Giuseppe Giugliano

Inflammation in Peripheral Artery Disease

Peripheral artery disease (PAD), which consists of partial or complete obstruction of the arteries in the lower limbs, is one of the most common manifestations of atherosclerosis, affecting ≈27 million individuals in Europe and North America.1 Its main symptomatic expression, intermittent claudication, was first described by the French veterinarian Bouley2 in a horse affected by progressive limping and lameness consequent to a fibrous clot that occluded the femoral arteries of the posterior limbs. In humans, this condition was noted by Brodie3 in 1846, but it was Charcot4 who in 1858 clearly defined and described the syndrome (and used the term “intermittent claudication”).3,4 Reproducibly elicited by walking-induced muscle ischemia and consistently relieved by rest that allows reperfusion of the affected limb, intermittent claudication may be considered “leg effort angina.” Indeed, for a long time, treatment was aimed exclusively at relieving leg symptoms and improving the functional status of affected individuals. However, in the 1950s, Stammers5 and Allen et al6 independently observed that patients with claudication were at high mortality risk. Subsequent prospective studies confirmed that patients with PAD rarely progress to limb loss but that the presence of PAD is a powerful and independent predictor of cardiac and cerebral ischemic events.7,–,11 However, this increased risk appears to be poorly related to classic risk factors, suggesting that once PAD is established, subsequent cardiovascular risk is related to the severity and extent of the underlying atherosclerotic disease and possibly other factors.7,–,11 It is well established that hypertension, smoking, diabetes mellitus, and hypercholesterolemia play a major role in the initiation and development of atherosclerosis and its clinical manifestations, although the prognostic potency of each of these factors in atherogenesis differs in the …

Drug-Eluting Balloons for the Treatment of the Superficial Femoral Artery In-Stent Restenosis: 2-Year Follow-Up

OBJECTIVES The aim of this prospective registry was to evaluate the safety and efficacy at 2-year follow-up of the use of drug-eluting balloons (DEBs) for the treatment of superficial femoral artery (SFA) in-stent restenosis (ISR). BACKGROUND The use of DEBs for the treatment of SFA ISR is associated with a satisfactory primary patency rate at 1 year, but no data are available for longer follow-up. Unfortunately, when DEBs were used to treat SFA de novo lesions, the occurrence of restenosis increased by 50% between the first and the second years of follow-up. METHODS From December 2009 to December 2010, 39 consecutive patients underwent percutaneous transluminal angioplasty of SFA ISR at our institution (Clinica Montevergine, Mercogliano, Italy). All patients underwent conventional SFA percutaneous transluminal angioplasty and final post-dilation with paclitaxel-eluting balloons (IN.PACT, Medtronic Inc., Minneapolis, Minnesota). Patients were evaluated for up to 24 months. RESULTS During follow-up, 1 patient died of heart failure and another of sudden death, for a 2-years rate of cardiovascular mortality rate of 5.12 %. The primary patency rate at 2 years was 70.3% (11 of 37 patients experienced restenosis recurrence at 2-year follow-up). The treatment of complex ISR lesions (classes II and III) was associated with an increased rate of recurrent restenosis compared with class I (33.3 % and 36.3 % vs. 12.5%; p = 0.05). CONCLUSIONS The data suggest that adjunctive use of DEBs for the treatment of SFA ISR is a safe and effective therapeutic strategy up to 2 years of follow-up.

Functional status measured by walking impairment questionnaire and cardiovascular risk prediction in peripheral arterial disease: results of the Peripheral Arteriopathy and Cardiovascular Events (PACE) study.

The prognostic impact of the functional status of patients with intermittent claudication is still obscure. From the lists of seven general practitioners, we identified all subjects aged 40-80 years (n = 4352). Of those reporting leg symptoms while walking on the Rose questionnaire (n = 760), 60 had a qualifying diagnosis of peripheral arterial disease (PAD). All of them received the Walking Impairment Questionnaire (WIQ). For each patient affected by PAD, three sex- and age-matched controls were selected randomly. After a 24-month follow-up, survival curves showed that PAD patients with WIQ scores > median had a higher cardiovascular risk than controls, and patients with WIQ scores < median had an even poorer prognosis (p < 0.001 for all WIQ domains). In PAD, after adjustment for age, sex, ankle-brachial index and comorbidity, two WIQ domains (ie walking speed and stairclimbing) were associated with cardiovascular events. The cardiovascular risk of claudicants who had a score > median for at least three WIQ domains was intermediate versus the risk of controls and PAD patients with a WIQ score < median, also when adjusted for the covariates indicated above (RR = 3.26, p = 0.019). In intermittent claudication, a worse functional status entails a greater risk of ischemic events versus low functional impairment.

