Arrhythmogenic right ventricular cardiomyopathy (ARVC) mimics: the knot unravelled by cardiovascular MRI.

AIM: To assess the role of cardiovascular magnetic resonance imaging (CMRI) in patients referred for suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), its ability to identify ARVC mimics, and subsequent clinical impact. MATERIALS AND METHODS: The CMRI registry of the year 2014 was analysed to identify all consecutive patients referred for suspected ARVC. A comprehensive CMRI protocol that included anatomy, bi-ventricular function modules, and late gadolinium enhancement (LGE) was performed in all patients. RESULTS: Out of 2,481 CMRI performed, 124 patients (5%) were referred for suspected ARVC. A pathological substrate was identified at CMRI in 36 patients (29%): five patients (4%) had ischaemic heart disease (IHD) and 10 (8%) non-IHD; five patients (4%) met CMRI criteria for ARVC and 16 (13%) were ARVC mimics. right ventricular end-diastolic volume (RVEDV) and right ventricular stroke volume (RVSV) were significantly higher in patients with ARVC mimics (RVEDV p=0.007, RVSV p=0.012) and ARVC (RVEDV p=0.013, RVSV p=0.013), as compared to those with structurally normal hearts. CMRI was superior to echocardiography in the identification of ARVC mimics (13% versus 1%, p=0.01). CONCLUSIONS: CMRI was able to identify 16 (13%) ARVC mimics, from congenital abnormalities to acquired heart disease. CMRI was superior in identifying ARVC mimics compared to echocardiography, and overall provided a change in diagnosis in 22% of patients.

Vitamin D status and non-alcoholic fatty liver disease in patients with type 1 diabetes.

PURPOSE: In patients with type 1 diabetes (T1D), the prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 10 to 53% and contrasting evidence suggests that vitamin D deficiency may favor liver fat accumulation. Here, we investigated the association between vitamin D status and NAFLD in adults with T1D. METHODS: 220 consecutive adult T1D patients on multiple daily injections or continuous subcutaneous insulin infusion and not taking calcium or vitamin D supplements were included. Patient characteristics, 25(OH)D serum levels, and metabolic parameters were analyzed. Vitamin D status was defined as sufficiency ( ≥ 75 nmol/L; 30 ng/ml), insufficiency (50-75 nmol/L; 20-30 ng/ml), or deficiency ( < 50 nmol/L; 20 ng/ml). NAFLD was diagnosed at ultrasound examination and graded 0-3. RESULTS: NAFLD was present in 57 patients (29.5%): 51 grade 1, 5 grade 2, and 1 grade 3. Median 25(OH)D levels were 53 nmol/L (IQR 38-70) in patients with NAFLD and 50 nmol/L (34-69) in patients without (p = 0.46). At multivariable analysis, NAFLD was not associated with 25(OH)D levels (p = 0.42) or vitamin D deficiency (p = 0.55), while BMI (OR 1.16, 95% CI 1.07-1.27) and serum triglycerides (OR 1.02, 95% CI 1.01-1.03) were independently associated with NAFLD. CONCLUSIONS: Vitamin D status appears to have no link with low-grade NAFLD in patients with type 1 diabetes.

Strain imaging using cardiac magnetic resonance.

The objective assessments of left ventricular (LV) and right ventricular (RV) ejection fractions (EFs) are the main important tasks of routine cardiovascular magnetic resonance (CMR). Over the years, CMR has emerged as the reference standard for the evaluation of biventricular morphology and function. However, changes in EF may occur in the late stages of the majority of cardiac diseases, and being a measure of global function, it has limited sensitivity for identifying regional myocardial impairment. On the other hand, current wall motion evaluation is done on a subjective basis and subjective, qualitative analysis has a substantial error rate. In an attempt to better quantify global and regional LV function; several techniques, to assess myocardial deformation, have been developed, over the past years. The aim of this review is to provide a comprehensive compendium of all the CMR techniques to assess myocardial deformation parameters as well as the application in different clinical scenarios.

Myocarditis and inflammatory bowel diseases: A single-center experience and a systematic literature review.

