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In our recent works we reported that physical and chemical characteristics of serum can vary in relation to the psychic activity of an individual depending on whether it is oriented to stress or relaxation. We wandered if these observations could be accompanied by an appreciable modification of the Ph, electric conductivity and Delayed Luminescence of the same serum samples. Our preliminary data may suggest that the serum pH could significantly increase during a Relaxation Response intervention while electric conductivity seems to decrease. Moreover, Delayed Luminescense could vary in the same subject according to the Relaxation Response practice. According to our proof of concept study, we postulate the appearance of a coherent system within the blood samples analyzed after the Relaxation Response. Further researches and some technical development are needed to support our preliminary findings.

Convincing evidence has documented that mechanical vibrations profoundly affect the behaviour of different cell types and even the functions of different organs. Pressure waves such as those of sound could affect cytoskeletal molecules with coherent changes in their spatial organization and are conveyed to cellular nucleus via mechanotransduction. HL1 cells were grown and exposed to different sounds. Subsequently, cells were stained for phalloidin, beta-actin, alpha-tubulin, alpha-actinin-1 and MitoTracker® mitochondrial probe. The cells were analyzed with time-lapse and immunofluorescence/confocal microscopy. In this paper, we describe that different sound stimuli seem to influence the growth or death of HL1 cells, resulting in a different mitochondrial localization and expression of cytoskeletal proteins. Since the cellular behaviour seems to correlate with the meaning of the sound used, we speculate that it can be “understood” by the cells by virtue of the different sound waves geometric properties that we have photographed and filmed. A theoretical physical model is proposed to explain our preliminary results.

Introduction Mental stress is potentially a major cardiovascular risk factor. Meditation and listening to music may be able to compensate by eliciting the Relaxation Response (RR) with a beneficial prognostic impact after myocardial infarction (MI), reducing the progression of the arteriosclerotic process and improving coronary blood flow. We aimed to study a possible epigenetic mechanism of the RR speculating that circulating microRNAs levels could change during relaxation. Methods We enrolled 150 consecutive patients after MI. 50 were trained to meditate, 50 given music appreciation and 50 served as controls. In addition, in order to rule out that the disease state could interfere with the possible movement of microRNAs, we enrolled 50 healthy volunteers (25 were trained to meditate and 25 had music appreciation). After training, and after 60 days of RR practice, we studied the individual variation, before and after the relaxation session, of some important cardiovascular circulating microRNAs: the microRNA-1, −16, −24, −33, −92, −144, −146, −155. Results As the RR appeared to be triggered in the same way irrespective of whether this was by music or meditation data was combined. After the RR, a reduction in microRNA-16, −33, −92, −144, −146, −155 (p Conclusions The RR modulates some microRNAs levels suggesting that psychic activity may be an important epigenetic and pathophysiological factor in the arteriosclerotic process and in ischemic heart disease. In particular, the analyzed microRNAs levels seems to vary in relation to the state of stress or relaxation of the subjects.

Pulmonary hypertension (PH) is a well-established adverse prognostic factor in patients with nonischemic dilated cardiomyopathy (NIDC) [(1,2)][1]. Recently, cardiac magnetic resonance (CMR) studies highlighted the presence of late gadolinium enhancement (LGE) in the right ventricular (RV) junctional

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

Purpose The aim of this preliminary study was to perform exploration, integration and analysis of large-scale, genome-wide data with transcriptome platform to evaluate, without a selection bias, the expression profile of mRNA on FFPE-EMBs of heart transplanted patients affected by CAV. Methods Our cohort of study was composed by 11 adult HTx patients. We selected FFPE-EMB from heart transplanted patients characterized by the presence of CAV (n=7), and control group (n=4) with absence of rejection and CAV, with age/sex match and same time interval from HTx. We performed a pangenomic expression microarray profiling (Clariom S assay) without a bias of transcript selection. Bioinformatic mRNA expression analysis on distinct FFPE-EMBs samples was performed using enrichment analysis software: EnrichR, an online software application including gene-set libraries to rank enriched terms; and GSEA (gene set enrichment analysis) a priori-free bioinformatic analytical tool for interpreting gene expression data. Results Through EnrichR and GSEA analysis we recognized specific patterns of expression of mRNA. Within the CAV group, in GSEA analysis, 700 gene sets were highlighted. 118 gene sets were significantly enriched at FDR Conclusion These preliminary data from categories emerged through enrichment analysis, suggested the presence of one prevalent mechanism correlated to CAV and related to enrichment in pathways connected to cell cycle dysregulation and DNA/chromatin metabolism. While these categories seemed to be silent in control group without CAV, a downregulation of pathways’ genes related more to neuronal tropism and cardiac contraction was observed. All these aspects may help us in highlighting novel and not-yet investigated molecular pathways involved in CAV development.

