Antonello Vado

Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme A Major Risk Factor and a Marker of Risk for Coronary Stent Restenosis

BACKGROUND Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (I/D) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the I/D polymorphism is analyzed in the present prospective study. METHODS AND RESULTS One hundred seventy-six consecutive patients with successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels (+/-SEM) were 40.8+/-3.5 and 20.7+/-1.0 U/L, respectively (P<.0001). Diameter stenosis percentage and minimum luminal diameter at 6 months showed statistically significant correlation with plasma ACE level (r=.352 and -.387, respectively P<.001). Twenty-one of 62 patients (33.9%) with D/D genotype, 13 of 80 (16.3%) with I/D genotype, and 1 of 34 (2.9%) with I/I genotype showed recurrence; the restenosis rate for each genotype is consistent with a codominant expression of the allele D. CONCLUSIONS In a selected cohort of patients, both the D/D genotype of the ACE gene, and high plasma activity of the enzyme are significantly associated with in-stent restenosis. Continued study with clinically different subsets of patients and various stent designs is warranted.

Long-Term Complications Related to Biventricular Defibrillator Implantation Rate of Surgical Revisions and Impact on Survival: Insights From the Italian ClinicalService Database

Background— Long-term data on device-related untoward events in patients receiving defibrillators for resynchronization therapy (CRT-D) are lacking. We quantified the frequency of repeat invasive procedures and the nature of long-term complications in current clinical practice and examined possible predictors of device-related events and their association with long-term patient outcome. Methods and Results— We analyzed data from 3253 patients who underwent de novo successful implantation of CRT-D and were followed up for a median of 18 months (25th to 75th percentiles: 9 to 30) in 117 Italian centers. Device-related events were reported in 416 patients, and, specifically, surgical interventions for system revision were described in 390 patients. Four years after the implantation procedure, 50% of patients underwent surgical revision for battery depletion and 14% for unanticipated events. For comparison, at 4 years battery depletion occurred in 10% and 13% of patients who received single- and dual-chamber defibrillators at the study centers, and unanticipated events were reported as 4% and 9%, respectively. In CRT-D, infections occurred at a rate of 1.0%/y, and the risk of infections increased after device replacement procedures (hazard ratio, 2.04; 95% confidence interval, 1.01 to 4.09; P =0.045). Left ventricular lead dislodgements were reported at a rate of 2.3%/y and were predicted by longer fluoroscopy time and higher pacing threshold on implantation. Device-related events were not associated with a worse clinical outcome; indeed, the risk of death was similar in patients with and without surgical revision (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.47; P =0.682). Conclusions— In current clinical practice device-related events are more frequent in CRT-D than in single- or dual-chamber defibrillators, and are frequently managed by surgical intervention for system revision. However, a worse clinical outcome is not associated with these events. Clinical Trial Registration— URL: . Unique identifier: [NCT01007474][1]. # Clinical Perspective {#article-title-32} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01007474&atom=%2Fcirculationaha%2F123%2F22%2F2526.atomBackground— Long-term data on device-related untoward events in patients receiving defibrillators for resynchronization therapy (CRT-D) are lacking. We quantified the frequency of repeat invasive procedures and the nature of long-term complications in current clinical practice and examined possible predictors of device-related events and their association with long-term patient outcome. Methods and Results— We analyzed data from 3253 patients who underwent de novo successful implantation of CRT-D and were followed up for a median of 18 months (25th to 75th percentiles: 9 to 30) in 117 Italian centers. Device-related events were reported in 416 patients, and, specifically, surgical interventions for system revision were described in 390 patients. Four years after the implantation procedure, 50% of patients underwent surgical revision for battery depletion and 14% for unanticipated events. For comparison, at 4 years battery depletion occurred in 10% and 13% of patients who received single- and dual-chamber defibrillators at the study centers, and unanticipated events were reported as 4% and 9%, respectively. In CRT-D, infections occurred at a rate of 1.0%/y, and the risk of infections increased after device replacement procedures (hazard ratio, 2.04; 95% confidence interval, 1.01 to 4.09; P=0.045). Left ventricular lead dislodgements were reported at a rate of 2.3%/y and were predicted by longer fluoroscopy time and higher pacing threshold on implantation. Device-related events were not associated with a worse clinical outcome; indeed, the risk of death was similar in patients with and without surgical revision (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.47; P=0.682). Conclusions— In current clinical practice device-related events are more frequent in CRT-D than in single- or dual-chamber defibrillators, and are frequently managed by surgical intervention for system revision. However, a worse clinical outcome is not associated with these events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01007474.

