Prognostic impact of coronary microcirculation abnormalities in systemic sclerosis: a prospective study to evaluate the role of non-invasive tests

INTRODUCTION: Microcirculation dysfunction is a typical feature of systemic sclerosis (SSc) and represents the earliest abnormality of primary myocardial involvement. We assessed coronary microcirculation status by combining two functional tests in SSc patients and estimating its impact on disease outcome. METHODS: Forty-one SSc patients, asymptomatic for coronary artery disease, were tested for coronary flow velocity reserve (CFR) by transthoracic-echo-Doppler with adenosine infusion (A-TTE) and for left ventricular wall motion abnormalities (WMA) by dobutamine stress echocardiography (DSE). Myocardial multi-detector computed tomography (MDCT) enabled the presence of epicardial stenosis, which could interfere with the accuracy of the tests, to be excluded. Patient survival rate was assessed over a 6.7- ± 3.5-year follow-up. RESULTS: Nineteen out of 41 (46%) SSc patients had a reduced CFR (≤2.5) and in 16/41 (39%) a WMA was observed during DSE. Furthermore, 13/41 (32%) patients showed pathological CFR and WMA. An inverse correlation between wall motion score index (WMSI) during DSE and CFR value (r = -0.57, P <0.0001) was observed; in addition, CFR was significantly reduced (2.21 ± 0.38) in patients with WMA as compared to those without (2.94 ± 0.60) (P <0.0001). In 12 patients with abnormal DSE, MDCT was used to exclude macrovasculopathy. During a 6.7- ± 3.5-year follow-up seven patients with abnormal coronary functional tests died of disease-related causes, compared to only one patient with normal tests. CONCLUSIONS: A-TTE and DSE tests are useful tools to detect non-invasively pre-clinical microcirculation abnormalities in SSc patients; moreover, abnormal CFR and WMA might be related to a worse disease outcome suggesting a prognostic value of these tests, similar to other myocardial diseases

Acute idiopathic pericarditis: current immunological theories

Alida LP Caforio,1 Renzo Marcolongo,2 Antonio Brucato,3 Luca Cantarini,4 Massimo Imazio,5 Sabino Iliceto11Division of Cardiology, Department of Cardiology, Thoracic and Vascular Sciences, University of Padua, Padua; 2Haematology and Clinical Immunology, Department of Medicine, University of Padua, Padua, 3Internal Medicine, Ospedali Riuniti, Bergamo, 4Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, 5Department of Cardiology, Maria Vittoria Hospital, Torino, ItalyAbstract: Idiopathic recurrent acute pericarditis (IRAP) is a rare disease of suspected immune-mediated pathogenesis. It represents a diagnosis of exclusion. It is necessary to rule out infectious and noninfectious causes of pericardial inflammation, including systemic autoimmune and immune-related disorders, eg, Sjögren's disease, systemic lupus erythematosus. Since pericarditis may precede diagnosis of these disorders, IRAP diagnosis is often made after a long follow-up. According to the two main pathogenetic theories IRAP may represent an organ-specific autoimmune disease or an autoinflammatory disease (AInfD). The main evidence for autoimmunity in IRAP is provided by the detection of serum antiheart and antiintercalated-disk autoantibodies, and the response to anti-inflammatory or immunosuppressive therapy. The findings of familial forms and of proinflammatory cytokines in the pericardial fluid in IRAP would be in keeping with both organ-specific autoimmune disease and AInfD. In fact, AInfD are genetic disorders characterized by primary dysfunction of the innate immune system, due to mutations of genes involved in the regulation of the inflammatory response, in the absence of antigen specific T cells or autoantibodies. In AInfD there are active disease phases with raised non-cardiac specific inflammatory markers, such as C-reactive protein, as well as symptom-free intervals with possible C-reactive protein normalization. A minority of IRAP patients (6%) carry a mutation in the TNFRSF1A gene, encoding the receptor for tumor necrosis factor-alfa. This suggests that some IRAP patients may have an atypical or subclinical form of AInfD. Thus, IRAP may represent a syndrome with distinct pathogenetic mechanisms in different patients' subsets.Keywords: pericarditis, autoimmunity, autoantibodies, heart disease, immune factor

Hyperhomocysteinemia in L-dopa treated patients with Parkinson's disease: potential implications in cognitive dysfunction and dementia?

