Resolution of late-onset heart and liver failures after reversion of jejuno-ileal bypass: a case report.

OBJECTIVES: Jejuno-ileal bypass (JIB) was a kind of bariatric surgery performed from 1960s to 1980s, able to induce sustainable weight loss by creating a surgical short bowel syndrome. MATERIALS AND METHODS: We report a case of an octogenarian woman who underwent in the early eighties this kind of surgery with consequent 40 kg weight loss. After 27 years, she first developed a reversible metabolic cardiomyopathy that began with signs and symptoms of heart failure. Thereafter, she was diagnosed with severe intractable liver insufficiency. RESULTS: Despite her old age, the patient underwent reversal of JIB with consequent early improvement of hepatic function. CONCLUSIONS: This case demonstrate that in case of long-term and life-threatening complications, it is possible to successfully reverse JIB surgery after upto 30 years. The hypothesis on pathophysiology of heart and liver insufficiency are discussed.

Key Enabling Technologies for Point-of-Care Diagnostics.

A major trend in biomedical engineering is the development of reliable, self-contained point-of-care (POC) devices for diagnostics and in-field assays. The new generation of such platforms increasingly addresses the clinical and environmental needs. Moreover, they are becoming more and more integrated with everyday objects, such as smartphones, and their spread among unskilled common people, has the power to improve the quality of life, both in the developed world and in low-resource settings. The future success of these tools will depend on the integration of the relevant key enabling technologies on an industrial scale (microfluidics with microelectronics, highly sensitive detection methods and low-cost materials for easy-to-use tools). Here, recent advances and perspectives will be reviewed across the large spectrum of their applications.

Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans.

Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 µg·kg-1·min-1 NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP (P < 0.005 vs. baseline), -10% GFR, -20% RBF, -49% UNaV (P < 0.001), and +120% U8-iso-PGF2αV (P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME (P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (-6%), RBF (-12%), and UNaV (-34%) were blunted vs. PL + l-NAME and LOS + l-NAME (P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.

Nitric oxide-angiotensin II interactions and renal hemodynamic function in patients with uncomplicated type 1 diabetes.

The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 µg·kg⁻¹·min⁻¹ NG-nitro-L-arginine-methyl-ester (L-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM (P < 0.005). In the C group, PL + L-NAME caused declines in GFR (101 ± 3 to 90 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (931 ± 22 to 754 ± 31 ml·min⁻¹·1.73 m⁻²), and UNaV (158 ± 12 to 82 ± 18 µmol/min) and an increase in FF (0.19 ± 0.02 to 0.21 ± 02; P < 0.001), which were not influenced by LOS pretreatment (P > 0.05 for LOS + L-NAME-C vs. PL + l-NAME-C). In DM, PL + L-NAME resulted in exaggerated renal effects, with changes in GFR (128 ± 3 to 104 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (1,019 ± 27 to 699 ± 34 ml·min⁻¹·1.73 m⁻²), UNaV (150 ± 13 to 39 ± 14 µmol/min), and FF (0.22 ± 0.03 to 0.26 ± 0.02) that were significantly greater vs. PL + L-NAME-C (P < 0.005). LOS pretreatment blunted GFR, RBF, FF, and UNaV responses to L-NAME in DM (P < 0.005 vs. PL + L-NAME-DM), resulting in a response profile that was similar to PL + L-NAME and LOS + L-NAME in C (P > 0.05). Renal responses to L-NAME in uncomplicated, type 1 DM are exaggerated vs. C, consistent with an upregulation of NO bioactivity. LOS, without effects in C, prevents the accentuated actions of L-NAME in DM, thus indicating an augmented role for NO-RAS interactions in renal hemodynamic function in DM.

Personalized Management of Sudden Death Risk in Primary Cardiomyopathies: From Clinical Evaluation and Multimodality Imaging to Ablation and Cardioverter-Defibrillator Implant.