Estrogen Receptor-α Polymorphisms and Angiographic Outcome After Coronary Artery Stenting

Objective—Because of the receptor-mediated antiproliferative effects of estradiol on vascular smooth muscle cells, our study aimed at identifying a role of PvuII and XbaI polymorphisms of the &agr;-estrogen receptor (&agr;ER) gene in the occurrence of restenosis after coronary stent implantation (in-stent restenosis [ISR]). Methods and Results—In 858 patients (148 women), 955 lesions were treated with stent implantation, and the PvuII C/T and XbaI G/A polymorphisms of the &agr;ER gene were determined. Quantitative angiography was performed before and after stenting and at 6-month follow-up. The allelic frequencies were similar between sexes (C/T allele, 0.43/0.57 and 0.44/0.56; P =0.9; G/A allele, 0.35/0.65 and 0.38/0.62; P =0.8; in women and men, respectively). A significantly higher ISR rate in women than in men homozygous for the T-allele of the PvuII polymorphism (42.6% versus 26.9%, P =0.03) or the G-allele of the XbaI polymorphism (41.2% versus 19.4%, P =0.04) was observed. At multivariate analysis, T/T genotype was the only independent predictor of ISR in women but not in men (odds ratio, 1.5; 95% CI, 1.0 to 2.1; P =0.03). XbaI polymorphism was no longer associated with ISR in both sexes. Conclusions—Women homozygous for the T-allele of the PvuII polymorphism of the &agr;ER gene treated with coronary stent implantation have a higher risk of ISR than men.

Longevity of implantable cardioverter-defibrillators for cardiac resynchronization therapy in current clinical practice: an analysis according to influencing factors, device generation, and manufacturer

Aims Device replacement at the time of battery depletion of implantable cardioverter-defibrillators (ICDs) may carry a considerable risk of complications and engenders costs for healthcare systems. Therefore, ICD device longevity is extremely important both from a clinical and economic standpoint. Cardiac resynchronization therapy defibrillators (CRT-D) battery longevity is shorter than ICDs. We determined the rate of replacements for battery depletion and we identified possible determinants of early depletion in a series of patients who had undergone implantation of CRT-D devices. Methods and results We retrieved data on 1726 consecutive CRT-D systems implanted from January 2008 to March 2010 in nine centres. Five years after a successful CRT-D implantation procedure, 46% of devices were replaced due to battery depletion. The time to device replacement for battery depletion differed considerably among currently available CRT-D systems from different manufacturers, with rates of batteries still in service at 5 years ranging from 52 to 88% (log-rank test, P < 0.001). Left ventricular lead output and unipolar pacing configuration were independent determinants of early depletion [hazard ratio (HR): 1.96; 95% 95% confidence interval (CI): 1.57–2.46; P < 0.001 and HR: 1.58, 95% CI: 1.25–2.01; P < 0.001, respectively]. The implantation of a recent-generation device (HR: 0.57; 95% CI: 0.45–0.72; P < 0.001), the battery chemistry and the CRT-D manufacturer (HR: 0.64; 95% CI: 0.47–0.89; P = 0.008) were additional factors associated with replacement for battery depletion. Conclusion The device longevity at 5 years was 54%. High left ventricular lead output and unipolar pacing configuration were associated with early battery depletion, while recent-generation CRT-Ds displayed better longevity. Significant differences emerged among currently available CRT-D systems from different manufacturers.

Plasma Lipoprotein(a) Is Not a Predictor for Restenosis After Elective High-Pressure Coronary Stenting

BACKGROUND Lipoprotein(a) is a risk factor for coronary artery disease. Although it has been implicated in restenosis after balloon angioplasty, its role in restenosis within coronary stents is unknown. The aim of the study was to assess the role of plasma lipoprotein(a) as a predictor for restenosis after elective coronary stenting. METHODS AND RESULTS Elective, high-pressure stenting of de novo lesions in native coronary arteries with Palmaz-Schatz stents was performed in 325 consecutive patients. Clinical, angiographic, and biochemical data were analyzed prospectively. Angiographic follow-up was performed at 6 months. Lipoprotein(a) levels were compared in patients with and without restenosis. Angiographic follow-up was obtained in 312 patients (96%); recurrence was observed in 67 patients (21.5%). No clinical or biochemical variable was associated with restenosis. Lipoprotein(a) level was 37.81+/-49. 01 mg/dL (median, 22 mg/dL; range, 3 to 262 mg/dL) in restenotic patients and 36.95+/-40.65 mg/dL (median, 22 mg/dL; range, 0 to 244 mg/dL) in nonrestenotic patients (P=NS). The correlations between percent diameter stenosis, minimum luminal diameter, and late loss at follow-up angiography and basal lipoprotein(a) plasma level after logarithmic transformation were 0.006, 0.002, and 0.0017, respectively. Multiple stents were associated with a higher incidence of restenosis (P=0.006), but biochemical data in these patients were similar to those treated with single stents. CONCLUSIONS The basal plasma level of lipoprotein(a) measured before the procedure is not a predictor for restenosis after elective high-pressure coronary stenting.