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, Graphical abstract Image 1

Background: The pathophysiology of angina-like symptoms in myocarditis is still unclear. Perivascular fat attenuation index (pFAI) by coronary computed tomography angiography (CCTA) is a non-invasive marker of coronary inflammation (CI) in atherosclerosis. We explored the presence of CI in clinically suspected myocarditis with infarct-like presentation. Methods: We retrospectively included 15 consecutive patients (67% male, age 30 ± 10 years) with clinically suspected infarct-like myocarditis who underwent CCTA to rule out coronary artery disease. Right coronary artery (RCA) pFAI mean value was compared with that of healthy volunteers. Results: Mean RCA pFAI value was −92.8 ± 8.4 HU, similar to that of healthy volunteers (−95.2 ± 6.0, p = 0.8). We found no correlation between RCA pFAI mean values and peak Troponin I (r = −0.43, p = 0.11) and C-reactive protein at diagnosis (r = −0.25, p = 0.42). Patients with higher pFAI values showed higher biventricular end-systolic volumes (ESV) (p = 0.038 for left and p = 0.024 for right ventricle) and lower right ventricular ejection fraction (RVEF) (p = 0.038) on cardiovascular magnetic resonance. Conclusions: In clinically suspected myocarditis with infarct-like presentation, RCA pFAI values are lower than those validated in atherosclerosis. The correlation between higher pFAI values, higher biventricular ESV and lower RVEF, may suggest a role of pFAI in predicting non-atherosclerotic CI (i.e., infective/immune-mediated “endothelialitis”).

Mechanical vibrations seem to affect the behaviour of different cell types and the functions of different organs. Pressure waves, including acoustic waves (sounds), could affect cytoskeletal molecules via coherent changes in their spatial organization and mechano-transduction signalling. We analyzed the sounds spectra and their fractal features. Cardiac muscle HL1 cells were exposed to different sounds, were stained for cytoskeletal markers (phalloidin, beta-actin, alpha-tubulin, alpha-actinin-1), and studied with multifractal analysis (using FracLac for ImageJ). A single cell was live-imaged and its dynamic contractility changes in response to each different sound were analysed (using Musclemotion for ImageJ). Different sound stimuli seem to influence the contractility and the spatial organization of HL1 cells, resulting in a different localization and fluorescence emission of cytoskeletal proteins. Since the cellular behaviour seems to correlate with the fractal structure of the sound used, we speculate that it can influence the cells by virtue of the different sound waves&rsquo, geometric properties that we have photographed and filmed. A theoretical physical model is proposed to explain our results, based on the coherent molecular dynamics. We stress the role of the systemic view in the understanding of the biological activity.

Background: Circulating extracellular vesicles (EVs) are raising considerable interest as a non-invasive diagnostic tool, as they are easily detectable in biologic fluids and contain a specific set of nucleic acids, proteins, and lipids reflecting pathophysiologic conditions. We aimed to investigate differences in plasma-derived EV surface protein profiles as a biomarker to be used in combination with endomyocardial biopsies (EMBs) for the diagnosis of allograft rejection. Methods: Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) before EMB. EV concentration was assessed by nanoparticle tracking analysis. EV surface antigens were measured using a multiplex flow cytometry assay composed of 37 fluorescently labeled capture bead populations coated with specific antibodies directed against respective EV surface epitopes. Results: The concentration of EVs was significantly increased and their diameter decreased in patients undergoing rejection as compared with negative ones. The trend was highly significant for both antibody-mediated rejection and acute cellular rejection (p < 0.001). Among EV surface markers, CD3, CD2, ROR1, SSEA-4, human leukocyte antigen (HLA)-I, and CD41b were identified as discriminants between controls and acute cellular rejection, whereas HLA-II, CD326, CD19, CD25, CD20, ROR1, SSEA-4, HLA-I, and CD41b discriminated controls from patients with antibody-mediated rejection. Receiver operating characteristics curves confirmed a reliable diagnostic performance for each single marker (area under the curve range, 0.727-0.939). According to differential EV-marker expression, a diagnostic model was built and validated in an external cohort of patients. Our model was able to distinguish patients undergoing rejection from those without rejection. The accuracy at validation in an independent external cohort reached 86.5%. Its application for patient management has the potential to reduce the number of EMBs. Further studies in a higher number of patients are required to validate this approach for clinical purposes. Conclusions: Circulating EVs are highly promising as a new tool to characterize cardiac allograft rejection and to be complementary to EMB monitoring.