Increased mortality after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and low ejection fraction: A meta-analysis of 6898 patients

BACKGROUND There is conflicting evidence regarding the safety and efficacy of transcatheter aortic valve implantation (TAVI) procedures in patients with severe aortic stenosis and low left ventricular ejection fraction (EF). The primary aim of this study was to determine the impact of TAVI on short- and long-term mortality in patients with low EF (EF <50%); the secondary aim was to analyze the impact of TAVI procedure on EF recovery in the same setting of patients. METHODS AND RESULTS Twenty-six studies enrolling 6898 patients with severe aortic stenosis undergoing TAVI procedure were included in the meta-analysis and analyzed for 30-day, 6-month and 1-year all-cause and cardiovascular mortality; a further meta-analysis was also performed in patients with low EF to assess EF changes post TAVI. In low EF patients, both all-cause and cardiovascular short- and long-term mortality were significantly higher when compared to patients with normal EF (30-day-all-cause mortality: 0.13; 95% confidence interval [CI]: 0.01 to 0.25, I(2)=49.65, Q=21.85; 1-year-all-cause mortality: 0.25; 95% [CI]: 0.16 to 0.34, I(2)=25.57, Q=16.12; 30-day-cardiovascular mortality: 0.03; 95% [CI]: -0.31 to 0.36, I(2)=66.84, Q=6.03; 1-year-cardiovascular mortality: 0.29; 95% [CI]: 0.12 to 0.45, I(2)=0.00, Q=1.88). Nevertheless, in low EF patients TAVI was associated with a significant recovery of EF, which started at discharge and proceeded up to 1-year-follow-up. CONCLUSIONS Patients with low EF severe aortic stenosis have higher mortality following TAVI compared to normal EF patients, despite a significant and sustained improvement in EF.

Effects of successful percutaneous lower extremity revascularization on cardiovascular outcome in patients with peripheral arterial disease

BACKGROUND Lower extremity peripheral arterial disease (LE-PAD) reduces walking capacity and is associated with an increased cardiovascular risk. Endovascular revascularization of LE-PAD improves walking performance and quality of life. In the present study, we determined whether successful lower limbs revascularization also impacts cardiovascular outcome in LE-PAD patients. METHODS 479 consecutive LE-PAD patients at stage II of Fontaines classification, with ankle/brachial index ≤ 0.90 and one or more stenosis >50% in at least one leg artery, were enrolled in the study. According to the Trans-Atlantic Inter Society Consensus II recommendations, 264 (55.1%) underwent percutaneous lower extremity angioplasty (PTA group), while 215 (44.9%) were managed with conservative therapy (MT group). The incidence of major cardiovascular events (including cardiovascular death, myocardial infarction, ischemic stroke, coronary and carotid revascularizations) was prospectively analyzed by Kaplan-Meier curves. Crude and adjusted HRs (95% CI) of developing a cardiovascular event were calculated by Cox analysis. RESULTS No baseline differences were observed among the groups, except for a lower maximum walking distance in the PTA group. During a median follow-up of 21 months (12.0-29.0), the incidence of cardiovascular events was markedly lower in PTA compared to MT patients (6.4% vs. 16.3%; p=0.003), and patients in the MT group showed a 4.1-fold increased cardiovascular risk compared to patients in the PTA group, after adjustment for potential confounders (95% CI 1.22-13.57, p=0.023). CONCLUSIONS This study shows that successful revascularization of LE-PAD patients affected by intermittent claudication, in addition to improving functional status, reduces the occurrence of future major cardiovascular events.

Abdominal aortic aneurysm in patients affected by intermittent claudication: prevalence and clinical predictors

BackgroundAbdominal aortic aneurysm (AAA) is a frequent cause of death among elderly. Patients affected by lower extremity peripheral arterial disease (LE-PAD) seem to be particularly at high risk for AAA. We aimed this study at assessing the prevalence and the clinical predictors of the presence of AAA in a homogeneous cohort of LE-PAD patients affected by intermittent claudication.MethodsWe performed an abdominal ultrasound in 213 consecutive patients with documented LE-PAD (ankle/brachial index ≤0.90) attending our outpatient clinic for intermittent claudication. For each patient we registered cardiovascular risk factors and comorbidities, and measured neutrophil count.ResultsThe ultrasound was inconclusive in 3 patients (1.4%), thus 210 patients (169 males, 41 females, mean age 65.9 ± 9.8 yr) entered the study. Overall, AAA was present in 19 patients (9.0%), with a not significant higher prevalence in men than in women (10.1% vs 4.9%, p = 0.300). Patients with AAA were older (71.2 ± 7.0 vs 65.4 ± 9.9 years, p = 0.015), were more likely to have hypertension (94.7% vs 71.2%, p = 0.027), and greater neutrophil count (5.5 [4.5 – 6.2] vs 4.1 [3.2 – 5.5] x103/μL, p = 0.010). Importantly, the c-statistic for neutrophil count (0.73, 95% CI 0.60 – 0.86, p =0.010) was higher than that for age (0.67, CI 0.56–0.78, p = 0.017). The prevalence of AAA in claudicant patients with a neutrophil count ≥ 5.1 x103/μL (cut-off identified at ROC analysis) was as high as 29.0%.ConclusionsPrevalence of AAA in claudicant patients is much higher than that reported in the general population. Ultrasound screening should be considered in these patients, especially in those with an elevated neutrophil count.

