Evidence that tirzepatide protects against diabetes-related cardiac damages.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. METHODS: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. RESULTS: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. CONCLUSION: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

SGLT-2 inhibitors and in-stent restenosis-related events after acute myocardial infarction: an observational study in patients with type 2 diabetes.

BACKGROUND: No study evaluated the incidence of intra-stent restenosis (ISR)-related events in patients with type 2 diabetes (T2DM) and acute myocardial infarction (AMI) treated or not with sodium/glucose cotransporter 2 inhibitors (SGLT2i). METHODS: We recruited 377 patients with T2DM and AMI undergoing percutaneous coronary intervention (PCI). Among them, 177 T2DM were treated with SGLT2 inhibitors before PCI. The primary outcome was major adverse cardiovascular events (MACE) defined as cardiac death, re-infarction, and heart failure related to ISR. In patients without ISR, minimal lumen area and minimal lumen diameter were assessed by coronary CT-angiography at 1-year follow-up. RESULTS: Glycemic control was similar in SGLT2i-treated patients and never SGLT2i-users. The incidence of ISR-related MACE was higher in never SGLT2i-users compared with SGLT2i-treated patients, an effect independent of glycemic status (HR = 0.418, 95% CI = 0.241-0.725, P = 0.002) and observed also in the subgroup of patients with HbA1c < 7% (HR = 0.393, 95% CI = 0.157-0.984, P = 0.027). In patients without the event, the stent patency was greater in SGLT2i-treated patients compared with never SGLT2i-users at 1-year follow-up. CONCLUSIONS: SGLT2i treatment in T2DM is associated with a reduced incidence of ISR-related events, independently of glycemic control.

Adiponectin, Leptin, and Resistin Are Dysregulated in Patients Infected by SARS-CoV-2.

Obesity, through adipose tissue (AT) inflammation and dysregulation, represents a critical factor for COVID-19; here, we investigated whether serum levels of adiponectin, HMW oligomers, leptin, and resistin are modulated and/or correlated with clinical and biochemical parameters of severe COVID-19 patients. This study included 62 severe COVID-19 patients; 62 age and sex-matched healthy subjects were recruited as a control group. Anthropometric and biochemical parameters were obtained and compared. Adiponectin, HMW oligomers, leptin, and resistin were analyzed by ELISA. The adiponectin oligomerization state was visualized by Western blotting. When compared to healthy subjects, total adiponectin levels were statistically lower in severe COVID-19 while, in contrast, the levels of leptin and resistin were statistically higher. Interestingly, HMW adiponectin oligomers negatively correlated with leptin and were positively associated with LUS scores. Resistin showed a positive association with IL-6, IL-2R, and KL-6. Our data strongly support that adipose tissue might play a functional role in COVID-19. Although it needs to be confirmed in larger cohorts, adiponectin HMW oligomers might represent a laboratory resource to predict patient seriousness. Whether adipokines can be integrated as a potential additional tool in the evolving landscape of biomarkers for the COVID-19 disease is still a matter of debate. Other studies are needed to understand the molecular mechanisms behind adipokine's involvement in COVID-19.

Endothelial Dysfunction Drives CRTd Outcome at 1-Year Follow-Up: A Novel Role as Biomarker for miR-130a-5p.