The contribution of functional and/or structural remodeling to reduced coronary flow velocity reserve (CFVR), reflecting impaired coronary microcirculation in Cushing's syndrome (CS), has not been clearly elucidated. We aimed to identify the potential mechanisms of coronary microvascular impairment in CS.We studied 15 CS patients (11 female, age 50 ± 9 years) without clinical evidence of cardiovascular disease. Coronary flow velocity in the left anterior descending coronary artery was measured by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. Average peak flow velocities, CFVR, and microvascular resistance in baseline (BMR) and hyperemic conditions (HMR) were assessed. CFVR ≤2.5 was considered a marker of microvascular disease (CMD). Diastolic function (E/e'), global longitudinal strain (GLS) and fractional pulse pressure (fPP), an index of arterial stiffness, were also assessed.CMD was present in 5 patients (33.3%). CMD was primarily driven by increased baseline peak flow velocity (29 ± 12 versus 19.6 ± 4.2 cm/s, p = .03) in the presence of decreased BMR (3.62 ± 0.6 versus 5.46 ± 1.4 mm Hg·s/cm, p = .03). Moreover, urinary cortisol and E/e' were higher (p = .001 and p = .001, respectively) and GLS was lower (p = .009) in patients with CMD. fPP was higher in patients with CMD (p = .01). Urinary cortisol correlated to CFVR (p = .008), E/e' (p .0001) and GLS (p .0001). fPP directly correlated to average peak flow velocities at rest (p = .01) and inversely to BMR (p = .03).Functional microvascular regulatory impairment seems to be the potential mechanism of CMD in CS. CMD seems to be related to decreased myocardial contractility and diastolic dysfunction associated with cortisol excess.

Background Standard Transthoracic Echocardiography (TTE) parameters have shown a low sensitivity in the detection of primary miocardial involvement (PMI) in systemic sclerosis (SSc). Arterial-ventricular coupling (VAC) is calculated by TTE as the ratio between arterial elastance (Ea) and ventricular end-systolic elastance (Ees), which reflects left ventricle stifness. VAC is a central determinant of cardiovascular performance. Objectives We aimed to assess TTE-derived measures of cardiac mechanics and the prognostic role of VAC in SSc. Methods 75 patients affected by SSc without symptoms of cardiac involvement and 10 controls matched for sex and age were retrospectively evaluated. We considered the first TTE available after SSc diagnosis. Determinants of cardiac mechanics were calculated by TTE1: end systolic elastance (Ees), arterial elastance (Ea), ventricular arterial coupling (VAC=Ees/Ea), end diastolic elastance (Eed). A value of VAC > 0.62 was considered indicative of altered VAC (i.e. uncoupling), whereas a lower value as normal (i.e. coupling). Finally, we considered the hospitalization for cardiovascular event during a mean follow-up of 10.8±1.8 years. Results Among the 75 patients 42 (59.2%) had a diffuse cutaneous form of SSc (dSSc) and 64 (85.3%) were female; in SSc patients the mean age was 53±12.1 yrs and the mean disease duration 10.1± 2.3 yrs. 36 (52.2%) patients had positive SCl70, 31 (44.9%) ACA, and 2 (2.9%) anti-RNA pol III. Compared to controls, SSc patients had higher Ea (2.28 vs 0.95 mmHg/ml, p=0.003) and Ees (3.95 vs 2.98 mmHg/ml, p=0.05), and increased diastolic stiffness (Eed) (0.210 vs 0.146 mmHg/ml, p=0.01). VAC was consequently comparable to controls. SSc patients affected with dcSSc had a lower Ees (2.90 vs 4.367, p Conclusion Our study suggests that both ventricular and arterial stifness may be increased in SSc patients without signs and symptoms of heart disease. Since VAC seems to have a prognostic role in the prediction of cardiovascular events in SSc, it could be helpful to define an early therapeutic strategy to prevent or delay cardiac manifestations in these patients. Reference 1.Sagawa K et al, Am J Cardiol 1977;40:748-753. Disclosure of Interests None declared

Background and aim: Mental stress represents a pivotal factor in cardiovascular diseases. The mechanism by which stress produces its deleterious ischemic effects is still under study but some of the most explored pathways are inflammation, endothelial function and balancing of the thrombotic state. In this scenario, von Willebrand factor (vWF) is a plasma glycoprotein best known for its crucial hemostatic role, also acting as key regulatory element of inflammation, being released by the activated vascular endothelium. Antistress techniques seem to be able to slow down inflammation. As we have recently verified how the practice of the Relaxation Response (RR), which counteracts psychological stress, causes favorable changes in some inflammatory genes’ expressions, neurotransmitters, hormones, cytokines and inflammatory circulating microRNAs with coronary endothelial function improvement, we aimed to verify a possible change even in serum levels of vWF. Experimental procedure: We measured vWF multimers and the total protein carbonyl contents in the sera of 90 patients with ischemic heart disease (and 30 healthy controls) immediately before and after an RR session, three times (baseline, 6 months, 12 months), during a one-year follow-up study. Results: According to our data, large vWF multimers decrease during the RR, as does the plasma total carbonyl content. Conclusion: vWF levels seem to vary rapidly between anti-inflammatory and antithrombotic behaviors dependent on psychological activity, leading to relaxation and also possibly changes in its quaternary structure.