Meta-Analysis of Mortality Outcomes and Mitral Regurgitation Evolution in 4,839 Patients Having Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis

Transcatheter aortic valve implantation (TAVI) is an effective alternative therapy in selected patients with severe aortic stenosis. The role and effects of coexistent moderate to severe mitral regurgitation (msMR) in patients who undergo TAVI remain unclear. Thirteen studies enrolling 4,839 patients who underwent TAVI, including patients with msMR, were considered in a meta-analysis and analyzed for all-cause-mortality; a further meta-analysis was performed to assess mitral regurgitation (MR) evolution after TAVI. In patients with msMR, all-cause-mortality after TAVI was significantly increased at 30-day (effect size [ES] -0.18, 95% confidence interval [CI] -0.31 to -0.04, I(2) = 46.51, Q = 7.48), 1-year (ES -0.22, 95% CI -0.36 to -0.08, I(2) = 56.20, Q = 11.41), and 2-year (ES -0.15, 95% CI -0.27 to -0.02, I(2) = 0.00, Q = 2.64) follow-up compared with patients with absent or mild MR, independent of baseline left ventricular ejection fraction. Interestingly, the impact of msMR on outcomes was statistically stronger when the CoreValve system was used. TAVI was also associated with an improvement in MR entity at 3- and 6-month follow-up (overall ES -0.19, 95% CI -0.37 to -0.01, I(2) = 61.52, Q = 10.39). In conclusion, the presence of preoperative msMR in patients with severe, symptomatic aortic stenosis who undergo TAVI negatively affects outcomes after TAVI. In addition, in the same group of patients, a trend toward a reduction in MR severity was observed. Whether the decrease in MR severity affects mortality after TAVI remains to be defined.

Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis

Aims Gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE). Methods and results MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26 167 subjects. The mean follow-up in our study population was 4.3 ± 1.5 years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15 662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, P < 0.0001, I2 = 94%] and MACCE (5 studies for 6 cohorts enrolling 13 944 subjects, HR: 1.67, 95% CI: 1.33-2.11, P < 0.00001, I2 = 46%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10 μmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), P < 0.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. Conclusions This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

Left Ventricular Hypertrophy Regression During Antihypertensive Treatment in an Outpatient Clinic (the Campania Salute Network)

Background Regression of left ventricular (LV) hypertrophy (LVH) has been a goal in clinical trials. This study tests the external validity of results of clinical trials on LVH regression using a large registry from a tertiary care center, to identify phenotypes less likely to achieve regression of LVH. Methods and Results Patients from the Campania Salute Network, free of prevalent cardiovascular disease, but with echocardiographic LVH (defined as LV mass index [LVMi] >47 g/m2.7 in women and >50 g/m2.7 in men) were included. During a median follow‐up of 67 months, clear‐cut regression of LVH was documented in 14% of patients (13±8% reduction of initial LVMi) or 23% when also considering those with a reduction of LVMi ≥5 g/m2.7. Patients with persistent LVH were older with longer duration of hypertension, suboptimal blood pressure (BP) control, larger body mass index, LV mass, and carotid intima‐media thickness and included more women and subjects with diabetes mellitus, isolated systolic hypertension, and metabolic syndrome (all P<0.05). Number and class of antihypertensive drugs during follow‐up did not differ between groups. In multiple logistic regression analysis, older age, female sex, obesity, higher baseline LVMi and carotid intima‐media thickness, and suboptimal BP control were significant covariates of persistent LVH (all P≤0.01), independent of diabetes, duration of hypertension, isolated systolic hypertension, follow‐up time and number and class of antihypertensive drugs. Conclusions Early initiation of antihypertensive treatment, aggressive BP control, and attention to metabolic aspects are critical to avoid irreversible LVH.

Dermcidin: a skeletal muscle myokine modulating cardiomyocyte survival and infarct size after coronary artery ligation

AIMS Coronary artery disease is the leading cause of death in western countries, and its association with lower extremity peripheral artery disease (LE-PAD) represents an independent predictor of worse outcome. However, the molecular mechanisms underlying these effects are currently unknown. METHODS AND RESULTS To investigate these processes, we used in vitro approaches and several mouse models: (i) unilateral limb ischaemia by left common femoral artery ligation [peripheral ischaemia (PI), n = 38]; (ii) myocardial infarction by permanent ligation of the left descending coronary artery (MI, n = 40); (iii) MI after 5 weeks of limb ischaemia (PI + MI, n = 44); (iv) sham operation (SHAM, n = 20). Compared with MI, PI + MI hearts were characterized by a significant increase in cardiomyocyte apoptosis, larger infarct areas, and decreased cardiac function. By using a proteomic approach, we identified a ≅ 8 kDa circulating peptide, Dermcidin (DCD), secreted by ischaemic skeletal muscles, enhancing cardiomyocytes apoptosis under hypoxic conditions and infarct size after permanent coronary artery ligation. siRNA interference experiments to reduce DCD circulating levels significantly reduced infarct size and ameliorated cardiac function after MI. CONCLUSION Our data demonstrate that chronic limb ischaemia activates detrimental pathways in the ischaemic heart through humoral mechanisms of remote organ crosstalk. Thus, DCD may represent a novel important myokine modulating cardiomyocyte survival and function.