Sudden cardiac death represents the leading cause of death worldwide; although the majority of sudden deaths occur in an elderly population with coronary artery disease, some occur in young and otherwise healthy individuals, as is the case of cardiomyopathies. The aim of the present review is to provide a stepwise hierarchical approach for the global sudden death risk estimation in primary cardiomyopathies. Each individual risk factor is analyzed for its contribution to the overall risk of sudden death for each specific cardiomyopathy as well as across all primary myocardial diseases. This stepwise hierarchical and personalized approach starts from the clinical evaluation, subsequently passes through the role of electrocardiographic monitoring and multimodality imaging, and finally concludes with genetic evaluation and electro-anatomical mapping. In fact, the sudden cardiac death risk assessment in cardiomyopathies depends on a multiparametric approach. Moreover, current indications for ventricular arrhythmia ablation and defibrillator implantation are discussed.

Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA).

BACKGROUND: Acute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. METHODS: The Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years, and had a median follow-up of 19.9 years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalisation for coronary revascularisation. RESULTS: MINOCA occurred in 317 patients (15.9%) and, during the follow-up, there was no significant difference in MACE rates between them and the patients with obstructive coronary artery disease (MICAD: 27.8% vs 37.5%; adjusted hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.57-1.09;p = 0.15). The CV death rate was lower in the MINOCA group (4.2% vs 8.4%, HR 0.26, 95%CI 0.08-0.86;p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4%; HR 0.76, 95%CI 0.52-1.13;p = 0.18), non-fatal ischemic stroke (9.5% vs 3.7%; HR 1.79, 95%CI 0.87-3.70;p = 0.12), and all-cause mortality (14.1% vs 20.7%, HR 0.73, 95%CI 0.43-1.25;p = 0.26) were not significantly different in the two groups. The rate of rehospitalisation for coronary revascularisation was lower among the MINOCA patients (6.7% vs 27.7%; HR 0.27, 95% CI 0.15-0.47;p < 0.001). CONCLUSIONS: MINOCA is frequent and not benign in patients with early-onset MI. Although there is a lower likelihood of CV death,the long-term risk of MACE and overall mortality is not significantly different from that of MICAD patients.

Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction.

Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure. Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1-22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Results: ST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52-0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up. Conclusions: There are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes. Trial Registration: 4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

Hypertrophic cardiomyopathy and nephrogenic diabetes insipidus associated with chronic lithium carbonate use.

Lithium carbonate is an effective mood stabilizer. We treated a patient for hypertrophic cardiomyopathy due to chronic unsupervised lithium carbonate use. We noted: a) a previously normal ECG; b) the absence of any familiarity for sudden cardiac death; c) the associated nephrogenic diabetes insipidus; d) probable exaggerated lithium plasma concentrations, which had not been monitored over the past few years; and e) the unusual traits of the right ventricle. We would like to stress the need for regular cardiologic follow-up in psychiatric patients treated with lithium carbonate, to minimize its potential cardiac untoward consequences.

Left atrial appendage occlusion in patients with atrial fibrillation and large prevalence of prior intracranial bleeding.

BACKGROUND: Left atrial appendage occlusion (LAAO) represents an alternative approach for the prevention of cardioembolic stroke in patients with nonvalvular atrial fibrillation (NVAF) and contraindication for oral anticoagulation (OAC). The aim of our study was to analyse the outcomes in patients treated with LAAO, with a focus on cases with previous intracranial bleeding. METHODS: Sixty patients with NVAF underwent LAAO (75.4 ±â€Š9 years); mean CHA2DS2-VASc was 4.4 ±â€Š1.7, mean HAS-BLED 3.2 ±â€Š0.9. Thirty-two patients (53.3%) reported previous intracranial bleeding. Ischaemic and bleeding events recorded during follow-up were compared with expected event rates according to CHA2DS2-VASc and HAS-BLED scores. RESULTS: Device implantation was successful in 58 patients (96.7%). The antiplatelet therapy was tailored according to patients' bleeding risk. During follow-up (2.32 ±â€Š1.5 years) 3 ischaemic strokes and 1 transient ischaemic attack occurred, versus 13 total expected thromboembolic events (P = 0.033); 5 major bleedings were observed, versus 7 expected ones, if the patients were under OAC. Considering the combined endpoint (thromboembolic and major bleeding events) 9 events were observed versus 20 expected major events (P = 0.031). In the prespecified subgroup of patients with previous intracranial bleeding, two ischaemic strokes and one transient ischaemic attack were observed during follow-up versus six total expected thromboembolic events; no intracranial bleeding recurrence was recorded. Regarding the combined endpoint four major events were recorded versus nine expected ones. CONCLUSION: LAAO is an efficient and safe option for the prevention of cardioembolic stroke in patients with NVAF, high thromboembolic risk and contraindication to OAC, particularly in patients with previous intracranial bleeding.