Purpose Circulating extracellular vesicles (EVs) are raising considerable interest as a non-invasive diagnostic tool.We aimed to investigate differences in plasma-derived EV surface protein profiles as a biomarker to be used in combination with endomyocardial biopsies (EMBs) for the diagnosis of allograft rejection. Methods Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) before EMB. EV concentration was assessed by nanoparticle tracking analysis. EV surface antigens were measured using a multiplex flow cytometry assay composed of 37 fluorescently labeled capture bead populations coated with specific antibodies directed against respective EV surface epitopes. According to differential EV-markers expression two diagnostic model were built and validated through supervised learning algorithms (linear discriminant analysis-LDA- and random forest model- RF) Results The concentration of EVs was significantly increased and their diameter decreased in patients undergoing rejection as compared with negative ones. The trend was highly significant for both antibody-mediated rejection and acute cellular rejection (p Conclusion Circulating EVs are highly promising as a new tool to characterize cardiac allograft rejection and to be complementary to EMB monitoring

Purpose The aim of the study was to evaluate the trend of all the three type of rejection, cellular, humoral and mixed, during 6 years of follow-up , from 2012 to 2017 at the our transplant center, to evaluate pre-transplant clinical predictive factors for acute rejections and mortality. Methods We evaluated 149 patients heart transplanted adult patients transplanted from January 2012 and December 2017 at the university of Padua . Post transplant monitoring EMBs from 2012 to December 2018 were reevaluated . All the pre-transplant clinical were collected in a data base. The statistical analysis was subdivided in two parts. In the first part we analyzed the trend of the three different type of rejections, calculated the rate expressed as a average number of rejections for patients per year, with a Poisson distribution. In the second part we applied Machine learning method (ML), and algorithm Random Forest (RF) to analyzed the pre-transplant factors for the onset of acute rejections and for mortality. Results Of the 149 pts , 108(72,5%) were male and 41 (27,5%) female, mean age at transplantation 53,7±11,9 years for male and 46,2±15,4 for female. Two thousand and thirty three EMBs were performed during follow up with a mean number of 13,5±4,27 EMBs per patient. Of these , 1163 (57,2%) were negative for rejection, 31 (1,5%) positive for humoral rejection (pAMR+), 796 (39,2%) positive for ACR , 43 (2,1%) positive for mixed rejection. For all type of rejection there were a decreasing trend during the 6 years of follow up. The reduction in the mean number of rejection was 53,4% for acute rejection. Pre transplant predictive factors of cellular rejection were the pathology leading to heart transplant with a predictive value of 0,9%, age at transplant with a value of 0,8%. For humoral rejection the predictive factors were preforming antibodies anti HLA class II with a predictive value of 1,9%, previous pregnancies and miscarriage with a predictive value of 1,8% . The risk of mortality was influenced by age of donor with a risk value of 7,8%, the age at transplant with a risk value of 6,6%. Conclusion We have demonstrated that there is a decreasing trend of the three types of rejection during the last 6 years of follow up, in particular of cellular rejection. This is not in relation with changing in immunosuppressive drugs , but probably is due to pre and postoperative better management of heart transplant patients.

Purpose Vasculitis had been considered a histopathological marker in severe form of both cellular and humoral rejection. However, in mild forms of rejections, it has not been considered a diagnostic and prognostic histopathologic criterion. Aim of this study is to assess clinical relevance of vasculitis, in terms of mortality and cardiac allograft vasculopathy development, in the mild forms of rejection in heart transplanted patients. Methods We reviewed 2794 monitoring endomyocardial biopsies from 170 adult heart transplanted pts at our center. On endomyocardial biopsies, we evaluated the presence of vasculitis in the different types of rejection . Clinical data were collected during follow up. A Multi-State Markov model was applied to describe the rejection dynamic profile and hazard for mortality, persistence of rejection and CAV development.. We used as reference population the registry data of patients who underwent HTX from 2004 to 2018 provided by the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry Results Vasculitis was detected in 442 endomyocardial biopsies ( 442/2794, 15,8%) with an incremental percent distribution according to the severity of rejection. In ACR, vasculitis significantly increased the risk of mortality by 9% (HR [95% CI]: 1.09; [1.00-1.18]) the hazard of mortality if the patient was negative for ACR and by 14% (HR [95% CI]: 1.14; [1.02-1.37], if the patients was negative for ACR, and by 14% in a mild form of rejection (1R). Similar results were obtained for pAMR and mixed rejection. In ACR, pAMR and mixed rejection patients with vasculitis have a shorter life expectancy than patients without with a loss of four months at ten year follow up for ACR, and of 9 months for pAMR and mixed rejection. Conclusion Vasculitis when present, independently from the grade and type of rejection, carries a negative prognostic value. The worse histopathological feature was represented by the association of pAMR+ACR and vasculitis.