Abstract: Background: Hyperhomocysteinemia has been associated with cognitive dysfunction and dementia. The incidence of dementia in Parkinson’s Disease (PD) patients is higher than in the general population and plasma Homocysteine concentrations are increased in L-dopa treated PD patients. Objective: We evaluated the possible correlations between L-Dopa related hyperhomocysteinemia and cognitive dysfunction in PD. Methods: A Medline literature search was performed to identify all published studies on Homocysteine and cognitive dysfunction and dementia during the course of PD from 1966 to 31/03/2010. Results: Sixteen studies were found for review; ten studies focused on homocysteine and cognitive dysfunction in PD patients, five on homocysteine and PD dementia and two on homocysteine and markers of neurodegeneration in PD. The design of the study was retrospective in 14 studies, while 2 had a prospective design, with a variable follow-up period (from 24-weeks to 2 years). In most of the studies plasma homocysteine levels significantly correlated with cognitive functions, dementia and markers of neurodegeneration in PD patients. However, some studies did not confirm these findings. Several factors may concur to explain these partially conflicting results, including the retrospective design of the studies, their small sample size, their high percentage of excluded patients, and the use of a wide range of neuropsychological tasks in assessment of cognitive dysfunctions across the available studies. Conclusions: Available data seem to indicate a potential role of L-dopa related hyperhomocysteinemia on cognitive impairment and dementia during the course of PD

Dielectric, Switching and System Requirements under Out-of-Phase Conditions, during Synchronisation and under Comparable Stresses

Recent developments in electrical networks can increase the probability of out-of-phase switching and dielectric stresses being applied to open circuit-breakers, due to asynchronous systems at both sides. This report presents a systematic study of TRV-stresses associated with generator separation and system separation. TRV peak values are higher than required in the Standards, even for relatively small out-of-phase angles (75º to 90º), and the dielectric stresses are high with respect to the shortduration power frequency withstand voltages across a circuit-breaker open contacts, especially taking into consideration the external insulation under pollution and ageing processes. To the opinion of the authors, the Standards should be revised to give users clear and adequate guidance on the assessment and specification of TRV-values and dielectric withstand requirements under out-of-phase conditions

Inclusion of motor evoked abnormalities in amyotrophic lateral sclerosis: a diagnostic algorithm to early classify lower motor neuron phenotypes

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Motor-evoked potentials in amyotrophic lateral sclerosis: potential implications in detecting subclinical UMN involvement in lower motor neuron phenotype

Background: In amyotrophic lateral sclerosis (ALS), the involvement of lower motor neuron is well defined by electromyography, whereas a reliable marker of upper motor neuron (UMN) damage still lacks. Aim of the study was to estimate the role of transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs) as marker of subclinical UMN involvement. Methods: Clinical evidence of UMN damage was prospectively compared to MEPs in 176 ALS patients diagnosed between 2011 and 2014, and classified according to existing diagnostic criteria. Finally, we evaluated the appearance of clinical UMN signs and the level of diagnostic certainty in ALS after 1 year of follow-up. Results: At presentation, abnormal MEPs were found in 80% of patients with clinical evidence of UMN damage and in 72% of patients without clinical involvement of UMN. Among these latter, 61% showed appearance of UMN clinical signs after 1 year. Approximately 70% of patients with clinical lower motor neuron (LMN) phenotype showed MEP abnormalities, while they were considered not classifiable ALS according to Airlie house or Awaji criteria. Furthermore, abnormal MEPs in absence of clinical UMN signs at baseline were found in 80% of spinal ALS that after 1-year developed UMN signs at limbs, compared to 50% of bulbar ALS. Conclusions: TMS is a reliable marker of subclinical UMN damage particularly among LMN phenotype and ensure an early ALS diagnosis in ~ 70% of such cases