Endothelial dysfunction (ED) causes worse prognoses in heart failure (HF) patients treated with cardiac resynchronization therapy (CRTd). ED triggers the downregulation of microRNA-130 (miR-130a-5p), which targets endothelin-1 (ET-1). Thus, we evaluated ED and the response to CRTd by assessing miR-130a-5p and ET-1 serum levels. We designed a prospective multi-center study with a 1-year follow-up to evaluate ED, ET-1, and miR-130a-5p in CRTd patients with ED (ED-CRTd) vs. patients without ED (NED-CRTd). Clinical outcomes were CRTd response, HF hospitalization, cardiac death, and all-cause death. At 1-year follow-up, NED-CRTd (n = 541) vs. ED-CRTd (n = 326) patients showed better clinical statuses, lower serum values of B type natriuretic peptide (BNP: 266.25 ± 10.8 vs. 297.43 ± 16.22 pg/mL; p < 0.05) and ET-1 (4.57 ± 0.17 vs. 5.41 ± 0.24 pmol/L; p < 0.05), and higher values of miR-130a-5p (0.51 ± 0.029 vs. 0.41 ± 0.034 A.U; p < 0.05). Compared with NED-CRTd patients, ED-CRTd patients were less likely to be CRTd responders (189 (58%) vs. 380 (70.2%); p < 0.05) and had higher rates of HF hospitalization (115 (35.3%) vs. 154 (28.5%); p < 0.05) and cardiac deaths (30 (9.2%) vs. 21 (3.9%); p < 0.05). Higher miR-130a-5p levels (HR 1.490, CI 95% [1.014−2.188]) significantly predicted CRTd response; the presence of hypertension (HR 0.818, CI 95% [0.669−0.999]), and displaying higher levels of ET-1 (HR 0.859, CI 98% [0.839−0.979]), lymphocytes (HR 0.820, CI 95% [0.758−0.987]), LVEF (HR 0.876, CI 95% [0.760−0.992]), and ED (HR 0.751, CI 95% [0.624−0.905]) predicted CRTd non-response. Higher serum miR-130a-5p levels (HR 0.332, CI 95% [0.347−0.804]) and use of ARNI (HR 0.319, CI 95% [0.310−0.572]) predicted lower risk of HF hospitalization, whereas hypertension (HR 1.818, CI 95% [1.720−2.907]), higher BNP levels (HR 1.210, CI 95% [1.000−1.401]), and presence of ED (HR 1.905, CI 95% [1.238−2.241]) predicted a higher risk of HF hospitalization. Hence, serum miR-130a-5p could identify different stages of ED and independently predict CRTd response, therefore representing a novel prognostic HF biomarker.

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts.

BACKGROUND: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. OBJECTIVES: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. METHODS: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis. RESULTS: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. CONCLUSION: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT03546062.

Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside.

OBJECTIVES: We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling. BACKGROUND: adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy. METHODS: miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users. RESULTS: At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users. CONCLUSIONS: ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd.

Impact of a contrast media volume control device on acute kidney injury rate in patients with acute coronary syndrome.

BACKGROUND: The DyeVert™ system (Osprey Medical Inc., Minnesota, MN) may reduce contrast media (CM) volume during coronary procedures while maintaining fluoroscopic image quality. Here, we assessed whether the use of the DyeVert system reduces acute kidney injury (AKI) rate in patients with acute coronary syndrome (ACS) undergoing invasive coronary procedures. METHODS: ACS patients scheduled for coronary procedure from January 2017 to December 2019 were included. Two groups were identified: (a) Control group (n = 339), including patients in which a conventional manual injection syringe was used; and (b) DyeVert group (n = 112), in which CM injection was handled by the DyeVert™ system. A propensity score matching was performed to reduce the effect of treatment selection bias and potential confounders. In all cases, a low-osmolar, nonionic CM was administered. The primary objective was the rate of AKI, defined as a serum creatinine increase ≥0.3 mg/dl within 72 hr after CM exposure. RESULTS: CM volume was higher in the Control group than in the DyeVert group (130 [120-188] ml vs. 99 [69-136] ml; p <.001). In the DyeVert group the mean percent CM volume saved was 38 ± 13%. AKI occurred in 7/90 patients (8%) in the DyeVert group and in 17/90 (19%) patients in the Control group (odds ratio = 0.37; 95% confidence interval 0.14-0.95; p =.047). CONCLUSIONS: This preliminary result suggests that CM volume reduction obtained by the DyeVert™ system is an effective strategy to prevent AKI in ACS patients undergoing invasive procedure.

Pericoronary fat inflammation and Major Adverse Cardiac Events (MACE) in prediabetic patients with acute myocardial infarction: effects of metformin.