In patients with psoriasis, the chronic exposure to systemic inflammation can result in coronary microvascular dysfunction (CMD). In this self-controlled, prospective pilot study, we investigated whether a long-term treatment with TNF-α inhibitors effective against skin symptoms also improves coronary flow reserve in psoriasis patients (CFR).We prospectively studied 37 consecutive psoriasis patients (31 male; age, 37.7 ± 8.5 years) without cardiovascular disease, before and after anti-TNF-α treatment. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest and during adenosine infusion. CFR was the ratio of hyperemic to resting diastolic flow velocity. A CFR≤2.5 was considered a marker of CMD. Psoriasis was assessed by Psoriasis Area and Severity Index (PASI). High sensitive C-reactive protein (hs-CRP) and serum TNF-α were assessed.Overall, CFR increased from 2.2 ± 0.7 to 3.02 ± 0.8 (p 0.0001) after TNF-α inhibitors therapy. In patients with CMD, CFR increased from 1.88 ± 0.3 to 2.74 ± 0.5 (p 0.0001). In patients with normal CFR, CFR increased from 3.0 ± 0.5 to 3.7 ± 0.9 (p = 0.08). CFR improvement after TNF-α inhibitors treatment was correlated with hs-CRP and TNF-α reduction (p = 0.004 and p = 0.02, respectively), but not with change in PASI (p = 0.5).The present study demonstrates that TNF-α inhibitors treatment ameliorates CMD in patients with established psoriasis not responding to long-term conventional therapy. These findings suggest that a therapy specifically targeted against inflammation is able to positively affect coronary microvascular function.

This review starts describing traditional Mediterranean, Ayurvedic and Chinese medicine systems. Then, the “psycho-neuro-endocrine-immunology” paradigm is examined and reasons for its increasing popularity in biological and medical scientific sciences. In particular, we focus on how this paradigm helps to understand and integrate in a modern view some seminal observations and symbolic languages from the past. Thanks to current technological possibilities, the future challenge will be to conduct medical and biological forefront research, able to successfully integrate traditional medicine into the newest therapeutic schemes. In conclusion, we propose some epistemological considerations based on different examples of therapeutic integration.

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.

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined &ldquo, epigenetic clock&rdquo, with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p &lt, 0.01) and healthy subjects (p &lt, 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

ADAMTS13 deficiency results in unusually large von Willebrand factor (ULVWF) multimers in the circulation and a higher risk of microthrombi due to high shear stress. In patients treated for acquired thrombotic thrombocytopenic purpura (TTP), a persistently severe ADAMTS13 deficiency (10%) in remission is associated with more relapses. A reduced plasma ADAMTS13 activity and increased VWF levels are associated with a higher risk of myocardial infarction. Assessing coronary flow reserve (CFR) enables a better cardiovascular risk stratification: a lower CFR correlates inversely with cardiovascular risk. The aim of the study was to establish whether patients with TTP in remission have an impaired coronary microcirculation, in terms of a lower CFR, and whether there is any correlation between ADAMTS13 activity, the presence of ULVWF multimers, and the occurrence of relapses.The clinical information and hemostatic parameters of 24 patients with TTP in remission managed at our center were analyzed. The CFR was assessed in a subgroup of the TTP patients and compared with a control group consisting of 50 healthy volunteers.The CFR was statistically lower in patients in remission of TTP than in controls, but there were no differences between TTP patients with normal and lower CFR. The occurrence of relapses correlated with the presence of ULVWF multimers and with a residual ADAMTS13 activity.When compared with healthy controls, TTP patients in remission have an impaired coronary microcirculation and the occurrence of relapses in the former reveal the presence of ULVWF multimers.