BACKGROUND: Myocarditis and inflammatory bowel diseases (IBD) are rare conditions, but may coexist. Myocarditis in IBD may be infective, immune-mediated, or due to mesalamine toxicity. A gap of knowledge exists on the clinical features of patients that present myocarditis in association with IBD, especially for endomyocardial biopsy-proven cases. Our aims are: 1) to describe the clinical characteristics of patients with an associated diagnosis of myocarditis and IBD in a single-center hospital, 2) to perform a systematic review of the literature of analogous cases. METHODS: We retrospectively analyzed data of patients followed up at the outpatient Cardio-immunology and Gastroenterology Clinic of Padua University Hospital, to identify those with an associated diagnosis of myocarditis and IBD. In addition, a systematic review of the literature was conducted. We performed a qualitative analysis of the overall study population. RESULTS: The study included 104 patients (21 from our single center cohort, 83 from the literature review). Myocarditis in IBD more frequently affects young (median age 31 years) males (72%), predominantly with infarct-like presentation (58%), within an acute phase of the IBD (67%) and with an overall benign clinical course (87%). Nevertheless, a not negligible quote of patients may present giant cell myocarditis, deserve immunosuppression and have a chronic, or even fatal course. Histological evidence of mesalamine hypersensitivity is scarce and its incidence may be overestimated. CONCLUSIONS: Our study shows that myocarditis in association with IBD, if correctly managed, may have a spontaneous benign course, but predictors of worse prognosis must be promptly recognized.

Are all left bundle branch blocks the same? Myocardial mechanical implications by cardiovascular magnetic resonance.

AIMS: Left bundle branch block (LBBB) is usually associated with structural myocardial diseases progressively leading to left ventricular (LV) dysfunction. We sought to determine the mechanical implications of LBBB (as defined based on Strauss' criteria) by Cardiovascular Magnetic Resonance (CMR). METHOD AND RESULTS: We included consecutive patients referred to CMR to assess the structural cause of LBBB. CMR scans consisted of cine, stress perfusion, and late gadolinium enhancement (LGE) sequences. Myocardial deformation was assessed by tissue tracking analysis; LGE was quantified using the full width at half maximum method. We included 86 patients [63% male, 70 years (60-72)] with mean QRS duration 150 ± 13 msec. A structural disease was identified on CMR in 53% of patients (ischemic heart disease, IHD, 31%; non-ischemic heart disease, NIHD, 22%), while LBBB-related septal dyssynchrony (SD) was the only abnormality in 47%. LGE was found in 42% of patients. LVEF and myocardial deformation were impaired. Despite similar ECG characteristics, myocardial strain differed significantly between IHD, NIHD and SD patients, and patients with SD showed less impaired myocardial deformation. Indexed LV end-systolic volume and LGE extent were independently associated with impaired strain. CONCLUSIONS: Patients with LBBB show different structural and mechanical properties, and LGE extent has an unfavourable effect on myocardial mechanics.

In Type 1 diabetic patients with good glycaemic control, blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine.

AIMS: The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross-over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end-point was glucose variability. METHODS: Thirty-nine patients [38.1 +/- 9.3 years old (mean +/- sd), diabetes duration 16.6 +/- 8.2 years, glycated haemoglobin (HbA(1c)) 7.6 +/- 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end-points we analysed blood glucose profile, HbA(1c), number of episodes of hypo- and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. RESULTS: During CSII, glucose variability was 5-12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA(1c) was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. CONCLUSIONS: During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.

Role of cardiovascular magnetic resonance in acute and chronic ischemic heart disease.

Cardiovascular magnetic resonance (CMR) is a multi-parametric, multi-planar, non-invasive imaging technique, which allows accurate determination of biventricular function and precise myocardial tissue characterization in a one-stop-shop technique, free from the use of ionizing radiations. Though CMR has been increasingly applied over the last two decades in every-day clinical practice, its widest application has been in the assessment of ischemic cardiomyopathy.

Multiple symmetric lipomatosis: a defect in adrenergic-stimulated lipolysis.

