-to-Total Lung Capacity ratio (IC/TLC) < 36% had a significant reduced SDNN (p = 0.004), TFA (p = 0.001), VLF (p = 0.001), Low Frequency band (p = 0.007). During 6mWT, changes of HRV parameters were significantly related to airflow obstruction and static hyperinflation indices. At rest and during submaximal exercise, COPD patients with moderate and severe disease had an abnormal cardiac autonomic modulation which was related to both systemic inflammation and lung function impairment.

The HEART study: a real-world experience using the CID Chrono Carbostent in primary and rescue PCI.

BACKGROUND: Chrono Carbostent (CID, Saluggia, Italy) is characterized by a peculiar coating with Carbofilm which could reduce the risk of thrombosis as compared to other bare metal stents (BMS). This feature should be particularly useful in the setting of primary or rescue percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We tested the efficacy and safety of this stent in patients with STEMI undergoing primary or rescue PCI. Inclusion criteria included the diagnosis of STEMI, a coronary anatomy suitable for stenting and no contraindications to dual antiplatelet therapy for at least 1 month. The primary endpoint was the composite of the following major adverse cardiac events (MACEs) at 12 months: death, recurrence of myocardial infarction and target vessel revascularization. RESULTS: One hundred and seven STEMI patients treated with Chrono Carbostent implantation were enrolled. Eighty-three (77%) patients underwent primary and 24 (23%) rescue PCI. A total of 148 stents were successfully implanted. Cardiogenic shock was present in 12 (11%) patients and in-hospital mortality was 6.5%. Cumulatively, the rate of MACEs at 12 months was 17.7% (deaths 7.4%, target lesion revascularization 9.3%). CONCLUSIONS: In unselected patients with STEMI treated by urgent PCI, the Chrono Carbostent showed a low rate of events in those patients surviving the acute phase of myocardial infarction. Unfortunately, and especially for patients in cardiogenic shock, survival continued to be relatively independent of interventional treatment, even when successfully completed, thus strictly linking prognosis of STEMI to severity of clinical presentation.

Baseline von Willebrand factor plasma levels and no-reflow phenomenon after primary percutaneous coronary intervention for ST segment elevation myocardial infarction.

No-reflow phenomenon is associated with a poor prognosis and its underlying mechanisms are still poorly understood. von Willebrand Factor (vWF) is a central molecule in haemostasis which plays an important role in acute coronary syndromes. However its possible role in no-reflow has not been assessed prior to this study. Quantitative baseline vWF plasma antigen was measured by immunoturbidometric assay in 54 consecutive patients with a first ST segment elevation acute myocardial infarction, treated by primary percutaneous coronary intervention within 12 h of symptom onset. Definitions of no-reflow were (1) angiographic: final TIMI flow ≤2 or final TIMI flow 3 with a myocardial blush grade <2; (2) electrocardiographic: lack of ST segment resolution (≤50% reduction of ST segment elevation at 90 min). Angiographic and electrocardiographic no-reflow was observed in 32 (59%) and 30 (56%) patients, respectively (only 9 patients had both type of no-reflow). Plasma levels of vWF were significantly higher in patients with angiographic no-reflow but not in those with electrocardiographic no-reflow. Also, vWF was the most powerful independent predictors of angiographic no-reflow (OR 3.8, 95% CI 1.1-12.9, p=0.033). Our results provide new insights into no-reflow pathophysiology with appealing therapeutic implications.

Provisional TAP-stenting strategy to treat bifurcated lesions with drug-eluting stents: one-year clinical results of a prospective registry.

OBJECTIVE: To assess the clinical outcome of unselected patients undergoing drug-eluting stent (DES) implantation on bifurcated lesions using a "provisional T And small Protrusion (TAP)" stenting strategy. METHODS: Consecutive patients undergoing DES implantation on one major bifurcation lesion were treated by main-vessel (MV) stenting, followed (if needed) by side-branch (SB) rewiring (with a "pullback" technique) and kissing balloon. SB stenting was performed according to the TAP-technique in selected cases. The endpoint of the study was a 12-month incidence of major adverse cardiac events (MACE) defined as cardiac death, myocardial infarction (MI), stent thrombosis and target vessel revascularization (TVR). RESULTS: The study population included 266 patients (9% unprotected left main). Only 19 patients (7.1%) (with more complex angiographic features) received stents in both the MV and SB using the TAP-technique. Overall, 22 (8.2%) patients had MACE at 1 year. Observed, non-hierarchical MACE were: 1 (0.4%) cardiac death, 11 (4.1%) MI, 2 probable stent thromboses and 12 (4.5%) TVRs. Postprocedural troponin T increase and adverse events up to 12 months were similar between patients treated by MV stenting only or double stenting. CONCLUSIONS: In unselected patients undergoing DES implantation on bifurcated lesions, a provisional TAP-stenting strategy (with a low rate of SB stenting) appears to be safe and effective.

