Negative bone scintigraphy in wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Amyloidosis is a rare systemic disease due to the extracellular tissue deposition of a fibrillar-shaped misfolded protein, called amyloid. Only two types of proteins commonly affect the heart leading to an infiltrative cardiomyopathy: immunoglobulin light chain and transthyretin (TTR) cardiac amyloidosis (CA). Despite the promising role of emerging imaging modalities, such as strain echocardiography, cardiac magnetic resonance and bone scintigraphy, its diagnosis is still often missed or delayed due to their inherent limitations and to a nonspecific clinical scenario with frequent concomitance of cardiac comorbidities. The gold standard for a definite diagnosis still remains endomyocardial biopsy, but in rare cases Congo Red staining could provide false negative results, as in our case, requiring immunoelectron microscopy. CASE PRESENTATION: A middle-aged male adult presented to the emergency department for relapse of heart failure. Echocardiography and cardiac magnetic resonance, along with the history of bilateral carpal tunnel syndrome, were suspicious for TTR-CA. The diagnosis, however, was hampered by concomitant cardiac comorbidities and conflicting results of imaging modalities. In fact bone scintigraphy was negative, as well as Congo Red Staining on myocardial tissue samples obtained by endomyocardial biopsy. Given the high clinical suspicion, immunoelectron microscopy was performed, showing TTR amyloid fibrils deposits, that confirmed the diagnosis. A genetic analysis excluded and hereditary form. The patient was then referred to a specialist center for specific treatment. CONCLUSIONS: This is a rare case of a TTR-CA with a negative Bone Scintigraphy and Congo red staining, which demonstrated that CA is frequently misdiagnosed because of the low specific clinical manifestations and the results of imaging modalities that sometimes could be misleading, with subsequent delayed diagnosis and correct treatment.

Coronary flow reserve is related to the extension and transmurality of myocardial necrosis and predicts functional recovery after acute myocardial infarction.

BACKGROUND: Few studies have examined the effect of transmurality of myocardial necrosis on coronary microcirculation. The aim of this study was to examine the influence of cardiac magnetic resonance-derived (GE-MRI) structural determinants of coronary flow reserve (CFR) after anterior myocardial infarction (STEMI), and their predictive value on regional functional recovery. METHODS: Noninvasive CFR and GE-MRI were studied in 37 anterior STEMI patients after primary coronary angioplasty. The wall motion score index in the left descending anterior coronary artery territory (A-WMSI) was calculated at admission and follow-up (FU). Recovery of regional left ventricular (LV) function was defined as the difference in A-WMSI at admission and FU. The necrosis score index (NSI) and transmurality score index (TSI) by GE-MRI were calculated in the risk area. Baseline (BMR) and hyperemic (HMR) microvascular resistance, arteriolar resistance index (ARI), and coronary resistance reserve (CRR) were calculated at the Doppler echocardiography. RESULTS: Bivariate analysis indicated that the CPK and troponin I peak, heart rate, NSI, TSI, BMR, the ARI, and CRR were related to CFR. Multivariable analysis revealed that TSI was the only independent determinant of CFR. The CFR value of >2.27, identified as optimal by ROC analysis, was 77% specific and 73% sensitive with accuracy of 76% in identifying patients with functional recovery. CONCLUSIONS: Preservation of microvascular function after AMI is related to the extent of transmurality of myocardial necrosis, is an important factor influencing regional LV recovery, and can be monitored by noninvasive CFR.

Transseptal BATMAN for High-Risk Valve-in-Ring Procedures: A Case Series.

Valve-in-ring procedures represent a feasible solution for high-risk patients with surgical repair failure. The risk of left ventricular outflow tract obstruction increases the challenge, and transcatheter approaches to prevent it are technically demanding and often do not resolve it. We demonstrate the feasibility and safety of a transseptal balloon-assisted translocation of the anterior mitral leaflet for valve-in-ring implantation.

Evaluation of tricuspid valve morphology and function by transthoracic three-dimensional echocardiography.