BACKGROUND/OBJECTIVES: Pericoronary adipose tissue inflammation might lead to the development and destabilization of coronary plaques in prediabetic patients. Here, we evaluated inflammation and leptin to adiponectin ratio in pericoronary fat from patients subjected to coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). Furthermore, we compared the 12-month prognosis of prediabetic patients compared to normoglycemic patients (NG). Finally, the effect of metformin therapy on pericoronary fat inflammation and 12-months prognosis in AMI-prediabetic patients was also evaluated. METHODS: An observational prospective study was conducted on patients with first AMI referred for CABG. Participants were divided in prediabetic and NG-patients. Prediabetic patients were divided in two groups; never-metformin-users and current-metformin-users receiving metformin therapy for almost 6 months before CABG. During the by-pass procedure on epicardial coronary portion, the pericoronary fat was removed from the surrounding stenosis area. The primary endpoints were the assessments of Major-Adverse-Cardiac-Events (MACE) at 12-month follow-up. Moreover, inflammatory tone was evaluated by measuring pericoronary fat levels of tumor necrosis factor-α (TNF-α), sirtuin 6 (SIRT6), and leptin to adiponectin ratio. Finally, inflammatory tone was correlated to the MACE during the 12-months follow-up. RESULTS: The MACE was 9.1% in all prediabetic patients and 3% in NG-patients. In prediabetic patients, current-metformin-users presented a significantly lower rate of MACE compared to prediabetic patients never-metformin-users. In addition, prediabetic patients showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to NG-patients (P < 0.001). Prediabetic never-metformin-users showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to current-metformin-users (P < 0.001). Remarkably, inflammatory tone and leptin to adiponectin ratio was significantly related to the MACE during the 12-months follow-up. CONCLUSION: Prediabetes increase inflammatory burden in pericoronary adipose tissue. Metformin by reducing inflammatory tone and leptin to adiponectin ratio in pericoronary fat may improve prognosis in prediabetic patients with AMI. Trial registration Clinical Trial NCT03360981, Retrospectively Registered 7 January 2018.

Sirolimus-eluting BiOSS LIM dedicated bifurcation stent in the treatment of unprotected distal left main stenosis.

BACKGROUND: Proximal optimization technique (POT) has been proposed to adapt the conventional drug-eluting stent (DES) with the fractal anatomy of the bifurcation. However, only few DES are labeled for post-expansion beyond 5.0 mm. Furthermore, recrossing in the side branch (SB) through the main vessel (MV) stent cells may be challenging. OBJECTIVES: To compare the sirolimus-eluting, balloon-expandable dedicated bifurcation stent BiOSS LIM DES versus the second generation DES in the treatment of distal unprotected left main coronary arteries (ULMCAs) lesions. METHODS: Forty-two consecutive patients with distal ULMCA lesions were treated with the BiOSS LIM (BiOSS LIM group) in our center. A matched-group of patients treated with second-generation DES was selected from our database (Control group). The primary endpoint was the procedural complication rate, including (a) SB occlusion, defined as intraprocedural TIMI flow grade <3 immediately after MV stenting; and/or (b) trouble in SB access, defined as the need of ≥2 guidewires or a failure to recross in the SB trough the MV stent cells. The need of POT in the two groups was also analyzed. RESULTS: The primary endpoint occurred in four (9.5%) patients in the BiOSS LIM group and in 13 (31%) in the Control group (p = 0.028; OR = 4.25; 95% confidence interval: 1.25-14.43). POT was performed more often in the Control group (71% vs. 35%; p = 0.004). CONCLUSIONS: Compared to conventional DES, the BiOSS LIM stent (1) facilitates SB recrossing and (2) fits well with the fractal anatomy of the left main bifurcation.

Long-term improvement in cardiac magnetic resonance in ß-thalassemia major patients treated with deferasirox extends to patients with abnormal baseline cardiac function.

The management of iron overload in thalassemia has changed dramatically since the implementation of magnetic resonance imaging, which allows detection of preclinical iron overload and prevention of clinical complications. This study evaluated the effect of deferasirox (DFX), the newest once-daily oral chelator, on cardiac function, iron overload and cardiovascular events over a longer follow up in a "real world" setting. Longitudinal changes in cardiac magnetic resonance T2*, cardiac function parameters and cardiovascular clinical events were assessed in a cohort of 98 TM patients exposed to DFX for a mean of 6.9 years (range 1.8-11.6 years). No cardiac death or incident heart failure occurred. Cardiac T2* significantly increased (+2.6 ± 11.9 msec; P = 0.035) in the whole population, with a significantly greater increase (+11.6 ± 15.5 msec, P = 0.019) in patients with cardiac iron overload (T2* <20 ms). A significant improvement in left-ventricular ejection fraction (LVEF) (from 50.6 ± 6 to 60.2 ± 5; P = 0.001) was observed in 11 (84.6%) out of 13 patients who normalized cardiac function (LVEF >56%). Arrhythmias were the most frequent cardiac adverse event noted but none led to DFX discontinuation. Our data indicate that DFX is effective in maintaining cardiac iron level in the normal range and in improving cardiac iron overload. No heart failure or cardiac death was reported over this longer observation up to 12 years. For the first time, a DFX-induced improvement in LVEF was observed in a subgroup of patients with abnormal cardiac function at baseline, a preliminary observation which deserves further evaluation.