Ventricular late potentials: a critical overview and current applications.

BACKGROUND: More than 450 000 Americans die suddenly each year from sustained ventricular tachycardia (VT) or fibrillation. Overall, event rates in Europe are similar to those in the United States. A correct risk stratification is essential to reduce the incidence of sudden cardiac death. Ventricular late potentials (VLPs) represent delayed conduction through a diseased myocardium and consist of the presence of electrical activity after the end of the standard QRS. The VLPs are potential substrates for reentry VT. CLINICAL APPLICATIONS: The VLPs were found highly predictive of cardiac events, in particular, arrhythmic events, in patients with acute myocardial infarction. The weakness of VLPs is the low positive predictive value, especially as a single technique. However, their negative predictive value for arrhythmic events is very high. The VLPs are observed in more than 50% of patients with arrhythmogenic right ventricular cardiomyopathy, and are actually considered a helpful diagnostic tool in this setting. In patients with syncope of unknown cause, VLP analysis, combined with patient history and other diagnostic tests, can help identify or exclude a mechanism of VT as a cause of the syncope. CONCLUSIONS: The VLP assessment offers a practical and low-cost tool to the clinical cardiologist to recognize the possible electrophysiologic substrate underlying life-threatening ventricular arrhythmias. The strength of VLPs is their high negative predictive value. When positive, VLPs still help better stratify the arrhythmic risk of patients in several clinical settings.

Spinal cord stimulation normalizes abnormal cortical pain processing in patients with cardiac syndrome X.

Cardiac syndrome X (CSX) is characterized by effort angina, ST-segment depression during stress tests and normal coronary arteries. Abnormal nociception was suggested in these patients by studies showing a reduced cardiac pain threshold; furthermore, we recently found a lack of habituation to pain stimuli using recording of laser evoked potentials (LEPs). In CSX patients with severe angina, spinal cord stimulation (SCS) was shown to improve symptoms. In this study we investigated whether, in these patients, SCS has any effects on the excitability of the nociceptive system, assessed by LEPs recording. We studied 16 CSX patients (61.6+/-7 years; 4 men) who underwent SCS for refractory angina. Cortical LEPs were recorded during stimulation of the chest and right-hand during active SCS (SCS-ON) and in the absence of SCS (SCS-OFF), using a randomized cross-over design. Three sequences of painful stimuli were applied at each site during each test. During the first sequence of chest stimuli, the N2/P2 LEP amplitude was higher during the SCS-ON, compared to the SCS-OFF phase (18.2+/-7.8 vs. 11.5+/-4.4 microV, P=0.006). The N2/P2 amplitude did not change significantly across the three stimulation sequences during the SCS-OFF phase (P=0.22), whereas it decreased progressively during the second and third sequence (to 87.1+/-29.5% and 76.4+/-24.1%, respectively) compared with the first sequence, during the SCS-ON phase (P=0.014). Similar results were observed during right-hand stimulation. Our study shows that in CSX patients SCS is able to restore habituation to peripheral pain stimuli. This effect might contribute to restore the ability of CSX patients to better tolerate cardiac pain.

Predictors of impaired heart rate variability and clinical outcome in patients with acute myocardial infarction treated by primary angioplasty.

OBJECTIVE: To investigate the determinants and prognostic value of heart rate variability (HRV) in acute myocardial infarction (AMI) patients treated by percutaneous coronary intervention (PCI). METHODS: We studied 64 patients with AMI (58.4 +/- 10 years, 56 men), treated by PCI within 12 h of symptom onset. Patients underwent 24-h electrocardiographic Holter recording before discharge. HRV was measured in the time- and frequency-domain. Cardiac events were assessed at 6 months. RESULTS: At univariate analysis, Thrombolysis in Myocardial Infarction (TIMI) flow grade < 3 was significantly predictive of reduced frequency-domain variables. On multivariate analysis, diabetes and pre-PCI time > 6 h were the strongest predictors of depressed HRV, with peak creatine kinase myocardial-type and lower left ventricular ejection fraction being also variably correlated with impaired HRV. At 6-month follow-up, seven patients (10.1%) had cardiac events (one AMI, six revascularization procedures). A low standard deviation of RR intervals was a significant predictor of events (P = 0.009), although only age was associated with the endpoint (P = 0.05) on multivariate analysis. CONCLUSIONS: Our study shows that, in AMI patients treated by primary PCI, a delay in coronary revascularization and AMI extension are key factors for determining depressed HRV.