Tricuspid valve (TV) disease commonly occurs in combination with left-sided heart disease. Despite the growing enthusiasm for developing novel minimally invasive therapies for the mitral or aortic valve, the TV disease formerly received less attention and was frequently left untreated. Strong evidence has increased the awareness of the impact of severe TV regurgitation on patient survival, functional capacity, and surgical risk. Preoperative TV accurate description is challenging because, unlike left-sided valves, a complete visualization of tricuspid annulus and all three leaflets in one view is routinely impossible by two-dimensional transthoracic or transesophageal echocardiography. Three-dimensional echocardiography (3DE) with its unrestricted imaging capabilities has sparked significant research interest for a better understanding and improved treatment of valvular heart disease. This review summarizes the current status of 3DE for the assessment of TV morphology and function, with its clinical applications and current limitations, as well as its potential implications for designing TV repair techniques.

Cardiac injury and mortality in patients with Coronavirus disease 2019 (COVID-19): insights from a mediation analysis.

BACKGROUNDS: Patients at greatest risk of severe clinical conditions from coronavirus disease 2019 (COVID-19) and death are elderly and comorbid patients. Increased levels of cardiac troponins identify patients with poor outcome. The present study aimed to describe the clinical characteristics and outcomes of a cohort of Italian inpatients, admitted to a medical COVID-19 Unit, and to investigate the relative role of cardiac injury on in-hospital mortality. METHODS AND RESULTS: We analyzed all consecutive patients with laboratory-confirmed COVID-19 referred to our dedicated medical Unit between February 26th and March 31st 2020. Patients' clinical data including comorbidities, laboratory values, and outcomes were collected. Predictors of in-hospital mortality were investigated. A mediation analysis was performed to identify the potential mediators in the relationship between cardiac injury and mortality. A total of 109 COVID-19 inpatients (female 36%, median age 71 years) were included. During in-hospital stay, 20 patients (18%) died and, compared with survivors, these patients were older, had more comorbidities defined by Charlson comorbidity index ≥ 3(65% vs 24%, p = 0.001), and higher levels of high-sensitivity cardiac troponin I (Hs-cTnI), both at first evaluation and peak levels. A dose-response curve between Hs-cTnI and in-hospital mortality risk up to 200 ng/L was detected. Hs-cTnI, chronic kidney disease, and chronic coronary artery disease mediated most of the risk of in-hospital death, with Hs-cTnI mediating 25% of such effect. Smaller effects were observed for age, lactic dehydrogenase, and D-dimer. CONCLUSIONS: In this cohort of elderly and comorbid COVID-19 patients, elevated Hs-cTnI levels were the most important and independent mediators of in-hospital mortality.

Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin.

BACKGROUND: Hydroxychloroquine and azithromycin combination therapy is often prescribed for coronavirus disease 2019 (COVID-19). Electrocardiographic (ECG) monitoring is warranted because both medications cause corrected QT-interval (QTc) prolongation. Whether QTc duration significantly varies during the day, potentially requiring multiple ECGs, remains to be established. METHODS: We performed 12­lead ECGs and 12­lead 24-h Holter ECG monitoring in all patients aged <80 years admitted to our medical unit for COVID-19, in oral therapy with hydroxychloroquine (200 mg, twice daily) and azithromycin (500 mg, once daily) for at least 3 days. A group of healthy individuals matched for age and sex served as control. RESULTS: Out of 126 patients, 22 (median age 64, 82% men) met the inclusion criteria. ECG after therapy showed longer QTc-interval than before therapy (450 vs 426 ms, p = .02). Four patients had a QTc ≥ 480 ms: they showed higher values of aspartate aminotransferase (52 vs 30 U/L, p = .03) and alanine aminotransferase (108 vs 33 U/L, p < .01) compared with those with QTc < 480 ms. At 24-h Holter ECG monitoring, 1 COVID-19 patient and no control had ≥1 run of non-sustained ventricular tachycardia (p = .4). No patients showed "R on T" premature ventricular beats. Analysis of 24-h QTc dynamics revealed that COVID-19 patients had higher QTc values than controls, with no significant hourly variability. CONCLUSION: Therapy with hydroxychloroquine and azithromycin prolongs QTc interval in patients with COVID-19, particularly in those with high levels of transaminases. Because QTc duration remains stable during the 24 h, multiple daily ECG are not recommendable.

The hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with Covid-19: The Padua province experience.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is responsible for a worldwide pandemic, with a high rate of morbidity and mortality. The increasing evidence of an associated relevant prothrombotic coagulopathy has resulted in an increasing use of antithrombotic doses higher than usual in COVID-19 patients. Information on the benefit/risk ratio of this approach is still lacking. OBJECTIVE: To assess the incidence of relevant bleeding complications in association with the antithrombotic strategy and its relationship with the amount of drug. METHODS: Consecutive COVID-19 patients admitted between February and April 2020 were included in a retrospective analysis. Major bleedings (MB) and clinically relevant non-major bleeding (CRNMB) were obtained from patient medical records and were adjudicated by an independent committee. RESULTS: Of the 324 patients who were recruited, 240 had been treated with prophylactic doses and 84 with higher doses of anticoagulants. The rate of the composite endpoint of MB or CRNMB was 6.9 per 100-person/months in patients who had been given prophylactic doses, and 26.4 per 100-person/months in those who had been prescribed higher doses (hazard ratio, 3.89; 95% confidence interval, 1.90-7.97). The corresponding rates for overall mortality were 12.2 and 20.1 per 100-person/months, respectively. CONCLUSIONS: The rate of relevant bleeding events was high in patients treated with (sub)therapeutic doses of anticoagulants. In the latter group, overall mortality did not differ from that of patients treated with standard prophylactic doses and was even higher. Our result does not support a strategy of giving (sub)therapeutic doses of anticoagulants in non-critically ill patients with COVID-19.

Acute intraoperative echocardiographic changes after transapical off-pump mitral valve repair with NeoChord implantation.

OBJECTIVES: Our aim is to investigate the acute intraoperative effects of the NeoChord repair procedure on mitral valve (MV) annular geometry and LV function and the impact of these changes on MR at 1-year follow-up. BACKGROUND: Recently transapical off-pump mitral valve repair with NeoChord implantation has been demonstrated to be safe and effective in patients with degenerative mitral regurgitation (DMR). METHODS: We retrospectively analyzed baseline and early postoperative 3-dimensional transesophageal echocardiography of 66 patients who underwent NeoChord repair for isolated posterior leaflet MV disease using semiautomatic off-line analysis software. RESULTS: We observed a significant acute reduction of indexed LV end diastolic volume (Δ% = 14, p < .001), LV ejection fraction (Δ = 5.7%, p = .002), indexed left atrial volume (Δ = 14.7%, p = .045), and pulmonary artery pressure (Δ = 2.1%, p = .026). Among MV geometric parameters, we observed a significant reduction of MV antero-posterior diameter (Δ = 7%, p < .001), sphericity index (Δ = 8%, p < .001), annulus circumference (Δ = 0.9%, p = .021), and annulus area (Δ = 2.7%, p = .018). At 1-year, 53 patients (85.5%) presented MR ≤ mild, while 9 patients (14.5%) had MR ≥ moderate. Reduction of AP diameter (OR = 0.14, CI -3.83; 0.08, p < .001), annulus circumference (OR = 0.27, CI -2.98; 0.37, p = .005), MV area (OR = 0.39, CI -2.46; 0.61, p = .04), aorto-mitral angle (OR = 0.38, CI -2.49; 0.54, p = .002) and iEDV (OR = 0.44, CI -2.44; 0.81, p = .001) were independent protective factors against recurrence of MR greater than mild at 1-year follow-up. CONCLUSIONS: Transapical NeoChord repair produces important acute intraoperative changes in MV anatomy in DMR patients. The acute changes observed were associated with procedure durability at 1-year FU.

Thoughts modulate the expression of inflammatory genes and may improve the coronary blood flow in patients after a myocardial infarction.

