Phenotyping congestion in patients with acutely decompensated heart failure with preserved and reduced ejection fraction: The Decongestion duRing therapY for acute decOmpensated heart failure in HFpEF vs HFrEF- DRY-OFF study.

AIMS: To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. METHODS AND RESULTS: Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9 ±â€¯0.4 vs 0.7 ±â€¯0.4; p<0.01; IVC end-expiratory diameter: 21.6 ±â€¯5.1 mm vs 20±5.5 mm, p<0.01; IVC collapsibility index 24.4 ±â€¯17.4% vs 30.9 ±â€¯21.1% p<0.01) and higher Nt-proBNP values (8010 vs 3900 ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4 ±â€¯4 vs 0.3 ±â€¯0.4; p = 0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, p = 0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. CONCLUSIONS: Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.

Bowel perforation due to methotrexate therapeutic error: an insidious adverse reaction.

OBJECTIVE: Methotrexate (MTX) is widely used in the treatment of rheumatic and non-rheumatic disorders. Severe adverse effects are often associated with therapeutic errors, such as daily intake rather than weekly intake. Among them, the risk of bowel perforation is extremely rare (0.1%). We describe a case of bowel perforation, occurred following daily intake of MTX. CASE REPORT: A 68-year-old man was prescribed to take MTX 7,5 mg orally once a week, while waiting for switch to abatacept for a recent reactivation of rheumatoid arthritis. After 10 days he started having pharyngodynia, hematochezia and general malaise. At medical examination he presented oral and nasal mucositis; moreover, blood exams showed thrombocytopenia. The anamnesis revealed that he had been taken the prescribed dosage of MTX daily, instead of weekly. Therapy with Lederfolin 1000 mg (mg/m²/die) and urine alkalinization started. After 7 days of hospitalization, there was an abrupt worsening of clinical conditions and an emergency CT scan revealed millimetric gas bubbles indicating bowel perforation. The patient underwent an emergency exploratory laparotomy that resulted in peritoneal toilette and sigma resections. Anatomopathological findings were suggestive of MTX poisoning. CONCLUSIONS: The patient was discharged on the 17th day in good clinical condition.

Beneficial effects of adaptive servo-ventilation on natriuretic peptides and diastolic function in acute heart failure patients with preserved ejection fraction and sleep-disordered breathing.

PURPOSE: Adaptive servo-ventilation (ASV) is a ventilator algorithm able to correct breathing through anticyclic support of breathing in patients with central sleep apnea (CSA). So far, very few data exist regarding the role of ASV on acute heart failure with preserved ejection fraction (HFpEF). METHODS: We performed a single-center prospective, randomized, case-control study in consecutive acute HFpEF (left ventricle ejection fraction, LVEF ≥ 45%) patients with sleep-disordered breathing (SDB, apnea-hypopnea index, AHI > 15/h) and prevalence of CSA. RESULTS: We included ten consecutive patients randomized for ASV on top of standard therapy for acute heart failure (group 1) versus standard care alone (group 2). ASV therapy significantly reduced AHI and CSA. An improvement in cardiac diastolic function was seen in group 1 compared to group 2 (E/E' 17.5 to 9.6, p < 0.02 vs 18.5 to 14.5, p = 0.4). Brain natriuretic peptide (BNP) markedly decreased in cases, but not in controls (298 to 84 pg/ml, p < 0.02 vs 280 to 120 pg/ml, p = 0.06). Right ventricle (RV) function significantly improved in group 1, differently from group 2. CONCLUSIONS: An acute use of ASV seems effective in reducing BNP and improving diastolic and RV function in acute HFpEF patients with SDB and CSA, compared to standard treatment.

Global Longitudinal Strain in master athletes and in hypertensive patients with the same degree of septal thickness.