Characterization of ventricular activation pattern and acute hemodynamics during multipoint left ventricular pacing

BACKGROUND Multipoint left ventricular (LV) pacing (MultiPoint Pacing [MPP], St Jude Medical, Sylmar, CA) in a single coronary sinus branch has been introduced as a novel means of cardiac resynchronization therapy (CRT). It is speculated that MPP improves LV function by capturing a larger LV tissue area, resulting in uniform wavefront propagation throughout the ventricles, in comparison to conventional biventricular pacing (BIV). OBJECTIVE The purpose of this study was to evaluate MPP by means of contact mapping and hemodynamic measures to understand the underlying mechanisms and effects. METHODS Ten patients with non-ischemic cardiomyopathy (mean age 69 ± 9 years; 6 men (60%); New York Heart Association heart failure class II or III; QRS duration 173 ± 20 ms; LV ejection fraction 27% ± 5%) received a CRT-defibrillator capable of MPP. After the implantation procedure, an acute pacing protocol was implemented, including 2 BIV and up to 9 MPP interventions. In all pacing interventions, LV electrical activation patterns and hemodynamics (dP/dtmax) were evaluated, and for each patient, both the resulting measures were compared between MPP and BIV interventions. RESULTS Compared with BIV, MPP resulted in an increase in LV dP/dtmax (30% ± 13% vs. 25% ± 11%; P = .041), a reduction in QRS duration (22% ± 11% vs. 11% ± 11%; P = .01), and a decrease in total endocardial activation time (25% ± 15% vs. 10% ± 20%; P = .01). MPP resulted in a larger capture of LV mass during the first 25 ms (35% ± 22% vs. 16% ± 8%; P = .005) and during the first 50 ms (78% ± 27% vs. 60% ± 23%; P = .03) of pacing, suggesting a quicker wavefront propagation throughout the left ventricle. CONCLUSION In this acute study, MPP in CRT improved both endocardial and surface electrical parameters and hemodynamics in comparison with BIV.

Relationship between Cognitive Function, Depression/Anxiety and Functional Parameters in Patients Admitted for Congestive Heart Failure

Cognitive impairment, anxiety and depression have been described in patients with congestive heart failure (CHF). We analyzed in-hospital CHF patients before discharge with neuropsychological tests attempting to correlate with prognostic parameters. Methods: All subjects underwent a mini mental state examination (MMSE), geriatric depression scale (GDS), anxiety and depression scale test (HADS). We evaluated NYHA class, brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF) and non-invasive cardiac output (CO). Results: Three-hundred and three CHF patients (age 71.6 ys) were analysed. The mean NYHA class was 2.9±0.8, LVEF was 43.4±15.8%; BNP plasma level and CO were calculated as 579.8±688.4 pg/ml and 3.9±1.1 l/min, respectively. In 9.6% a pathological MMSE score emerged; a depression of mood in 18.2% and anxiety in 23.4% of patients were observed. A significant correlation between MMSE and age (r=0.11 p=0.001), BNP (r=0.64 p=0.03) but not between MMSE and NYHA class and LVEF was observed. GDS and HADS were inversely correlated with NYHA class (r=0.38 p=0.04) and six-minute walking test (r=0.18 p=0.01) without an association with objective parameters in CHF (BNP, LVEF and cardiac output). At multivariate analysis only MMSE and BNP are inversely correlated significantly (p=0.019 OR=-0.64, CI=-042-0.86). Conclusions: in-hospital CHF patients may manifest a reduction of MMSE and important anxiety/depression disorders. The results of the study suggest that the presence of cognitive impairment in older CHF patients with higher BNP plasma level should be considered. In admitted CHF patients anxiety and depression of mood are commonly reported and influenced the perception of the severity of illness.