Correction to: Thrombus aspiration in hyperglycemic ST-elevation myocardial infarction (STEMI) patients: clinical outcomes at 1-year follow-up.

Following publication of the original article [1], the authors reported an error in Acknowledgment section. The last sentence should read as "All authors have read and approval the submission to Cardiovascular Diabetology.

Thrombus aspiration in hyperglycemic ST-elevation myocardial infarction (STEMI) patients: clinical outcomes at 1-year follow-up.

OBJECTIVES: We evaluate whether the thrombus aspiration (TA) before primary percutaneous coronary intervention (PPCI) may improve STEMI outcomes in hyperglycemic patients. BACKGROUND: The management of hyperglycemic patients during STEMI is unclear. METHODS: We undertook an observational cohort study of 3166 first STEMI. Patients were grouped on the basis of whether they received TA or not. Moreover, among these patients we selected a subgroup of STEMI patients with hyperglycemia during the event (glycaemia > 140 mg/dl). The endpoint at 1 year included all-cause mortality, cardiac mortality and re-hospitalization for coronary disease, heart failure and stroke. RESULTS: One-thousand STEMI patients undergoing PPCI to plus TA (TA-group) and 1504 STEMI patients treated with PPCI alone (no-TA group) completed the study. In overall study-population, Kaplan-Meier-analysis demonstrated no significant difference in mortality rates between patients with and without TA (P = 0.065). After multivariate Cox-analysis (HR: 0.94, 95% CI 0.641-1.383) and the addition of propensity matching (HR: 0.86 95% CI 0.412-1.798) TA was still not associated with decreased mortality. By contrast, in hyperglycemic subgroup STEMI patients (TA-group, n = 331; no-TA group, n = 566), Kaplan-Meier-analysis demonstrated a significantly lower mortality (P = 0.019) in TA-group than the no-TA group. After multivariate Cox-analysis (HR: 0.64, 95% CI 0.379-0.963) and the addition of propensity matching (HR: 0.54, 95% CI 0.294-0.984) TA was still associated with decreased mortality. CONCLUSIONS: TA was not associated with lower mortality in PPCI for STEMI when used in our large all-comer cohort. Conversely, TA during PPCI for STEMI reduces clinical outcomes in hyperglycemic patients. Trial registration NCT02817542. 25th, June 2016.

Non-ST-elevation myocardial infarction outcomes in patients with type 2 diabetes with non-obstructive coronary artery stenosis: Effects of incretin treatment.

There are insufficient data on the prognosis and management of people with type 2 diabetes who experience a non-obstructive coronary artery stenosis (NOCS)-non-ST-elevation myocardial infarction (NSTEMI) event. We evaluated the 12-month prognosis of patients with diabetes and NOCS (20%-49% luminal stenosis) who experience a first NSTEMI as compared with patients without diabetes. In addition, we investigated the 12-month prognosis in patients with diabetes and NSTEMI-NOCS previously treated with incretin-based therapy compared with a matched cohort of patients with NSTEMI-NOCS never treated with such therapy. We categorized the patients with diabetes as current incretin users (6 months' treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors) and non-users of incretins. The endpoint was all-cause mortality, cardiac death, recurrent acute coronary syndrome (ACS), and heart failure. The unadjusted Kaplan-Meier analysis, and a risk-adjusted hazard analysis showed that, all-cause mortality, cardiac death, readmission for ACS and heart failure rates during the 12-month follow-up were higher in patients with diabetes and NOCS-NSTEMI than in those with NOCS-NSTEMI without diabetes. Among the patients with diabetes, the current incretin users had a significantly lower rate of all-cause mortality, cardiac death and readmission for ACS at 12 months. In patients with type 2 diabetes and NOCS-NSTEMI, we observed a higher incidence of 1-year mortality and adverse cardiovascular outcomes, as compared with patients without diabetes with NOCS-NSTEMI. In people with diabetes, non-users of incretins had a worse prognosis than current incretin users.