Cardiac rehabilitation of elderly patients in eight rehabilitation units in western Europe: Outcome data from the EU-CaRE multi-centre observational study.

AIMS: The European Cardiac Rehabilitation in the Elderly (EU-CaRE) HORIZON 2020 project compares the sustainable effects of cardiac rehabilitation (CR) in elderly patients. METHODS AND RESULTS: A total of 1633 patients with coronary artery disease (CAD) or heart valve replacement (HVR), with or without revascularization, aged 65 or above, who participated in CR were included. Peak oxygen uptake (VO2peak), smoking, body mass index, diet, physical activity, serum lipids, psychological distress and medication were assessed before and after CR (T0 and T1) and after 12 months (T2). Patients undergoing coronary artery bypass surgery or surgical HVR had lower VO2peak at T0 and a greater increase to T1 and T2 (2.8 and 4.4 ml/kg/min, respectively) than CAD patients undergoing percutaneous or no revascularization (1.6 and 1.4 ml/kg/min, respectively). After multivariable adjustment, earlier CR uptake was associated with greater improvements in VO2peak. The proportion of CAD patients with three or more uncontrolled risk factors declined from 58.4% at T0 to 40.1% at T2 (p < 0.0001). Psychological distress scores all improved and adherence to medication was overall good at all sites. There were significant differences in risk factor burden across sites, but no CR program was superior to others. CONCLUSIONS: The outcomes of VO2peak in CR programs across Europe seemed mainly determined by timing of uptake and were maintained or even further improved at 1-year follow-up. Despite significant improvements, 40.1% of CAD patients still had three or more risk factors not at target after 1 year. Differences across sites could not be ascribed to characteristics of the CR programs offered.

Hemodynamic and ECG responses to stress test in early adolescent athletes explain ethnicity-related cardiac differences.

BACKGROUND: Ethnicity is an important determinant of athletes' cardiovascular adaptation. Black adolescent and adult athletes exhibit a left ventricular (LV) hypertrophy with a concentric remodelling higher than their Caucasian counterparts. Scant data, however, are available on race-related differences in hemodynamic response of adolescent athletes to exercise and its relation with heart remodelling. We evaluated if race-specific, sport-related structural and electrical remodelling in adolescent athletes of Caucasian and African ethnicity exclusively depends on race itself rather than on different cardiovascular responses to physical exercise. METHODS: We examined 90 adolescent athletes, 60 Caucasian (WA) and 30 Black (BA). All participants underwent thorough clinical, echocardiographic and stress test evaluations. RESULTS: BA had greater indexed LV mass (LVM/BSA) with increased relative wall thickness (RWT) implying a concentric remodelling. BA showed higher systolic blood pressure (SBP) compared to WA during the whole exercise test. ECG data showed that BA vs WA had a significant shorter QRS duration in each step considered with a significant greater QT dispersion. BA reached a higher relative pressure peak as compared to WA. RWT was strongly influenced by ethnicity and less by SBP at peak of exercise (PE), although LVM/BSA was significantly related to SBP at PE and just marginally to age and not significantly to race. CONCLUSIONS: Black adolescent athletes showed higher SBP during all steps of exercise associated to a different trend. Ethnicity was the main determinant of RWT, suggesting that LV geometry is principally race-related rather than influenced by a different hemodynamic profile to physical activity.