Purpose The aim of the study was to evaluate the trend of all the three type of rejection, cellular, humoral and mixed, during 6 years of follow-up, from 2012 to 2017 at the our transplant center, to evaluate pre-transplant clinical predictive factors for acute rejections and mortality. Methods We evaluated 149 patients heart transplanted adult patients transplanted from January 2012 and December 2017 at the university of Padua. Post transplant monitoring EMBs from 2012 to December 2018 were reevaluated . All the pre-transplant clinical were collected in a data base. The statistical analysis was subdivided in two parts. In the first part we analyzed the trend of the three different type of rejections, calculated the rate expressed as a average number of rejections for patients per year, with a Poisson distribution. In the second part we applied Machine learning method (ML), and algorithm Random Forest (RF) to analyzed the pre-transplant factors for the onset of acute rejections and for mortality. Results 1163 (57,2%) were negative for rejection, 31 (1,5%) positive for humoral rejection (pAMR+), 796 (39,2%) positive for ACR, 43 (2,1%) positive for mixed rejection. For all type of rejection there were a decreasing trend during the 6 years of follow up. The reduction in the mean number of rejection was 53,4% for acute rejection. Acute cellular rejection decreased significantly in relation to humoral rejection, in particular for the severe grade. Pre transplant predictive factors of cellular rejection were the pathology leading to heart transplant with a predictive value of 0,9%, age at transplant with a value of 0,8%. For humoral rejection the predictive factors were preforming antibodies anti HLA class II with a predictive value of 1,9%, previous pregnancies and miscarriage with a predictive value of 1,8% . The risk of mortality was influenced by age of donor with a risk value of 7,8%, the age at transplant with a risk value of 6,6%. Conclusion We have demonstrated that there is a decreasing trend of the three types of rejection during the last 6 years of follow up, in particular of cellular rejection. This is not in relation with changing in immunosuppressive drugs, but probably is due to pre and postoperative better management of heart transplant patients.

The heart can be viewed not just as muscle pump but also as an important checkpoint for a complex network of nervous, endocrine, and immune signals. The heart is able to process neurological signals independently from the brain and to crosstalk with the endocrine and immune systems. The heart communicates with the psyche through the neuro-endocrine-immune system in a highly integrated way, in order to maintain the homeostasis of the whole body with peculiarities specific to males and females.

Orthotopic heart transplantation (OHT) is the "gold standard" treatment for patients with end-stage heart failure, with approximately 5000 transplants performed each year worldwide. Heart transplantation survival rates have progressively improved at all time points, despite an increase in donor and recipient age and comorbidity and greater recipient urgency; according to the registry of the International Society of Heart and Lung Transplantation (ISHLT), the median survival of patients posttransplantation is currently 12.2 years.Long-term survival is sub-optimal, and outcomes after OHT remain constrained by the development of acute rejection and cardiac allograft vasculopathy (CAV). Moreover, donor organs are in short supply, making optimal organ utilization an ongoing priority. For these reasons, substantial interest continues to exist in identifying factors portending increased survival and improved organ utilization.

The heart can be viewed not just as muscle pump but also as an important checkpoint for a complex network of nervous, endocrine, and immune signals. The heart is able to process neurological signals independently from the brain and to crosstalk with the endocrine and immune systems. The heart communicates with the psyche through the neuro-endocrine-immune system in a highly integrated way, in order to maintain the homeostasis of the whole body with peculiarities specific to males and females.

Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly.We studied 40 acromegalic patients (23 male, age 52 ± 11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity.CFR was lower in patients than in controls (2.9 ± 0.8 vs. 3.7 ± 0.6, p 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) (p 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = -0.5, p 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381-898] μg/l versus 246 [186-484] μg/l, p 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8-13.7] μg/l versus 5 [2.8-8.9] μg/l, p = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR (p 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 (p = 0.009). In four patients with active disease (all with CFR2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder.Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly.

Myeloproliferative neoplasms are most commonly associated with venous thrombosis. Up to 60% of patients experience a thrombotic event in their lifetimes, including stroke or myocardial infarction. It is unclear whether pathogenetic factors linking essential thrombocythemia (ET) and polycythemia vera (PV) to thrombotic complications do play a role in the risk of coronary artery disease (CAD). We aimed to assess coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic patients with ET and PV. Fifty-two patients with ET (M/F 13/39, age 61 ± 7 years) and 22 patients with PV (M/F 13/9, age 60.4 ± 13 years) without clinical evidence of heart disease, and 50 controls matched for age and gender were studied. None had CAD. All control subjects were asymptomatic with no history of heart disease. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. In patients with ET and PV, CFR was lower than in controls (2.9 ± 0.94 and 2.2 ± 0.7 vs. 3.8 ± 0.7, P