Coronary artery bifurcation narrowing treated by Axxess stent implantation: The CARINAX registry.

OBJECTIVES: To compare the safety and efficacy of the Axxess™ biolimus-eluting stent with the second-generation drug-eluting stent (DES) in the treatment of bifurcation lesions. BACKGROUND: The Axxess™ is a dedicated bifurcation stent, designed to cover the lesion at the carina level. METHODS: Between April 2012 and August 2014, 165 patients with de novo bifurcation lesions were treated with the Axxess™ stent (Axxess group). A propensity-score matched group of 165 patients treated with DES in the same period was selected (Control group). The primary objectives were (1) the procedural complication rate, including side branch (SB) occlusion and trouble in SB access after main vessel stenting; and (2) the device, the angiographic, and the procedural success rate. RESULTS: Procedural complications occurred in 1 patient (0.6%) in the Axxess group and in 20 patients (12%) in the Control group (OR = 0.03; 95% confidence interval 0.005-0.27; P < 0.001). Device success was obtained in 164 (99.5%) patients in the Axxess group and in all in the Control group (P = 1.00). Angiographic success was obtained in all patients. Inaccurate Axxess™ stent position occurred in 21 (13%) patients, and was more often associated with moderate-to-severe calcifications and distal lesion site. Procedural success was obtained in 91.5% patients in the Axxess group and in 90% patients in the Control group (P = 0.72). CONCLUSIONS: The present registry suggests that the Axxess™ stent (1) may represent a valid alternative approach for the treatment of bifurcation lesions and (2) should be avoided in moderate-to-severe calcifications and/or in distal lesions. © 2016 Wiley Periodicals, Inc.

RenalGuard system in high-risk patients for contrast-induced acute kidney injury.

BACKGROUND: High urine flow rate (UFR) has been suggested as a target for effective prevention of contrast-induced acute kidney injury (CI-AKI). The RenalGuard therapy (saline infusion plus furosemide controlled by the RenalGuard system) facilitates the achievement of this target. METHODS: Four hundred consecutive patients with an estimated glomerular filtration rate ≤30 mL/min per 1.73 m(2) and/or a high predicted risk (according to the Mehran score ≥11 and/or the Gurm score >7%) treated by the RenalGuard therapy were analyzed. The primary end points were (1) the relationship between CI-AKI and UFR during preprocedural, intraprocedural, and postprocedural phases of the RenalGuard therapy and (2) the rate of acute pulmonary edema and impairment in electrolytes balance. RESULTS: Urine flow rate was significantly lower in the patients with CI-AKI in the preprocedural phase (208 ± 117 vs 283 ± 160 mL/h, P < .001) and in the intraprocedural phase (389 ± 198 vs 483 ± 225 mL/h, P = .009). The best threshold for CI-AKI prevention was a mean intraprocedural phase UFR ≥450 mL/h (area under curve 0.62, P = .009, sensitivity 80%, specificity 46%). Performance of percutaneous coronary intervention (hazard ratio [HR] 4.13, 95% CI 1.81-9.10, P < .001), the intraprocedural phase UFR <450 mL/h (HR 2.27, 95% CI 1.05-2.01, P = .012), and total furosemide dose >0.32 mg/kg (HR 5.03, 95% CI 2.33-10.87, P < .001) were independent predictors of CI-AKI. Pulmonary edema occurred in 4 patients (1%). Potassium replacement was required in 16 patients (4%). No patients developed severe hypomagnesemia, hyponatremia, or hypernatremia. CONCLUSIONS: RenalGuard therapy is safe and effective in reaching high UFR. Mean intraprocedural UFR ≥450 mL/h should be the target for optimal CI-AKI prevention.

Performance of the XLIMUS Sirolimus-Eluting Coronary Stent in Very Complex Lesions.