Sighting acute myocardial infarction through platelet gene expression.

Acute myocardial infarction is primarily due to coronary atherosclerotic plaque rupture and subsequent thrombus formation. Platelets play a key role in the genesis and progression of both atherosclerosis and thrombosis. Since platelets are anuclear cells that inherit their mRNA from megakaryocyte precursors and maintain it unchanged during their life span, gene expression profiling at the time of an acute myocardial infarction provides information concerning the platelet gene expression preceding the coronary event. In ST-segment elevation myocardial infarction (STEMI), a gene-by-gene analysis of the platelet gene expression identified five differentially expressed genes: FKBP5, S100P, SAMSN1, CLEC4E and S100A12. The logistic regression model used to combine the gene expression in a STEMI vs healthy donors score showed an AUC of 0.95. The same five differentially expressed genes were externally validated using platelet gene expression data from patients with coronary atherosclerosis but without thrombosis. Platelet gene expression profile highlights five genes able to identify STEMI patients and to discriminate them in the background of atherosclerosis. Consequently, early signals of an imminent acute myocardial infarction are likely to be found by platelet gene expression profiling before the infarction occurs.

Vasodilator Stress Single-Photon Emission Computed Tomography or Contrast Stress Echocardiography Association with Hard Cardiac Events in Suspected Coronary Artery Disease.

BACKGROUND: We compared the long-term outcome of subjects without prior cardiac disease who underwent either vasodilator single-photon emission computed tomography (SPECT) or contrast stress-echocardiography (cSE) for suspected coronary artery disease (CAD). METHODS: Subjects who underwent vasodilator SPECT or cSE between 2008 and 2012 for suspected CAD but no history of cardiac disease were included. We retrospectively compared the association of each method with combined all-cause death and nonfatal myocardial infarction and their positive predictive value (PPV) for angiographically obstructive CAD. RESULTS: A total of 1,387 subjects were selected: 497 who underwent SPECT and 890 who underwent cSE. During 4 years of mean follow-up there were 78 hard events in the cSE group and 51 in the SPECT group. Event-free survival in subjects testing positive for ischemia, either with SPECT or cSE, was significantly worse both in the overall population and after propensity matching patients. In multivariable analyses, vasodilator SPECT or cSE demonstrated significant stratification capability with an ischemic test doubling (SPECT) or more than doubling (cSE) the risk of future hard events independently from other variables. PPV of vasodilator SPECT for the diagnosis of obstructive CAD was inferior to vasodilator cSE (PPV = 63% vs 89%, respectively; P < .001). CONCLUSIONS: Our study suggests that the associations of vasodilator SPECT or cSE with outcome are comparable, with cSE demonstrating better diagnostic PPV for CAD. The absence of ionizing radiation and anticipated lower costs from higher PPV suggest that vasodilator cSE is a valid alternative to vasodilator SPECT as a gatekeeper in subjects without a prior history of CAD.

Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial.

BACKGROUND: Although clopidogrel is still frequently used in patients with acute coronary syndromes (ACS), its efficacy is hampered by interpatient response variability caused by genetic polymorphisms associated with clopidogrel's metabolism. OBJECTIVES: The goal of this study was to evaluate whether selecting antiplatelet therapy (clopidogrel, prasugrel, or ticagrelor) on the basis of a patient's genetic and clinical characteristics leads to better clinical outcomes compared with the standard of care, which bases the selection on clinical characteristics alone. METHODS: Patients hospitalized for ACS were randomly assigned to standard of care or the pharmacogenomic arm, which included the genotyping of ABCB1, CYP2C19*2, and CYP2C19*17 using an ST Q3 system that provides data within 70 min at each patient's bedside. The patients were followed up for 12 ± 1 month for the primary composite endpoint of cardiovascular death and the first occurrence of nonfatal myocardial infarction, nonfatal stroke, and major bleeding defined according to Bleeding Academic Research Consortium type 3 to 5 criteria. RESULTS: After enrolling 888 patients, the study was prematurely stopped. Clopidogrel was used more frequently in the standard-of-care arm (50.7% vs. 43.3%), ticagrelor in the pharmacogenomic arm (42.6% vs. 32.7%; p = 0.02), and prasugrel was equally used in both arms. The primary endpoint occurred in 71 patients (15.9%) in the pharmacogenomic arm and in 114 (25.9%) in the standard-of-care arm (hazard ratio: 0.58; 95% confidence interval: 0.43 to 0.78; p < 0.001). CONCLUSIONS: A personalized approach to selecting antiplatelet therapy for patients with ACS may reduce ischemic and bleeding events. (Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes [PHARMCLO]; NCT03347435).