Athletes may have electrocardiogram (ECG) repolarization abnormalities during stress test suggestive for ischemia in the absence of ischemic coronary artery disease, often in a setting of myocardial septum hypertrophy. Global longitudinal strain (GLS) might be altered in these athletes compared to hypertensive patients with the same degree of septal thickness. About 735 consecutive athletes were screened for mandatory assessment of fitness to participate in competitive sports. At the stress test, 23 (19 M, 4 F) were found to have ECG repolarization abnormalities suggestive for ischemia in the presence of normal coronary vessels. They were matched to a control group of 23 hypertensive patients with no ECG abnormalities during stress test and the same degree of septal thickness. A transthoracic echocardiography for evaluation of global longitudinal strain (GLS) was performed. Interventricular septum thickness (IST) and relative wall thickness (RWT) were also calculated. A preserved ventricular function was seen in both groups (64 ± 8% in cases vs 60 ± 6% in controls, P = 0.42). IST and RWT were not significantly different. GLS was significantly lower in athletes vs hypertensive patients (-18.7 ± 2.5 vs -21.67 ± 0.27, P = 0.001). In athletes with septal hypertrophy and a positive stress test not associated to coronary disease, GLS is lower with respect to a population of hypertensive patient with the same degree of septal hypertrophy. Further investigations in a larger population are required to better define the potentiality of GLS in differentiating pathological vs physiological septum hypertrophy.

The burden of chronic noncommunicable diseases in undocumented migrants: a 1-year survey of drugs dispensation by a non-governmental organization in Italy.

OBJECTIVES: This study was carried out with two objectives. The first one was to have an insight into the prevalence of chronic noncommunicable diseases (CNCD) in undocumented migrants, and the second one was to evaluate if differences existed among different ethnic groups. STUDY DESIGN: The study is based on the collection of data on drug dispensation by a non-governmental organization (NGO) providing free medical assistance to undocumented migrants in Milan, Italy. All the prescriptions to adult subjects from January 1 to December 31 2014 (total 8438) were recorded and analyzed. All the data available for the patients receiving prescriptions (age, gender and country of birth) were also collected in anonymous form. Ethical approval for the study was given by the Ethics Committee of the NGO. METHODS: Drugs were grouped according to the anatomical therapeutic chemical (ATC) classification and their quantities expressed as daily defined doses (DDDs)/1000 patients/day. The 56 ATC levels were divided into three groups according to their use for acute, chronic, or both acute and chronic diseases. The statistical analysis of drug dispensation was performed for the whole population and for the five ethnic groups into which it had been divided. RESULTS: Prescription of medicines for chronic conditions was significantly greater than for acute (154.2 ± 45.9 vs 51.3 ± 18.4 DDD/1000 patients/day, P < 0.02) and for both acute and chronic conditions (57.9 ± 12.8 DDD/1000 patients/day, P < 0.02). Five ATC classes accounted for 60% of all chronic prescriptions. They were differently distributed among the five ethnic groups (e.g., Asians required more antihypertensives and antidiabetics, East Europeans required more lipid modifying drugs, antihypertensives and antithrombotics). CONCLUSIONS: Our data show an important use of medicines for chronic diseases in a population of undocumented migrants. Though with some limitations, this could be an indicator of a high prevalence of CNCD in this population, with significant differences among different ethnic groups. This situation should be considered when planning health interventions, also in consideration of the fact that it could have an impact on European Health Services in a short time.

Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area.

Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor.

Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case-control study on 174 patients.

Oral melphalan and dexamethasone (MDex) is a standard treatment for patients with AL amyloidosis who are not eligible for stem cell transplantation at many referral centers. However, following encouraging reports on the activity of bortezomib combined with alkylators and dexamethasone, these combinations are being moved to frontline therapy. We compared the outcome of 87 patients treated with bortezomib plus MDex (BMDex) with that of 87 controls treated with MDex. Patients and controls were matched for age, cardiac and renal function and free light chain burden. A higher rate of complete responses was observed with BMDex (42 vs 19%), but this did not result in a survival improvement in the overall population. However, a significant survival advantage for BMDex was observed in patients without severe (New York Heart Association class III or IV) heart failure and with N-terminal pro-natriuretic peptide type-B <8500 ng/l. Patients treated with full-dose dexamethasone had similar response rates and survival whether they received bortezomib or not. Intermediate-risk patients who are not fit enough to receive high-dose dexamethasone are likely to take the greatest advantage from the addition of bortezomib to MDex.