INTRODUCTION: Stent delivery failure may occur especially when treating complex coronary artery stenosis. XLIMUS (CARDIONOVUM GmbH, Bonn, Germany) is a new sirolimus-eluting stent (SES) with the following features: 1) cobalt chromium stent platform, with low (73 µm) strut thickness, (2) biodegradable polymer, and 3) potent antiproliferative drug (Sirolimus). Preliminary data suggest that XLIMUS SES may be ideal for the treatment of complex lesions. METHODS: In this registry, we assessed the deliverability, safety, and efficacy of percutaneous coronary interventions (PCI) using the XLIMUS SES in patients undergoing elective PCI in native coronary vessels for complex de novo lesions, including severe calcification, severe tortuosity, and chronic total occlusion. The primary objective of the study is the delivery success of the XLIMUS SES. The secondary objective is the 1-year rate of major adverse cardiac events (MACE; including all-cause death, nonfatal myocardial infarction, and repeat revascularization). RESULTS: A total of 200 consecutive patients with 255 lesions were included. Delivery success was obtained in 196 (98%) patients and in 251 (98.4%) lesions. The XLIMUS SES was successfully implanted on the first attempt with a single guidewire in 176 (88%) patients and in 208 (81.6%) lesions. Additional techniques to facilitate stent delivery (i.e., buddy wire, anchoring-balloon, or GuideLiner catheter) were necessary in 47 (18.4%) lesions. Failure in XLIMUS SES implantation occurred in 4 (1.6%) lesions. MACE rate at 1 year was 9%. CONCLUSIONS: This registry supports the positive performance of the XLIMUS SES in the treatment of complex coronary artery lesions.

Effects of Surgical Techniques on Long-Term Results in Patients with Degenerative Mitral Valve Bileaflet Prolapse.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the long-term results in patients with degenerative mitral valve bileaflet prolapse (DMVBLP) undergoing mitral valve repair (MVr) or mitral valve replacement (MVR), and to compare the consequences of survival related to each technique. METHODS: Between 2001 and 2012, a total of 421 patients underwent isolated primary surgery for DMVBLP. MVr was performed in 146 patients (34.7%), and MVR in 275 (65.3%). MVR patients were allocated to two subgroups. Subgroup A were operated on in routine fashion, preserving the posterior subvalvular apparatus, and in selected cases the anterior or both apparatus (n = 119; 43.3%). In subgroup B, surgery was performed without preservation of the subvalvular apparatus (n = 156; 56.7%). RESULTS: There were no intraoperative deaths in all patient groups. The median length of follow up was 5.96 ± 3.28 years. Five patients (3.4%) in the MVr group died, while 11 in MVR subgroup A (9.2%) died, and 29 in MVR subgroup B (18.6%). Patients in the MVr group demonstrated significant and persistent postoperative decreases in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) during the follow up, while the left ventricular ejection fraction (LVEF) showed a trend to improve. In MVR subgroup A, preservation of the mitral subvalvular structures resulted in a decrease in LVEDD; this resulted in a lesser worsening of the LVEF, as occurs when subvalvular structures are resected. In MVR subgroup B, the LVEDD and LVESD were each increased constantly, which resulted in a statistically significant worsening of the LVEF. CONCLUSIONS: MVr in DMVBLP patients achieved a better preservation of left ventricular systolic indices than MVR, and guaranteed better shortand long-term survivals. When MVr is not feasible, it is recommended that subvalvular preservation be performed during MVR, in order to reduce the risk of early and late mortality and to improve left ventricular function.

The long-term immunogenicity of recombinant hepatitis B virus (HBV) vaccine: contribution of universal HBV vaccination in Italy.