BACKGROUND: Mental stress is one of the main risk factors for cardiovascular disease. Meditation and music listening are two techniques that are able to counteract it through the activation of specific brain areas, eliciting the so-called Relaxing Response (RR). Epidemiological evidence reveals that the RR practice has a beneficial prognostic impact on patients after myocardial infarction. We aimed to study the possible molecular mechanisms of RR underlying these findings. METHODS: We enrolled 30 consecutive patients after myocardial infarction and 10 healthy controls. 10 patients were taught to meditate, 10 to appreciate music and 10 did not carry out any intervention and served as controls. After training, and after 60 days of RR practice, we studied the individual variations, before and after the relaxation sessions, of the vital signs, the electrocardiographic and echocardiographic parameters along with coronary flow reserve (CFR) and the carotid's intima media thickness (IMT). Neuro-endocrine-immune (NEI) messengers and the expression of inflammatory genes (p53, Nuclear factor Kappa B (NfKB), and toll like receptor 4 (TLR4)) in circulating peripheral blood mononuclear cells were also all observed. RESULTS: The RR results in a reduction of NEI molecules (p < 0.05) and oxidative stress (p < 0.001). The expression of the genes p53, NFkB and TLR4 is reduced after the RR and also at 60 days (p < 0.001). The CFR increases with the relaxation (p < 0.001) and the IMT regressed significantly (p < 0.001) after 6 months of RR practice. CONCLUSIONS: The RR helps to advantageously modulate the expression of inflammatory genes through a cascade of NEI messengers improving, over time, microvascular function and the arteriosclerotic process.

[Cardiologists and mucopolysaccharidoses. Recommendations of GICEM (Cardiology Experts on Metabolic Disease Italian Group) for diagnosis, follow-up and cardiological management]. / Il cardiologo e le mucopolisaccaridosi. Raccomandazioni del GICEM (Gruppo Italiano Cardiologi Esperti Malattie Metaboliche) su diagnosi, follow-up e management cardiologico.

Mucopolysaccharidoses (MPS) represent a group of rare lysosomal storage disorders, with a heterogeneous clinical presentation in terms of inheritance (autosomal and X-linked recessive), age of onset (infants, children, and adults), systemic and cardiac manifestations (mild to severe disease forms). Evidence-based recommendations on the diagnosis and management of cardiovascular disease in MPS are scarce. GICEM (Gruppo Italiano Cardiologi Esperti Malattie Metaboliche) is a group of cardiologists, cardiac surgeons and pediatricians with a specific expertise in metabolic diseases including MPS. In this paper, we report our experience and recommendations on the diagnosis and management of cardiovascular aspects in MPS, with a tailored approach based on current evidence, and taking into account MPS phenotype (particularly, I, II, IVa, VI), age at presentation, and severity of systemic and cardiac manifestations.

Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina.

BACKGROUND: Intramyocardial injection of autologous bone marrow (ABM) may induce angiogenesis. We tested the safety and feasibility of catheter-based direct percutaneous intramyocardial delivery of ABM in patients with refractory angina pectoris. METHODS: Ten patients (9 men, 67 +/- 8 years) with refractory angina (Canadian Cardiovascular Society class III-IV) and documented myocardial ischemia were enrolled. After left ventricular electromechanical mapping, freshly aspirated and filtered ABM was percutaneously injected into target myocardial ischemic areas. Clinical symptoms (as assessed according to the Canadian Cardiovascular Society class), quality of life, and myocardial perfusion were evaluated before the procedure and through the follow-up. RESULTS: In all patients, ABM was successfully injected into the target regions. No periprocedural complications occurred. At 12 months, no major cardiac events (death, acute myocardial infarction, stroke, and malignant ventricular arrhythmias) occurred. Severity of angina improved of > or = 2 classes in 3 patients. Quality of life showed a significant improvement in all patients. Myocardial perfusion in the target regions improved in 4 of 8 patients. CONCLUSIONS: Direct percutaneous intramyocardial delivery of ABM appears feasible and safe. Further evaluation is warranted to test its clinical efficacy.

Influence of transmurality, infarct size, and severe microvascular obstruction on left ventricular remodeling and function after primary coronary angioplasty.