Different effect of percutaneous and surgical coronary revascularization on cardiac autonomic function and inflammation in patients with stable angina.

We assessed heart rate variability (HRV) and high-sensitivity C-reactive protein (CRP) serum levels in 77 patients with chronic stable angina (CSA), 47 of whom had obstructive coronary artery disease (CAD) and 30 normal or near-normal coronary arteries (NCA). The effect of percutaneous coronary interventions (PCI) and bypass surgery (CABG) on HRV and CRP was assessed in 36 patients (18 PCI, 18 CABG) 6 months after the intervention. A significant inverse correlation was found between CRP levels and HRV variables in CAD patients (best r value=-0.31, p=0.036 for very low frequency amplitude), but not in NCA patients. At follow-up, however, no significant correlation was found between CRP and HRV in PCI and CABG treated patients. Thus, while confirming the presence of a relation between cardiac autonomic dysfunction and inflammation in CAD patients, our data show that the association is lost after revascularization procedures.

Association between cardiac autonomic dysfunction and inflammation in type 1 diabetic patients: effect of beta-blockade.

AIMS: To assess the relationship between cardiac autonomic dysfunction and inflammation in patients with type 1 diabetes and whether beta-blocker therapy might improve both abnormalities in these patients. METHODS AND RESULTS: We studied 49 patients with type 1 diabetes (age 50.5 +/- 11 years, 33 men). Serum levels of high-sensitivity C-reactive protein, as a marker of inflammation, and frequency-domain heart rate variability (HRV) on 24 h Holter monitoring, as a measure of cardiac autonomic function, were assessed in all patients. Twenty-one patients with depressed HRV were subsequently randomized to receive atenolol (50 mg daily) or no-beta-blockade. HRV and C-reactive protein were re-assessed after 3-4 weeks from randomization. An inverse correlation was found between C-reactive protein levels and HRV parameters, with the highest r coefficient shown with low-frequency (LF) power (r = -0.38; P = 0.007). Furthermore, C-reactive protein serum levels were significantly higher in patients with bottom quartile values of LF power compared with patients with values in the three top quartiles (4.64 +/- 2.8 vs.1.79 +/- 1.6 mg/L, respectively; P = 0.003), also after adjustment for potential confounding variables (P = 0.013). HRV parameters improved significantly in patients treated with atenolol, but not in the no-atenolol group. Furthermore, C-reactive protein levels decreased in the beta-blockade group, but not in the no-beta-blockade group (P = 0.04 for changes between groups). CONCLUSION: In type 1 diabetic patients, serum C-reactive protein levels are significantly associated with depressed HRV; the favourable effects of beta-blockade on both HRV parameters and C-reactive protein serum levels suggest that autonomic nervous system may have significant modulator effects on inflammation.

Long-term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation.

OBJECTIVE: To assess the long-term effect of spinal cord stimulation (SCS) in patients with refractory cardiac syndrome X (CSX). METHODS: A prospective, controlled, long-term follow-up was performed of 19 patients with CSX with refractory angina who underwent SCS (SCS group, 5 men, mean (SD) age 60.9 (8.5) years); 9 comparable patients with CSX who refused SCS treatment (3 men, mean (SD) age 60.9 (8.8) years) constituted the control group. Clinical and functional status were assessed at the time of screening for SCS indication (basal evaluation) and at a median (range) follow-up of 36 (15-82) months. RESULTS: The two groups at baseline did not show any difference in clinical characteristics and angina status. All indicators of angina status (angina episode frequency, duration and short-acting nitrate use) improved significantly at follow-up in the SCS group (p<0.001) but not in controls. Functional status, as assessed by the Seattle Angina Questionnaire and a visual analogue scale for quality of life, improved at follow-up in the SCS group (p<0.001 for all scales) but not in controls. Exercise tolerance, exercise-induced angina and ST segment changes also significantly improved in the SCS group but not in controls. CONCLUSIONS: Data show that SCS can be a valid form of treatment for long-term control of angina episodes in patients with refractory CSX.

Current clinical features, diagnostic assessment and prognostic determinants of patients with variant angina.