The cellularity of normal and lipomatous adipose tissue and its response to different lipolytic agents have been studied in a group of 10 patients with multiple symmetric lipomatosis (MSL). In MSL patients, fat cells from lipomatous tissue are smaller than normal, uninvolved adipocytes. Fat cells from lipomata show minimal variations in size following conspicuous increase of lipomatous masses. These findings suggest that the growth of lipomata can be attributed to the neoformation of adipocytes rather than to an enlargement in the single fat cells. The incidence of reduced glucose tolerance and of hyperlipoproteinemia is similar in MSL patients and in controls. A significant reduction in plasma free fatty acids was observed in MSL patients after a 24-h fast as well as after noradrenaline infusion. A specific insensitivity of lipomatous tissue to the lipolytic effect of noradrenaline and isoprenaline was observed in vitro, as indicated by glycerol release in the medium, whereas response to theophylline and to dibutyryl cyclic AMP was retained. The lipolytic response to catecholamines was retained. The lipolytic response to catecholamines was normal in the nonlipomatous adipose tissue of MSL patients. In basal conditions ATP concentrations were similar in normal and in lipomatous adipose tissue. However, incubation with noradrenaline induced a significant fall in intracellular ATP levels in normal tissue, whereas no variations were observed in lipomatous tissue. Theophylline, instead, induced a prompt and significant decrease in intracellular ATP levels in lipomatous tissue. These observations indicate that the block in catecholamine-stimulated lipolysis in lipomatous tissue of MSL patients can be localized at a level preceding the formation of cyclic AMP.

Diagnostic yield of cardiovascular magnetic resonance in young-middle aged patients with high-grade atrio-ventricular block.

BACKGROUND: Atrio-ventricular block (AVB) is a rare finding in young or middle-aged adults, often leading to pacemaker implantation (PM) without further investigation. We sought to assess the diagnostic role of cardiovascular magnetic resonance (CMR) in young and middle-aged adults with high-grade AVB. METHODS: We consecutively enrolled young-middle aged (18-65years) patients with high grade AVB referred to CMR after standard clinical assessment (history, electrocardiogram and cardiac rhythm monitoring) prior to PM implantation. Cine and post-contrast imaging were performed in a 1.5T scanner. RESULTS: 34 patients (59% male, mean age 42±12years) with high grade AVB were referred to CMR for suspected ischemic heart disease (IHD)(n=4) and non-ischemic heart disease (NIHD)(n=20); no clear cause was found in 9 patients prior to CMR and 1 patient had suspected lung disease. A pathologic substrate was found on CMR in 15 patients (44%), while a structurally normal heart was reported in 18 (53%). Non-specific findings were reported in 1 patient (3%). There was a fair agreement between CMR and echocardiographic findings (Cohen's kappa 0.243), and CMR provided an entirely new diagnosis in 34% of patients. As compared to the standard clinical assessment, CMR had an additional role in 65% of patients and guided further testing (genetic testing, extra-cardiac imaging) in 9%. CONCLUSIONS: CMR found a pathologic substrate in 44% of patients, mainly NIHD (32%). Half of the patients (53%) had a structurally normal heart. When added to the standard clinical assessment, CMR had an incremental diagnostic role in two thirds of patients.

Out of hospital cardiac arrest survivors with inconclusive coronary angiogram: Impact of cardiovascular magnetic resonance on clinical management and decision-making.

BACKGROUND: Non-traumatic out of hospital cardiac arrest (OHCA) is the leading cause of death worldwide, mainly due to acute coronary syndromes. Urgent coronary angiography with view to revascularisation is recommended in patients with suspected acute coronary syndrome. Diagnosis and management of patients with inconclusive coronary angiogram (unobstructed coronaries or unidentified culprit lesion) is challenging. We sought to assess the role of Cardiovascular Magnetic Resonance (CMR) in the diagnosis and management of OHCA survivors with an inconclusive coronary angiogram. METHODS AND RESULTS: This is a retrospective multicentre CMR registry analysis of OHCA survivors with an inconclusive angiogram. Clinical, ECG and multi-modality imaging data were analysed. Clinical impact of CMR was defined as a change in diagnosis or management. Out of 174 OHCA survivors referred for CMR, 110 patients (63%, 84 male, median age 58) had an inconclusive angiogram. CMR identified a pathologic substrate in 76/110 patients (69%): ischemic heart disease was found in 45 (41%) and non-ischemic heart disease in 31 (28%). A structurally normal heart was found in 25 patients (23%) and non-specific findings in 9 (8%). As compared to trans-thoracic echocardiogram, CMR proved to be superior in identifying a pathologic substrate (69% vs 54%, p=0.018). The CMR study carried a clinical impact in 70% of patients, determining a change in diagnosis in 25%, in management in 29% and a change in both in 16%. CONCLUSIONS: CMR showed a promising role in the diagnostic work-up of OHCA survivors with inconclusive angiogram and its wider use should be considered.

Educating diabetic patients about insulin use: changes over time in certainty and correctness of knowledge.