BACKGROUND: Universal hepatitis B virus (HBV) vaccination of newborn babies was introduced in Italy in 1991 and was extended to 12-years-old children for the first 12 years of application so as to cover in a dozen years the Italian population aged 0-24 years. The aim of this study was to identify factors associated with long-term immunogenicity against HBV 17 years after primary vaccination in students attending medical schools in Naples, Italy. METHODS: 1,704 students attending the school of medicine, schools of the healthcare professions, or postgraduate medical schools of the Second University of Naples, Italy, from September 2012 to December 2013 were enrolled in this study. Of these, 588 had been vaccinated against HBV in infancy and 1,116 when 12 years old. Multivariate logistic regression analysis was used to identify factors associated with the level of long-term immunogenicity. RESULTS: All vaccinated subjects were HBsAg/anti-HBc negative: 270 (15.8%) had an anti-HBs titer between 1 and 9 IU/L, 987 (57.9%) between 10 and 400 IU/L, and 447 (26.3%) over 400 IU/L. When compared with the latter two subgroups, those with anti-HBs titers lower than 10 IU/L were younger (24±5.2 years vs. 26±4.9 years, p<0.000), more frequently students attending a healthcare school (59% vs. 47%, p<0.001), and more frequently had been vaccinated in infancy (50% vs. 31.5%, p<0.0001). Multivariate logistic regression identified age at vaccination as the only factor independently associated with an anti-HBs titer<0 IU/L (OR: 2.43; C.I. 95%: 1.57-3.76, p=0.001). CONCLUSIONS: Universal HBV vaccination in Italy has been more effective in generating a prolonged protective response in subjects vaccinated at adolescence than in infancy. Students with a low anti-HBs titer should be considered for a booster dose because most will be exposed to the risk of acquiring HBV for decades.

Hepatocellular carcinoma in chronic HBV-HCV co-infection is correlated to fibrosis and disease duration.

Hepatocellular carcinoma (HCC) is a development of severe liver disease frequently due to HBV and/or HCV infection. The aim of this retrospective study was to evaluate the development of HCC in patients with HBV-HCV chronic infection compared with patients with single HBV or HCV infection and the viral and host factors correlated to HCC in co-infected patients. We studied 268 patients with histology proven chronic hepatitis: 56 had HBV-HCV co-infection (HBV-HCV group), 46 had HBV infection (HBV group) and 166 had HCV infection (HCV group). Patients were followed up for at least 3 years. Viral and host factors were studied. HCC was more frequent in HBV-HCV group (14%) compared with HBV (2%, p = 0.006) and HCV monoinfected (4%, p = 0.006). The Mantel-Haenszel test used to investigate the relationship between HBV-HCV co-infection and development of HCC indicated an association between development of HCC and HBV-HCV co-infection (p < 0.001). In the HBV-HCV group, patients with HCC were significantly older (p = 0.000), had longer disease duration (p = 0.001), higher blood glucose levels (p = 0.001), lower levels of steatosis (p = 0.02), higher levels of fibrosis (p = 0.000), higher HCV RNA (p = 0.01) than those without HCC. ALT, lipid profile, PNPLA3 variant distribution and HBV viral load did not differ among co-infected patients with or without HCC. In conclusion HCC was more frequent in our patients with HBV-HCV co-infection, than in those with HBV or HCV mono-infection; possible associated risk factors for HCC development seem a long duration of disease, high levels of fibrosis and carbohydrate intolerance.

Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma.

BACKGROUND: Occult HBV infection (OBI) is defined by the persistence of HBV in the liver without serum HBsAg and HBVDNA. It represents a life-threatening event during immunosuppressive chemotherapies. An OBI occurs in approximately 18% of HBcAb + patients. International guidelines suggest surveillance for HBV markers in immunosuppressed patients. In Non-Hodgkin Lymphoma (NHL), the prevalence of OBI reactivation remains to be established. METHODS: In order to determine the prevalence of occult HBV reactivation in a large cohort of patients during chemotherapy for NHL, we analysed 498 NHL patients in a centre of Southern Italy. We evaluated HBV markers, NHL type, treatment type and occurrence of HBV reactivation. RESULTS: Forty % of patients were treated with monoclonal antibodies and 60.3% without. Ninety-six patients were HBcAb+, HBsAg-. HBV reactivation occurred in ten subjects of this subgroup. All of them were successfully treated with Lamivudine. None of the patients experienced liver-related death. The prevalence of OBI reactivation was of 10.42% in HBcAb + HBsAb- patients. This event occurred in 50% of patients treated with mild immunosuppressive therapies. Each reactivation was treated with Lamivudine. DISCUSSION: This report suggests that a strict surveillance is important and cost-effective in HBcAb + HBsAg- NHL patients treated with mild immunosuppressive therapies, in order to detect an occult HBV reactivation.