Sex-related differences in left ventricular structure in early adolescent non-professional athletes.

BACKGROUND: Professional athletes exhibit lower left ventricular wall thicknesses, diameters and mass (in females), with less frequent training-related electrocardiogram (ECG) changes, as compared with controls. METHODS: We studied the association of sex with left ventricular structure in trained early adolescents. Two hundred and six adolescent Caucasian athletes (mean age 13.8 ± 1.6, range 11.8-16.9 years, 158 males and 48 females), with similar degree of training underwent ECG and echocardiographic measurements of left ventricular diameters, thicknesses and mass, with relative wall thickness as the remodelling index. RESULTS: As compared with females, males exhibited greater maximal wall thickness (males = 8.7 ± 1.2 vs. females = 7.9 ± 0.8) and indexed left ventricular mass (100 ± 18 g/m(2) vs. 79 ± 12, p < 0.001), without differences in relative wall thickness (males = 0.35 ± 0.04 vs. females = 0.34 ± 0.04) and with higher prevalence of ECG-based left ventricular hypertrophy, sinus bradycardia and ST-elevation. An analysis of covariance, using age, body surface area, systolic blood pressure, heart rate and sex as the covariates, reported that sex is a strong predictor of left ventricular mass, maximal wall thickness, left ventricular diastolic diameter and ECG-based left ventricular hypertrophy. In a binary logistic regression model analysis sex, like left ventricular mass, predicted ST-trait elevation. CONCLUSIONS: Our results suggest that, in early adolescence, female athletes have lower left ventricular mass and thicknesses compared with males, without geometrical differences. Therefore, sex, independent of age, is a strong determinant of structural parameters also in early adolescent athletes. These data indicate that sex-specific parameters are needed in the pre-participation cardiovascular screening of adolescent athletes.

Rapid and portable, lab-on-chip, point-of-care genotyping for evaluating clopidogrel metabolism.

BACKGROUND: Dual antiplatelet therapy with aspirin and a platelet P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) is a cornerstone of antithrombotic treatment in patients with acute coronary syndromes (ACS). Clopidogrel has been the standard of care for nearly a decade; however, its clinical efficacy is influenced by a considerable inter-patient variability in response, clearly associated to cytochrome P (CYP) enzyme genetic variations. We used a novel point-of-care lab-on-chip instrument to genotype ACS patients in order to identify carriers of the ATB-binding cassette ABCB1 3435, CYP2C19*2 and CYPC2C19*17 alleles and adjust the pharmacological approach accordingly. METHODS AND RESULTS: Between October 2012 and January 2013, 160 ACS patients were enrolled at the Cardiology Unit of the Ospedale Niguarda Cà Granda and genotyped at the patients' point-of-care using the newly developed Q3 portable real-time PCR instrument, which remarkably scored the CYP2C19*2, CYP2C19*17, and ABCB1 3435 alleles in a time of 70 min from DNA extraction to final genotype calls; concordance with the other gold-standard genotyping techniques was 100%. CONCLUSIONS: The Q3 instrument proved to be as reliable as the current conventional techniques. As genotyping in the ACS setting cannot be delegated to centralised clinical laboratories for reasons of time, genotyping at the patients' bedside provides an opportunity to conduct large-scale randomised trials in order to assess whether adding genotype data to clinical variables improves clinical outcomes.