Pulse pressure and heart rate in patients with metabolic syndrome across Europe: insights from the GOOD survey.

The Global Cardiometabolic Risk Profile in Patients with hypertension disease (GOOD) survey investigated the global cardiometabolic risk profile in 3464 adult outpatients with hypertension across 289 sites in 12 European countries. The pulse pressure and heart rate profile of the survey population was evaluated according to the presence or absence of metabolic syndrome and/or type 2 diabetes mellitus. History and treatment of hypertension were not counted as criteria for metabolic syndrome as they applied to all patients. Out of the 3370 recruited patients, 1033 had metabolic syndrome and 1177 had neither metabolic syndrome nor diabetes. When compared with patients with no metabolic syndrome or diabetes, patients with metabolic syndrome had higher pulse pressure (59±14 vs. 55±14 mm Hg) and heart rate (75.2±11.0 vs. 72.5±10.0 beats per min) (P<0.001 for both), independent of the concomitant presence or absence of diabetes, despite a more prevalent use of ß-blockers. In conclusion, in hypertensive outpatients the presence of metabolic syndrome is associated with increased heart rate and pulse pressure, which may at least in part reflect increased arterial stiffness and increased sympathetic tone. This may contribute, to some extent, to explaining the increased cardiovascular risk attributed to the presence of metabolic syndrome.

[Influence of thyroid morphology on psychomotor development in patients with congenital hypothyroidism during 8 year follow-up]. / Influenza della morfologia tiroidea sullo sviluppo psicomotorio di bambini affetti da ipotiroidismo congenito durante 8 anni di follow-up.

AIM: The aim of this paper was to evaluate the impact of thyroid morphology on auxological and neuropsychological development in children affected by congenital hypothyroidism (CH), treated with levothyroxine, up to 8 years of age. METHODS: Fifty-three children affected by CH divided into 3 groups on the basis of thyroid morphology determined at birth: patients with athyreosis (N=17), with ectopic gland (N=23), with in situ thyroid (N=13). The developmental quotient (DQ) was evaluated by the Brunet-Lezine test up to 3 years, and intelligent quotient (IQ) by the Terman-Merril test after 3 years of age. RESULTS: DQs at one year in athyreotic patients are lower (P<0,05) as compared to those determined in patients with other thyroid morphology. Later on these patients still showed lower DQ and IQ values than in other groups, although statistically not significant. CONCLUSION: Thyroid morphology seems to be fundamental in psychomotor development, in fact patients with athyreosis show a transient impairment at one year of age. This difference could be transient or to have repercussions on adult. Individualization of the starting dose of levothyroxine on the basis of thyroid morphology, could be useful.

Inter-regional comparisons of the prevalence of cardiometabolic risk factors in patients with hypertension in Europe: the GOOD survey.

The GOOD survey investigated the global cardiometabolic risk profile in adult patients with hypertension across 289 sites in four European regions (Northwest, Mediterranean, Atlantic European Mainland and Central Europe). Demographic, lifestyle, clinical and laboratory data were collected from eligible patients (n=3370) during a single clinic visit. In Central Europe, represented by Hungary, 44% of the participants had type II diabetes compared with 33% in the Atlantic European Mainland, and 26% in the Northwest and the Mediterranean regions. The prevalence of metabolic syndrome was also significantly higher in Central Europe (68%) and the Atlantic European Mainland (60%) than in the Northwest and the Mediterranean regions (50 and 52%, respectively). Fasting blood glucose, total cholesterol and triglyceride levels were all highest in Central Europe compared with the other three regions (P<0.001). In the Atlantic European Mainland, more patients had uncontrolled blood pressure (80%) compared with the other three regions (70-71%). Declared alcohol consumption was highest in the Atlantic European Mainland and exercise lowest in Central Europe. The prevalence of congestive heart failure, left ventricular hypertrophy, coronary artery disease and stable/unstable angina was higher in Central Europe compared with the other regions, whereas a family history of premature stroke or myocardial infarction, stroke, coronary revascularization and transient ischaemic attacks was all highest in the Atlantic European Mainland. These data indicate that many hypertensive patients across Europe have multiple cardiometabolic risk factors with the prevalence higher in Central Europe and the Atlantic European Mainland compared with Northwest and Mediterranean regions.