Infarct size has been considered an established marker of left ventricular (LV) remodeling. We assessed the predictive value of myocardial/microvascular injury assessed by delayed enhanced magnetic resonance imaging (MRI) on LV remodeling and LV ejection fraction after primary coronary intervention (PCI) compared with peak troponin levels, an established index of myocardial infarct size. We performed MRI in 76 patients with first acute myocardial infarction 6 +/- 2 days after successful PCI. Necrosis was judged as transmural when delayed enhancement was extended to >or=75% of LV segment thickness. Severe microvascular obstruction was identified as areas of late hypoenhancement surrounded by delayed enhancement. Infarct size was expressed as an index by dividing the total percentage of delayed enhancement involvement by the number of LV segments. LV end-diastolic volume index and function were quantified by 2-dimensional echocardiography at 6 +/- 1 months after acute myocardial infarction. Remodeling was evaluated as a change in LV end-diastolic volume index at follow-up compared with baseline. At univariate analyses, transmural necrosis, severe microvascular obstruction, infarct size, and troponin level were correlated directly with remodeling and inversely with LV function at follow-up (p <0.001). At multiple regression, only transmural necrosis and troponin level remained independent predictors of LV remodeling and function. With respect to troponin, transmural necrosis improved the predictive power of LV remodeling (R2 for change = 0.19) and function (R2 for change = 0.16). In conclusion, in patients with acute myocardial infarction undergoing PCI, the amount of transmural necrosis as assessed by MRI is a major determinant of LV remodeling and function, with significant additional predictive value to infarct size and severe microvascular obstruction.

Transapical off-pump mitral valve repair with Neochord implantation: Early clinical results.

BACKGROUND: This prospective study aims to assess early clinical outcomes in patients undergoing Transapical Off-Pump Mitral Valve Intervention with Neochord Implantation (TOP-MINI). METHODS AND RESULTS: Forty-nine patients with severe symptomatic degenerative mitral regurgitation (MR) were treated. Median age was 72 years (IQR 58-78) and median Euroscore-I was 3.26% (IQR 0.88-8.15). Forty-four patients (89.8%) presented with posterior leaflet prolapse (LP), 4 (8.2%) with anterior LP and 1 (2%) with combined disease. Acute procedure success (defined as successful placement of at least 3 neochords with reduction of residual MR to less than 2+) was achieved in all patients. In-hospital mortality was 2%. At 30 days major adverse events included one AMI (2%) successfully treated percutaneously and one sepsis (2%), no stroke or bleeding events occurred. At 3 months overall survival was 98%. MR was absent in 16 patients (33.4%), was grade 1+ in 15 (31.2%), and was grade 2+ in 12 (25%). Five patients (10.4%) developed recurrent severe MR due to anterior native chordae rupture. Four of them were successfully re-operated. At 3 months follow-up freedom from reoperation was 91.7 ± 4%. CONCLUSIONS: Early results with Neochord procedure indicate that TOP-MINI is feasible and safe. Efficacy is maintained up to 3 months follow-up with significant clinical benefit for the patients.

In-stent restenosis in small coronary arteries: impact of strut thickness.

UNLABELLED: OBJECTIVES; We sought to evaluate whether strut thickness may impact the restenosis rate after stent implantation in small coronary arteries. BACKGROUND: Small vessel size (<3.0 mm) is an independent risk factor for the occurrence of in-stent restenosis. It has been reported that vessel damage induced during stent deployment is an important factor in restenosis. METHODS: From our database, we selected all patients who had successful stenting in small native vessels, with angiographic follow-up available, between March 1996 and April 2001. The strut was defined as thin when <0.10 mm and thick when > or = 0.10 mm. According to these criteria, we identified two subgroups: a thin group and a thick group. RESULTS: A total of 821 (57%) of the 1,447 patients had angiographic follow-up available and were included in the analysis. The thin group included 400 patients with 505 lesions. The thick group included 421 patients with 436 lesions. The restenosis rate was 28.5% in the thin group and 36.6% in the thick group (p = 0.009; odds ratio [OR] 1.44, 95% confidence interval [CI] 1.09 to 1.90). The study group was classified into three subgroups according to the reference vessel diameter: < or = 2.50 mm, 2.51 to 2.75 mm and 2.76 to 2.99 mm. Strut thickness influenced the restenosis rate only in the subgroup with a reference vessel diameter between 2.76 and 2.99 mm, with rates of 23.5% in the thin group and 37% in the thick group (p = 0.006). By logistic regression analysis, predictors of restenosis were stent length (OR 1.03, 95% CI 1.01 to 1.04; p = 0.001), strut thickness (OR 1.68, 95% CI 1.23 to 2.29; p = 0.001) and diabetes mellitus (OR 2.10, 95% CI 1.21 to 3.68; p = 0.007). CONCLUSIONS: This study supports that strut thickness is an independent predictor of restenosis in coronary arteries with a reference diameter of 2.75 to 2.99 mm.