BACKGROUND: Clinical characteristics and outcome of patients with variant angina were assessed in the 1970-1980s of the past Century. The recent progress in prevention, diagnosis and treatment of coronary artery disease may have significantly modified clinical characteristics and prognosis of these patients. METHODS: From January 1991 to December 2002, 202 patients (57.1+/-12 years; 166 men) were diagnosed to have variant angina at our Institute. Detailed clinical findings and clinical events were prospectively collected for each patient. RESULTS: The median time from the first angina attack to diagnosis was 2 months (range 1-276), with diagnosis requiring >6 months in 31.7% of patients. Coronary angiography (n=183) showed normal coronary arteries in 42.1% of patients and significant coronary stenoses (>50%) in 44.3%, with multi-vessel disease in 8.7%. Diagnosis of variant angina was done during coronary angiography in 3% of cases during the first half of the study period, but in 42% of patients in the second half of the study period. Major cardiac events (MCE, i.e., death, resuscitation from cardiac arrest, myocardial infarction) occurred in 41 patients (20.3%), with 43.9% of events occurring within 1 month of symptom onset. The only variable significantly associated with MCE was the detection during angina of ST segment elevation in both anterior and inferior ECG leads (odds ratio 3.24; 95% confidence interval 1.43-7.36; P=0.005). CONCLUSION: Our data suggest that variant angina is still a frequently overlooked diagnosis, and a timely diagnosis would be crucial to prevent early life-threatening events. Patients with diffuse ST segment elevation on ECG are those at the highest risk of MCE, independently of angiographic findings.

Increased platelet reactivity in unstable angina patients is not related to C-reactive protein levels.

Platelets are a major component of thrombi, and coronary thrombosis plays a key role in the pathogenesis of unstable angina (UA). Whether platelet aggregability is increased in UA patients however, is not known. Furthermore, no study has investigated the relationship between platelet reactivity and inflammation in UA patients In this study, venous blood samples were collected at admission in coronary care unit in 37 patients with unstable angina (Braunwald class IIIB) and in 37 sex- and age-matched patients with chronic stable angina (CSA). Patients taking thienopyridine or anticoagulant drugs were excluded from the study, as also were excluded patients with a history of acute myocardial infarction in the previous 12 months. Platelet aggregability was measured on flowing blood as time to occlude a ring coated with collagen-adenosine diphosphate (ADP), using the platelet function analyzer (PFA-100) system. By this method, the time to occlusion (closure time) is taken as a measure of platelet adhesion/aggregability, with shorter times indicating greater platelet reactivity. There were 23 men and 14 women in both groups, and age was 67.7 +/- 8 and 67.5 +/- 8 years in UA and SA, respectively (P = 0.93). Closure time was significantly reduced in UA patients (78.8 +/- 14 s), compared to SA patients (93.3 +/- 19 s, P < 0.001). Among UA patients, serum C-reactive protein (CRP) levels had a median value of 5.1 mg/l (bottom and top quartile levels, 1.50-7.95). There was no significant correlation between closure time and CRP levels (r = 0.22, P = 0.29). Our data show that, in patients with unstable angina there is an increase of platelet reactivity in response to ADP/collagen stimulation, which is not related to inflammation.

Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris.

Heart rate variability (HRV) and systemic markers of inflammation have prognostic value in patients with unstable angina pectoris (UAP). However, it is unknown whether any relation exists between HRV parameters and indexes of inflammation in this clinical context. We assessed HRV on 24-hour electrocardiographic Holter recordings, performed within 24 hours of admission, and measured C-reactive protein (CRP) serum levels by a high-sensitivity assay on admission, in 531 patients with UAP (65+/-10 years of age; 347 men) who were enrolled in the prospective multicenter study Stratificazione Prognostica dell'Angina Instabile (SPAI). A significant inverse correlation was found between CRP levels and all HRV parameters, with the highest r coefficient shown with SD of all RR intervals (r= -0.23; p<0.001) in the time domain and with very low-frequency amplitude (r= -0.22; p<0.001) in the frequency domain. When patients were categorized into 4 groups according to CRP quartile levels, statistically significant lower HRV values were observed in the upper CRP quartile. On separate multiple regression analyses, including the most important clinical and laboratory variables, SD of all RR intervals and very low-frequency amplitude were the most significant predictors of increasing CRP levels (p<0.001 for the 2 comparisons). In contrast, in models with SD of all RR intervals and very low-frequency amplitude as dependent variables, CRP was a strong predictor of impaired cardiac autonomic function (p<0.001 for the 2 comparisons). Thus, our data show that, in patients with UAP, high levels of serum CRP levels are significantly associated with decreased HRV, suggesting a possible pathophysiologic link between cardiac autonomic dysfunction and inflammatory activity.