Higher ventricular-arterial coupling derived from three-dimensional echocardiography is associated with a worse clinical outcome in systemic sclerosis

Primary myocardial involvement is common in systemic sclerosis (SSc). Ventricular-arterial coupling (VAC) reflecting the interplay between ventricular performance and arterial load, is a key determinant of cardiovascular (CV) performance. We aimed to investigate VAC, VAC-derived indices, and the potential association between altered VAC and survival free from death/hospitalization for major adverse CV events (MACE) in scleroderma. Only SSc patients without any anamnes-tic and echocardiographic evidence of primary myocardial involvement who underwent three-dimensional echocardiography (3DE) were included in this cross-sectional study and compared with healthy matched controls. 3DE was used for noninvasive measurements of end-systolic elastance (Ees), arterial elastance (Ea), VAC (Ea/Ees) and end-diastolic elastance (Eed); the occurrence of death/hospitalization for MACE was recorded during follow-up. Sixty-five SSc patients (54 female; aged 56 ± 14 years) were included. Ees (p = 0.04), Ea (p = 0.04) and Eed (p = 0.01) were higher in patients vs. controls. Thus, VAC was similar in both groups. Ees was lower and VAC was higher in patients with diffuse cutaneous form (dcSSc) vs. patients with limited form (lcSSc) (p = 0.001 and p = 0.02, respectively). Over a median follow-up of 4 years, four patients died for heart failure and 34 were hospitalized for CV events. In patients with VAC &gt;0.63 the risk of MACE was higher (HR 2.5; 95% CI 1.13–5.7; p = 0.01) and survival free from death/hospitalization was lower (p = 0.005) than in those with VAC &lt; 0.63. Our study suggests that VAC may be impaired in SSc patients without signs and symptoms of primary myocardial involvement. Moreover, VAC appears to have a prognostic role in SSc

Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The L-carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial

Objectives. This study was performed to evaluate the effects of l-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Background. Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous carnitine administration during these events has a beneficial effect on function. Methods. The l-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or l-carnitine (233 patients) within 24 h of onset of chest pain. Placebo or l-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. Results. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with l-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and endsystolic volumes from admission to 3-, 6- and 12-mouth evaluation was significantly reduced in the l-carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the l-carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients. Conclusions. l-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event

Two-years therapy with bosentan of pulmonary arterial hypertension related to connective tissue diseases

Objective: Pulmonary arterial hypertension (PAH) is a rare but severe complication of connective tissue diseases (CTD), with a negative impact on patients survival. Bosentan, a receptor antagonist of endothelin, has been proved effective for the treatment of PAH. The aim of this study was to evaluate the effects and the safety of bosentan administered for 2 years in a group of patients with PAH related to CTD. Methods: Twelve patients with PAH related to systemic sclerosis (8 cases), SLE (2 cases), mixed connective tissue disease (1 case) and polymyositis (1 case) attending the Rheumatology Unit of Padova University were treated with bosentan for two years. Distance walked in 6 minutes, right ventricular systolic pressure and mean pulmonary artery pressure estimated by doppler echocardiography were evaluated at baseline and after 6, 12, 18 and 24 months of treatment. Safety was assessed by laboratory tests performed every two months. Results: During bosentan treatment, a significant decrease of right ventricular systolic pressure was observed after 6, 12, 18 and 24 months in comparison to baseline, whereas pulmonary artery mean pressure remained unchanged. Distance walked in 6 minutes slightly increased after 6 and 12 months, but significantly decreased after 18 and 24 months, mostly because complications of CTD which compromised the ability to walk arose in 4 patients. Adverse events related to bosentan were observed in 2 cases. Conclusions: Bosentan has been demonstrated effective in reducing pulmonary arterial pressure in a two-year period of treatment. Exercise capacity improved only in the first year of therapy and worsened thereafter, suggesting the opportunity of a combination therapy for a long-term treatment of PAH related to CTD