Rationale, aims and objectives Heart failure (HF) is a concerning public health burden in Western society because, despite the improvement of medical treatments, it is still associated with adverse outcomes (high morbidity and mortality), resulting in one of the most expensive chronic disease in Western countries. Hospital admission particularly is the most expensive cost driver among the several resources involved in the management of HF. The aim of our study was to investigate the cost of hospitalization before and after the enrolment to a new strategy (GISC) in the management of patients with HF. Methods We enrolled a cohort of 90 patients. Patients were eligible to the study if they were hospitalized with a new diagnosis of HF or a diagnosis of decompensated HF. The enrolment to the study corresponded to the enrolment to the GISC intervention. We calculated the cost for every hospital admission at 6 and 12 months before and after the enrolment using the tariff paid for the diagnosis-related group. Results Comparing per-patient cumulative cost before and after the enrolment, we showed that patient's hospitalization was less expensive after the enrolment to the GISC intervention. The strategy resulted in an average cumulative estimated saving of €439 322.00 (95% CI €413 890.70; €464 753.40) at 6 months and of €832 276.80 (95% CI €786 863.70; €877 690.00) at 12 months after the enrolment. Conclusions We found out that the intervention was a cost-saving strategy for follow-up of the patients suffering from HF at 6 and 12 months after the enrolment compared with hospitalizations' cost before the recruitment.

Background Some patients with idiopathic pulmonary fibrosis (IPF) develop severe acute respiratory failure (ARF) requiring admission to an intensive care unit (ICU) and ventilatory support. A limited number of observational studies have reported that noninvasive ventilation (NIV) can be an effective treatment to support breathing and to prevent use of invasive mechanical ventilation in these patients. This study aimed to retrospectively investigate the clinical status and outcomes in IPF patients receiving NIV for ARF and to identify those clinical and laboratory characteristics, which could be considered risk factors for its failure. Methods This is a retrospective analysis of short-term outcomes in 18 IPF patients being administered NIV for ARF. This study was conducted in a 4-bed respiratory ICU (RICU) in a university hospital. Eighteen IPF patients who were administered NIV between January 1, 2005, and April 30, 2013, were included. The outcome measures are the need for endotracheal intubation despite NIV treatment and mortality rate during their RICU stay. The length of the patients' stay in the RICU and their survival rate following RICU admission were also evaluated. Results Noninvasive ventilation was successful in 8 patients and unsuccessful in 10 who required endotracheal intubation. All the patients in the NIV failure group died within 20.2 ± 15.3 days of intubation. The patients in the NIV success group spent fewer days in the RICU (11.6 ± 4.5 vs 24.6 ± 13.7; P = .0146). The median survival time was significantly shorter for the patients in the NIV failure with respect to the success group (18.0 [95% confidence interval {CI}, 9.0-25.0] vs 90.0 [95% CI, 65.0-305.0] days; P 900 pg/mL). Conclusions The outcome of IPF patients who were administered NIV was quite poor. The use of NIV was, nevertheless, found to be associated with clinical benefits in selected IPF patients, preventing the need for intubation and reducing the rate of complications/death. Elevated plasma NT-proBNP levels at the time of ICU admission is a simple clinical marker for poor NIV outcome.

Current risk stratification for sudden cardiac death (SCD) in nonischemic dilated cardiomyopathy (NIDC) relies on left ventricular (LV) dysfunction, a poor marker of ventricular electrical instability. Contrast-enhanced cardiac magnetic resonance has the ability to accurately identify and quantify ventricular myocardial fibrosis (late gadolinium enhancement [LGE]).To evaluate the impact of the presence and amount of myocardial fibrosis on arrhythmogenic risk prediction in NIDC.One hundred thirty-seven consecutive patients with angiographically proven NIDC were enrolled for this study. All patients were followed up for a combined arrhythmic end point including sustained ventricular tachycardia (VT), appropriate implantable cardioverter-defibrillator (ICD) intervention, ventricular fibrillation (VF), and SCD.LV-LGE was identified in 76 (55.5%) patients. During a median follow-up of 3 years, the combined arrhythmic end point occurred in 22 (16.1%) patients: 8 (5.8%) sustained VT, 9 (6.6%) appropriate ICD intervention, either against VF (n = 5; 3.6%) or VT (n = 4; 2.9%), 3 (2.2%) aborted SCD, and 2 (1.5%) died suddenly. Kaplan-Meier analysis revealed a significant correlation between the LV-LGE presence (not the amount and distribution) and malignant arrhythmic events (P.001). In univariate Cox regression analysis, LV-LGE (hazard ratio [HR] 4.17; 95% confidence interval [CI] 1.56-11.2; P = .005) and left bundle branch block (HR 2.43; 95% CI 1.01-5.41; P = .048) were found to be associated with arrhythmias. In multivariable analysis, the presence of LGE was the only independent predictor of arrhythmias (HR 3.8; 95% CI 1.3-10.4; P = .01).LV-LGE is a powerful and independent predictor of malignant arrhythmic prognosis, while its amount and distribution do not provide additional prognostic value. Contrast-enhanced cardiac magnetic resonance may contribute to identify candidates for ICD therapy not fulfilling the current criteria based on left ventricular ejection fraction.