Coronary artery spasm induced by capecitabine.

Capecitabine is a new chemotherapeutic agent considered highly specific for sensitive tumour cells, which convert the drug to 5-fluorouracil. Capecitabine is administered on an ambulatory basis for the treatment of metastatic breast and colorectal cancer, and both general practitioners and specialists are likely to deal with patients treated with this drug. We describe the case of a 44-year-old woman, with no cardiovascular risk factors, who started therapy with capecitabine for relapsing of breast carcinoma. She subsequently developed effort angina. Standard electrocardiogram and echocardiography were normal, whereas ST-segment elevation and angina were induced during exercise stress test. Capecitabine was withdrawn and therapy with diltiazem and transdermal nitroglycerine was started. The patient became asymptomatic and repeated symptom-limited exercise stress test did not induce any ST-segment changes or angina, even after withdrawal of anti-ischaemic therapy, thus confirming the hypothesis of capecitabine-induced coronary artery spasm as the cause of patient's symptoms.

Platelet reactivity in response to mental stress in syndrome X and in stable or unstable coronary artery disease.

INTRODUCTION: Previous studies showed differences in platelet reactivity in response to exercise in patients with syndrome X (SX) and those with obstructive coronary artery disease (CAD). In this study, we investigated whether similar differences could be detectable in response to a mental stressful stimulus. MATERIALS AND METHODS: We studied 30 SX patients (60+/-8 years, 8 men), 20 patients with stable angina and angiographically documented CAD (SA, 66+/-8 years, 14 men), and 11 patients with unstable angina (UA, 67+/-8 years, 6 men). A control group of 22 healthy controls (50+/-7 years, 5 men) was also studied. All subjects underwent a mathematical mental stress test (MST) consisting of rapid consecutive subtractions of number 7 for a period of 5 min. A venous blood sample was collected at baseline and immediately after MST. Platelet reactivity was measured on flowing blood as time necessary to occlude a ring coated with collagen-adenosine diphosphate (ADP; closure time, CT), using the platelet function analyzer (PFA-100) system. RESULTS: At rest, CT was lower in UA patients (87+/-19 s) compared to controls (109+/-24 s, p=0.02) and SA patients (105+/-37 s, p=0.055), and also tended to be lower in SX patients (96+/-18 s) compared to controls (p=0.07). The CT response to MST differed significantly among groups (p=0.0009). At peak MST, CT did not change in controls (110+/-27 s, p=0.88), whereas it decreased in SA patients (96+/-29 s, p=0.003) and tended to decrease in UA patients (82+/-15 s, p=0.25). In contrast, a significant increase in CT with MST was shown in SX patients (103+/-21 s, p=0.007). CONCLUSIONS: Platelet reactivity is increased by MST in patients with CAD, whereas it paradoxically decreases in SX patients, which may constitute a protective effect against stress-induced events in these patients.

Abnormal cortical pain processing in patients with cardiac syndrome X.

AIMS: Previous studies suggested that an enhanced pain sensitivity is present in patients with cardiac syndrome X (SX). We investigated whether SX patients present abnormalities in the electrical cerebral signals generated by pain stimuli. METHODS AND RESULTS: Cortical laser evoked potentials (LEPs) were recorded in 16 SX patients, in 10 patients with refractory angina due to obstructive coronary artery disease (CAD) and in 13 healthy controls. LEPs were recorded during stimulation of chest and right hand dorsum. Three sequences of painful stimuli were applied at each site. Subjective pain rating was assessed by a 0-100 mm visual analogic scale (VAS). Basal LEPs did not differ among groups and there were no differences for most LEP components across the repetitions of stimuli. However, the amplitude of the N2/P2 LEP component, specifically reflecting cortical pain processing, decreased across the three sequences of stimuli in controls and CAD patients, but not in SX patients. Compared with the first sequence, the N2/P2 amplitude during the third sequence of stimuli in the three groups was 77+/-16, 56+/-24, and 99+/-34%, respectively, for chest (P=0.001), and 63+/-31, 72+/-17, and 98+/-46%, respectively, for right hand (P=0.03) stimulation. The changes in VAS pain score across the three sequences paralleled those of N2/P2 amplitude. CONCLUSION: Our data show that in SX patients, central handling of painful stimuli is characterized by inadequate habituation, which might play a role in determining the peculiar clinical characteristics of anginal chest pain of these patients.