AIM: Diabetic patients should understand their disease correctly and be sure of what they know, but certainty is rarely considered by educators. Furthermore little is known about how certainty changes with time after an educational intervention. To clarify this, in 38 patients with type 1 diabetes (0.3-36 years duration) we analysed the effect of a course on insulin use by administering a questionnaire before the course, after the course and 1 and 3 years later. METHODS: Answers, accompanied by a subjective estimate of the degree of certainty, were assigned to mastered knowledge (certainty>or=90%, correctness>or=90%), hazardous knowledge (certainty>or=90%, correctnessor=90%) and residual knowledge (total-[mastered+hazardous+uncertain]). Answers were then counted and changes in distribution among areas were analysed by the chi2 test. We also followed the fate of wrong answers. RESULTS: The course increased mastered knowledge, while other types of knowledge decreased. With time mastered knowledge decreased, patients losing both correctness and certainty. The loss affected declarative knowledge, based purely on theory, more than procedural knowledge, which concerns the way things are done. Wrong answers, mostly given with high degree of certainty, were heterogeneous since some became correct after the course, some remained wrong, some became wrong after the course, some became mistaken after having been corrected earlier. CONCLUSIONS: The analysis of certainty helps in evaluating patient's knowledge; programmes tending to improve procedural knowledge are more likely to have long lasting effects; wrong answers need to be considered on a individual basis.

Precursor-product relationship between rabbit type II cell lamellar bodies and alveolar surface-active material. Surfactant turnover time.

To estimate the turnover time of alveolar surfactant in New Zealand white rabbits, we injected [9,10-(3)H] palmitic acid and [2-(14)C] glycerol intravenously. From 1-48 h after injection, wer killed the animals, lavaged the lungs for alveolar surfactant with saline, and isolated the lamellar bodies by homogenization and sucrose density gradient centrifugation. Lamellar bodies and alveola surfactant had comparable phospholipid composition and surface activity. Lamellar bodies contained little DNA, no mitochondrial enzyme activity and less than 5% contaminating phospholipids from microsomal and Golgi-enriched fractions. We measured radioactivity of phosphatidylcholine, saturated phosphatidylcholine and phosphatidylglycerol for each isotope in lamellar bodies and surfactant at each time point. The plot of the integral with respect to time of the difference between lamellar body and surfactant specific activity against surfactant specific activity has a slope determined by the turnover time, and a shape which tests the precision of the precursor-product relationship. This analysis does not assume a pulse label and allows for possible recycling of tracer from surfactant to lamellar bodies. We obtained turnover times of 4-11 h. We detected an imprecise precursor-product relationship between lamellar bodies and alveolar surfactant, which is not due to experimental variability or to contamination of lamellar bodies by other subcellular fractions but may reflect imperfect mixing within surfactant compartments.

Postnatal transformations of alveolar surfactant in the rabbit: changes in pool size, pool morphology and isoforms of the 32-38 kDa apolipoprotein.

To clarify perinatal transformations of surfactant we performed lung lavage in term fetuses and in 0-24-h-old newborn rabbits. Lavage fluid was separated into three pools, namely lavage pellet, lavage supernatant and cells. We found that at birth the pellet contains 94.1 +/- 1.4% (S.E.) saturated phosphatidylcholine, while the supernatant and cells contain traces of it. At birth the pellet contains secreted lamellar bodies while the supernatant lacks any recognizable structure. After birth, the alveolar saturated phosphatidylcholine level increases 5.1-times in 24 h, the proportions between pools reaching adult values in 90 min (pellet = 75.9 + 4.8%, supernatant = 22.7 +/- 4.9%), and small vesicles appear in the supernatant, probably originating from the turnover of alveolar surfactant during breathing. The saturated phosphatidylcholine associated with cells remains unchanged. At birth, the 32-38 kDa surfactant apolipoprotein appears to be less extensively sialylated than in adult life.

The life cycle of a low-molecular-weight protein of surfactant (SP-C) in 3-day-old rabbits.

To clarify the metabolic cycle of a low-molecular-weight protein of surfactant (SP-C), we obtained alveolar surfactant from 3 day old rabbits killed 24 h after the tracheal administration of 32P or L-[35S]methionine (donors). Aliquots of this naturally labelled surfactant were administered into trachea to 3-day-old rabbits (recipients) which were killed after 1 min or 3, 8 or 24 h. We then analyzed the radioactivity associated with SP-C and with saturated phosphatidylcholine in fractions of lung lavage fluid and in lung homogenate. We found that alveolar SP-C is turned over faster than saturated phosphatidylcholine, that alveolar macrophages do participate in the removal of SP-C and that SP-C does not enter the fraction of alveolar surfactant that remains unsedimented after ultracentrifugation. Considering the whole lung, SP-C and saturated phosphatidylcholine are turned over at a comparable speed.