Elective versus provisional intra-aortic balloon pumping in high-risk percutaneous transluminal coronary angioplasty.

BACKGROUND: Elective intra-aortic balloon pump (IABP) support may reduce acute complications occurring during percutaneous coronary interventions (PCI) in patients with severe depression of the left ventricular ejection fraction (EF < or = 30%). METHODS: Since February 1998, 133 consecutive patients with EF < or =30% underwent elective PCI in our institution; 61 had elective preprocedural IABP support (group A) and 72 patients had conventional PCI (group B). Jeopardy score was calculated in each patient from the coronary angiograms to quantify the myocardium at risk. RESULTS: EF was similar in the 2 groups. Jeopardy score was higher in group A (8.0 +/- 2.8 vs 6.7 +/- 2.4, P =.008). The other principal clinical and angiographic characteristics were similar in the 2 groups. Severe hypotension and/or shock occurred in 11 patients, all in group B (P =.001). All required urgent IABP support, and 3 eventually died. Intraprocedural major adverse cardiac and cerebral events (eg, myocardial infarction, severe hypotension and/or shock, urgent bypass surgery, stroke, and death) were higher in group B (17% vs 0%, P =.001). By stepwise logistic regression analysis, elective IABP support (odds ration [OR] 0.11 [95% CI 0.21-0.60], P =.011), jeopardy score (OR 5.37 [95% CI 1.10-8.70], P =.040), and female sex (OR 2.72 [95% CI 1.85-3.10], P =.015), were the correlates of intraprocedural events. CONCLUSIONS: This study supports the potential usefulness of elective versus provisional IABP to prevent intraprocedural major adverse cardiac and cerebral events in high-risk PCI.

Effect of atorvastatin on endothelium-dependent vasodilation in postmenopausal women with average serum cholesterol levels.

After menopause, most healthy women show an impairment of peripheral vasodilation and an increase of plasma cholesterol levels. Statins have been shown to improve endothelial function in hypercholesterolemic men and women. The present study tests whether atorvastatin (10 mg) influences endothelium-dependent vasodilation in postmenopausal normocholesterolemic women. Twenty-eight healthy, postmenopausal women (mean age 51 +/- 2 years) with serum total cholesterol and low-density lipoprotein cholesterol within the desirable range entered a double-blind, single-crossover study. Postmenopausal women were randomized to receive either atorvastatin (10 mg/day) or placebo for 10 days and then crossed to the complementary treatment. Endothelium-dependent and -independent responses were assessed by means of strain-gauge plethysmography before and after intra-arterial infusion of acethylcholine (ACh) and sodium nitroprusside, in comparison to physiologic saline. The nitric oxide pathway was evaluated by repeating the infusion of ACh during admininstration of L-arginine and (G)-monomethyl-L-arginine (L-NMMA). Serum lipoproteins were not significantly modified by the active treatment. The vasodilation induced by ACh was significantly higher in the atorvastatin-treated women compared with the placebo-treated group (24 +/- 3 vs 13 +/- 2 ml/100 ml tissue/min, p <0.01). In contrast, responses to the endothelium-independent vasodilator sodium nitroprusside were not significantly modified by atorvastatin. The ACh-stimulated vasodilation induced by atorvastatin was additionally potentiated by L-arginine (800 +/- 105% vs 370 +/- 60%, p <0.05) and blunted by L-NMMA. No correlation was found between changes in plasma cholesterol and improvement in forearm blood flow. Our data show that the beneficial effect of atorvastatin on endothelium-dependent vasodilation is independent from changes in the lipid profile.

Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy.

Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.

Refining calcium test for the diagnosis of medullary thyroid cancer: cutoffs, procedures, and safety.

CONTEXT: Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice. OBJECTIVE: Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test. PATIENTS AND METHODS: A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied. RESULTS: bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test. CONCLUSIONS: Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.

Use of three-dimensional speckle tracking to assess left ventricular myocardial mechanics: inter-vendor consistency and reproducibility of strain measurements.

AIMS: Since there is insufficient data available about the inter-vendor consistency of three-dimensional (3D) speckle-tracking (STE) measurements, we undertook this study to (i) assess the inter-vendor consistency of 3D LV global strain values obtained using two different scanners; (ii) identify the sources of inter-vendor inconsistencies, if any; and (iii) compare their respective intrinsic variability. METHODS AND RESULTS: Sixty patients (38 ± 12 years, 64% males) with a wide range of LV end-diastolic volumes (from 74 to 205 ml) and ejection fractions (from 17 to 70%) underwent two 3D LV data set acquisitions using VividE9 and Artida ultrasound systems. Global longitudinal (Lε), radial (Rε), circumferential (Cε) and area (Aε) strain values were obtained offline using the corresponding 3D STE softwares. Despite being significantly different, Lε showed the closest values between the two platforms (bias = 1.5%, limits of agreement (LOA) from -2.9 to -5.9%, P < 0.05). Artida produced significantly higher values of both Cε and Aε than VividE9 (bias = 6.6, LOA: -14.1 to 0.9%, and bias = 6.0, LOA = -28.2-8.6%, respectively, P < 0.001). Conversely, Rε values obtained with Artida were significantly lower than those measured using VividE9 platform (bias = -24.2, LOA: 1.5-49.9, P < 0.001). All strain components showed good reproducibility (intra-class correlation coefficients: 0.82-0.98), except for Rε by Artida, which showed only a moderate reproducibility. CONCLUSION: Apart from Lε, the inter-vendor agreement of Rε, Cε and Aε measured with Artida and VividE9 was poor. Reference values should be specific for each system and baseline and follow-up data in longitudinal studies should be obtained using the same 3D STE platform.

Subclinical diastolic dysfunction in type 2 diabetic patients with and without carotid atherosclerosis: relationship with glyco-oxidation, lipid-oxidation and antioxidant status.

OBJECTIVES: The aim of this study was to evaluate subclinical diastolic dysfunction in type 2 diabetic patients and its relationship with glyco-oxidation, lipo-oxidation and antioxidant capacity in the presence or absence of carotid plaques. BACKGROUND: Subclinical diastolic dysfunction is the early stage of diabetic cardiomyopathy, the pathogenic mechanisms of which are still little known. In particular, few data are available on the role of glyco-oxidation, lipo-oxidation and antioxidant status, factors known to be involved in the atherosclerotic process. METHODS: We assessed myocardial systolic and diastolic functions in 57 consecutive asymptomatic type 2 diabetic patients (24 patients with no carotid plaques; 33 with plaques) and 27 healthy volunteers using transthoracic echocardiography. Glyco-oxidation and lipo-oxidation parameters and antioxidant status were also evaluated in fasting venous blood samples. RESULTS: Systolic function was similar between diabetic patients and controls, while most of the diastolic parameters (A, e', E/A, E/e') differed significantly between diabetics and controls, being worse in the former. Among the diastolic parameters, only the peak late diastolic velocity A differed significantly between the two groups of diabetic patients with no carotid plaques and with plaques (0.72 ± 0.16 m/s vs 0.84 ± 0.25 m/s, p<0.05). The diastolic parameters A and E/e' related to glycemic control, glyco-oxidation and antioxidant capacity, and to LDL size and density. CONCLUSIONS: Glyco-oxidation and antioxidant status, combined with the presence of small, dense LDL correlate with subclinical diastolic dysfunction in type 2 diabetic patients. Atherosclerotic lesions are associated with an altered atrial function.