Histochemical study of cardiac mast cells degranulation and collagen deposition: interaction with the cathecolaminergic system in the rat.

Although their role in the cardiovascular system is still largely unknown, mast cells are present in the myocardium of both experimental animals and humans. Interestingly, cathecolaminergic nerve fibres and mast cells are often described in close morphological and functional interactions in various organs. In the present study we investigated the effects of chronic interference with beta-adrenergic receptors (via either sympathectomy or beta-blockade) on cardiac mast cell morphology/activation and on interstitial collagen deposition. In rats subjected to chemical sympathectomizy with the neurotoxin 6-hydroxydopamine (6-OHDA) we observed a significant increase of mast cell density, and in particular of degranulating mast cells, suggesting a close relationship between the cardiac catecholaminergic system and mast cell activation. In parallel, chronic 6-OHDA treatment was associated with increased collagen deposition. The influence of the beta-adrenergic receptor component was investigated in rats subjected to chronic propranolol administration, that caused a further significant increase in mast cell activation associated with a lower extent of collagen deposition when compared to chemical sympathectomy. These data are the first demonstration of a close relationship between rat cardiac mast cell activation and the catecholaminergic system, with a complex interplay with cardiac collagen deposition. Specifically, abrogation of the cardiac sympathetic efferent drive by chemical sympathectomy causes mast cell activation and interstitial fibrosis, possibly due to the local effects of the neurotoxin 6-hydroxydopamine. In contrast, beta-adrenergic blockade is associated with enhanced mast cell degranulation and a lower extent of collagen deposition in the normal myocardium. In conclusion, cardiac mast cell activation is influenced by beta-adrenergic influences.

Time course of matrix metalloproteases and tissue inhibitors in bleomycin-induced pulmonary fibrosis.

To investigate simultaneously localization and relative activity of MMPs during extracellular matrix (ECM) remodeling in bleomycin-induced pulmonary fibrosis in rat, we analyzed the time course of the expression, activity and/or concentration of gelatinases MMP-2 and MMP-9, collagenase MMP-1, matrylisin MMP-7, TIMP-1 and TIMP-2, both in alveolar space (cellular and extracellular compartments) and in lung tissue. MMP and TIMP expression was detected (immunohistochemistry) in lung tissue. MMP activity (zymography) and TIMP concentration (ELISA) were evaluated in lung tissue homogenate (LTH), BAL supernatant (BALs) and BAL cell pellet (BALp) 3, 7, 14, and 28 days after bleomycin intratracheal instillation. Immunohistochemistry showed an extensive MMP and TIMP expression from day 7 in a wide range of structural and inflammatory cells in treated rats. MMP-2 was present mainly in epithelia, MMP-9 in inflammatory cells. MMP-2 and MMP-9 activity was increased respectively in BAL fluid and BAL cells, with a peak at day 7. TIMP-1 and TIMP-2 concentration (ELISA) enhancement was delayed at day 14. In conclusion gelatinases and their inhibitors are significantly activated during bleomycin-induced pulmonary fibrosis. Marked changes in gelatinases activity are observed early in the alveolar compartment, with a prevailing extracellular activity of MMP-2 and a predominant intracellular distribution of MMP-9, while enzyme activity changes in lung parenchyma were less evident. In the repairing phase the reduction of gelatinases activity is synchronous with a peak of alveolar concentration of their inhibitors.

Antiadrenergic effects of adenosine in pressure overload hypertrophy.

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.