Subfractionation of lung surfactant. Implications for metabolism and surface activity.

Because previous studies have suggested that lung surfactant is not a simple compartment of homogeneous material, we subfractionated lamellar bodies and components of alveolar lavage from male New Zealand white rabbits, according to differences in sedimentability. We recovered two lamellar body populations at different densities in discontinuous sucrose density gradients; we separated six subfractions of alveolar lavage by differential centrifugation. To determine whether or not precursor-product relationships existed among the subfractions, we injected radioactive palmitate intravenously, killed the rabbits 1-72 h later, and measured phospholipid specific activities. The two populations of lamellar bodies had similar phospholipid composition, fatty acyl composition of phosphatidylcholine and phosphatidylglycerol, and surface activity. Light lamellar bodies had a higher ratio of phospholipid to protein, and labelled with tracer later in time than dense ones. For alveolar lavage subfractions, later labelling with tracer, lower adsorption rate and lower total protein and phosphatidylglycerol content seemed to correlate with decreasing average density and particle size as well as with the disappearance of tubular myelin structure and appearance of predominantly vesicular structure. The subfractions appear to be in a metabolic sequence in which heavier, more dense material is a precursor to lighter, less dense material. The results suggest that subfractions of surfactant are extensively recycled.

Altered surfactant synthesis and function in rats with diet-induced hyperlipidemia.

Altered lung function in hyperlipidemic patients has been reported by many authors. An alteration of surfactant synthesis has been suggested. Isolated lungs of rats rendered hyperlipidemic by suitable diets display an increased distensibility at maximal inflation and a higher degree of alveolar stability during deflation. These alterations are related to modifications of surfactant properties. Lung lavage fluid obtained from hyperlipidemic rats displays an increase in percent content of phosphatidylglycerol and a decrease of phosphatidylethanolamine. The percent content of phosphatidylglycerol correlates with the circulating levels if free fatty acids (FFA). It is suggested that FFA might affect the activity of enzymes operating in lung phospholipid synthesis. The reported increase of surfactant phosphatidylglycerol might explain the increment of alveolar stability observed in hyperlipidemic rats.

Turnover of phospholipids isolated from fractions of lung lavage fluid.

To clarify the steps following surfactant secretion, we injected adult rabbits with radioactive palmitate, lavaged the airways, removed the cells, separated by ultracentrifugation lavage components into two fractions (B and C), and followed the labeling of phospholipids of these fractions. The results were compatible with the view that total and saturated phosphatidylcholine are transferred from B to C. Furthermore, the fluxes of total and saturated phosphatidylcholine through fraction C (0.45 and 0.30 mumol . h-1 . g lung-1, respectively) were compatible with the actual estimates of surfactant recycling. The labeling of phosphatidylglycerol ruled out a simple precursor-product relationship between B and C but was compatible with a nonideal first-order relationship. The labeling of phosphatidylinositol, cardiolipin, and phosphatidylethanolamine was incompatible with the existence of a direct precursor-product relationship between B and C. The labeling of total and saturated phosphatidylcholine suggests that fraction B may be made by active surfactant, whereas fraction C may contain surfactant modified for reuptake or for reuptake and catabolism.

Short-term and long-term clinical evaluation of a non-amphetaminic anorexiant (mazindol) in the treatment of obesity.

The effectiveness and tolerance of a non-amphetaminic anorexiant drug has been evaluated in a short-term and in a long-term clinical trial in simple obesity and in refractory obesity. In the short-term 'crossover' trial, a more evident effectiveness and tolerance result when the anorexiant is given in a late phase of treatment. The association of an anorexiant drug with the hypocaloric diet was seen to be effective in the treatment of so-called refractory obesity. In the evaluation of the long-term treatment it is seen that weight loss is greater and remains so farr longer periods in patients receiving anorexiant, as compared to controls. This is related to a better maintenance of a restricted calorie regimen. Mazindol did not affect the improvement of glucose tolerance and insulin secretion which follows the weight reduction.