Association study of the I/D polymorphism and plasma angiotensin-converting enzyme (ACE) as risk factors for stent restenosis

The ID (insertion/deletion) polymorphism of the ACE (angiotensin-converting enzyme) gene controls plasma ACE levels. Both have been correlated with ISR (in-stent restenosis) in preliminary analyses, but not confirmed in larger studies. In the present study, baseline and 6-month quantitative coronary analysis were performed in 897 patients who had stent implantation and the ID polymorphism genotyped. Plasma ACE levels were measured in 848 patients (95%). Restenosis rates among genotypes were 31.2% DD, 25.5% ID and 28.8% II (not significant). Plasma ACE levels were significantly higher in restenotic patients compared with patients without restenosis (30.7+/-18.6 units/l compared with 22.8+/-12.8 units/l; P=0.0001) and a strong independent predictor of ISR [OR (odds ratio)=3.70; 95% CI (confidence interval), 2.40-5.71; P<0.0001], except in diabetics. In the subgroup of diabetics and patients with AMI (acute myocardial infarction), the DD genotypes actually had a lower risk of ISR than the II genotypes (diabetics, OR=0.16; 95% CI, 0.04-0.69; P=0.014; and patients with AMI, OR=0.21; 95% CI, 0.061-0.749; P=0.016). After exclusion of diabetics and patients with AMI, ISR rates for genotypes in 632 patients were 31.7% DD, 24.3% ID and 17.6% II (P=0.02; DD compared with non-DD OR=1.57; 95% CI, 1.09-2.25). The association between the D allele and ISR observed in selected populations does not hold with a larger sample size. Other than sample size, clinical variables can modulate the association between ID polymorphism and ISR. Plasma ACE level is a risk factor for ISR, independently of the ID genotype.

Risk stratification of ischaemic patients with implantable cardioverter defibrillators by C-reactive protein and a multi-markers strategy: results of the CAMI-GUIDE study

AIMS Patients at risk of sudden cardiac death (SCD) after myocardial infarction (MI) can be offered therapy with implantable cardioverter defibrillators (ICDs). Whether plasma biomarkers can help risk stratify for SCD and ventricular arrhythmias (VT/VF) is unclear. METHODS AND RESULTS The primary objective of the CAMI-GUIDE study is to assess the predictive role of C-reactive protein for SCD or VT/VF in ischaemic patients with the ejection fraction <30% and ICDs. Secondary endpoints included all-cause mortality, hospitalizations, and death from heart failure. Additional analyses incorporated cystatin-C and NT-ProBNP in multi-marker approach for the prediction of adverse outcomes. A total of 300 patients were enrolled. All-cause mortality at 2 years was 22.6%, mortality from heart failure was 8.3%. Primary endpoint occurred in 17.3%. At a competing risk multivariable analysis adjusted for baseline variables, no significant difference in primary endpoint was found between patients with C-reactive protein ≤3 vs. >3 mg/L [heart rate (HR) 0.91 (0.50-1.64) P = 0.76], while C-reactive protein >3 mg/L was strongly associated with mortality due to heart failure [HR: 3.17 (1.54-6.54) P = 0.002]. NT-proBNP above median was significantly associated with the primary endpoint [adjusted HR: 1.46 (1.020-2.129) P = 0.042]. A risk function, including the three biomarkers, NYHA class and resting HR, allowed stratification of patient mortality risk from 5 to 50%. CONCLUSION C-reactive protein >3 mg/L is not associated with SCD or fast VT/VF, however, is a strong predictor of HF mortality. Biomarkers combined with clinical markers allow an excellent risk stratification of mortality at 2 years.

Cardiac Resynchronization Therapy Modifies the Neurohormonal Profile, Hemodynamic and Functional Capacity in Heart Failure Patients

BACKGROUND Cardiac resynchronization therapy (CRT) has been shown to improve the clinical status and survival in congestive heart failure (CHF) patients, but little is known about its influence on neurohormonal profile. METHODS Heart failure patients treated with CRT for moderate/severe heart failure were studied with echocardiography, cardiopulmonary test, and neurohormonal profile [brain natriuretic peptide (BNP), endothelin (END), big endothelin (big-END), epinephrine (EPI), tumor necrosis factor-alpha (TNF-alpha)] at baseline and after 1 year from the pacemaker implantation. RESULTS 120 NYHA II-IV patients entered this study, all with an indication to CRT; 100 agreed to be implanted (group A), whereas 20 refused, identifying a control group (group B). In group A NYHA class (from 3.15+/-0.49-1.15+/-0.49, p=0.001), left ventricular ejection fraction (from 19.6+/-4.95-35.6+/-5.95%, p=0.001), severity of mitral regurgitation (from 13.3+/-4.19-6.09+/-4.11 cmq, p=0.001), and peak VO(2) (from 9.68+/-4.61-13.35+/-3.32 mL/kg/min, p=0.001) improved at 1-year follow-up. In the neurohormonal profile only plasma BNP (from 185.1+/-185.9-110.2+/-137.5 pg/mL, p=0.03) and big-END (from 1.8+/-1.5-0.87+/-0.7 fmol/mL, p=0.007) were reduced significantly. None of these parameters significantly changed in the control group at 1-year follow-up. CONCLUSIONS In patients with moderate/severe heart failure, CRT improved clinical status and the functional parameters modifying the neurohormonal profile at 1-year follow-up.