Autoimmune rheumatic diseases (ARDs) form a heterogeneous group of disorders that include systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), idiopathic inflammatory myopathies (IIMs), and systemic vasculitis. Coronary microvascular dysfunction (CMD) is quite common in patients with ARDs and is linked to increased cardiovascular morbidity and mortality. Inflammation plays a crucial role in the pathogenesis of both accelerated atherosclerosis and CMD in ARDs, especially in patients affected by SLE and RA. In this regard, some studies have highlighted the efficacy of immunosuppressants and/or biologics in restoring CMD in these patients. By contrast, the role of inflammation in the pathogenesis of CMD-SSc appears to be much less relevant compared to endothelial dysfunction and microvascular ischemia, with calcium-channel blockers providing some benefits. Few studies have endeavored to assess the occurrence of CMD in IIMs and systemic vasculitis, thus warranting further investigations. The present review summarizes the current evidence on the occurrence of CMD in ARDs, focusing on the role of inflammation and possible therapeutic approaches.

Introduction Vascular erectile dysfunction (ED) is the expression of a systemic vascular disease and in particular of endothelial dysfunction. Dysfunctional endothelium plays also a significant role in the onset and progression of coronary artery vasculopathy (CAV). Aim This pilot study was designed to evaluate the prevalence and pathogenesis of ED and its correlation with CAV in heart transplanted male. Methods A total of 77 male heart transplanted patients (HTx) evaluated in our center (mean age 61.6 + 10.6 years) were enrolled in the study. Main Outcome Measures All subjects underwent accurate medical history collection, including lifestyle (cigarette smoking, dietary and sedentary habits, drug intake, and erectile function before cardiac transplantation), physical examination (body mass index and arterial pressure), biochemical blood tests (fasting glucose, total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and hormones (prolactin, luteinizing hormone and total testosterone). Furthermore, they were studied with penile, carotid, femoral echo-color Doppler ultrasonography and coronary angiogram. Results Incidence of ED was 24% before HTx and increased up to 65% after. Postischemic cardiomiopathy was an indication to HTx in ED group more frequently than in patients without ED (No-ED group) (45.1% vs. 20%). ED patients showed a lower peak systolic velocity, a higher cavernosal intima-media thickness (IMT), a higher prevalence of cavernosal plaques (26.7% vs. 5.2%, P P P P Conclusions We showed that ED is a frequent disease in HTx patients, more common when the original pathology is postischemic cardiomiopathy and associated with higher prevalence of cavernous plaques and CAV. Its evaluation should be integral to an HTx rehab program. Caretta N, Feltrin G, Tarantini G, D'Agostino C, Tona F, Schipilliti M, Selice R, Minicuci N, Gerosa G, and Foresta C. Erectile dysfunction, penile atherosclerosis, and coronary artery vasculopathy in heart transplant recipients. J Sex Med 2013;10:2295–2302.

A crucial prerequisite for an effective treatment of arrhythmias and cardiac conduction disturbances is the accurate identification of the specific rhythm disorder, with the identification of the clinical picture associated with it and the definition of precise, safe, and effective therapeutic targets. The clinical pictures fall into two broad categories: those that cause acute and transient electrophysiological abnormalities and those who, being chronic, provide the substrate for persistent or recurrent arrhythmias. In the first case we find the acute myocardial ischemia and the early stages of infarction, electrolyte disturbances, and the proarrhythmic action of certain drugs. The second category includes the chronic ischemic heart disease, cardiomyopathies, and the anatomical substrates for supraventricular arrhythmias. The cardiac rhythm disorders may be aggravated by hemodynamic, electrolyte, and metabolic changes and respiratory diseases that must be corrected in order to obtain an effective therapeutic response. The therapeutic strategy depends on the presence and the characteristics of the symptoms and the potential morbidity and mortality. Some arrhythmias can be very annoying but do not affect the long-term prognosis, while others with mild symptoms or absolutely asymptomatic are burdened with a poor prognosis.

About 20 million persons in the United States have coronary heart disease (CHD):10.2 million with angina pectoris and 8.5 million with myocardial infarction [1]. The lifetime risk of developing coronary artery disease for people in middle age is 50 % for men and 30 % for women [2]. According to a 2013–2014 World Health Organization study, over 4 million annual deaths are due to cardiovascular disease, of which ischemic heart disease is the main factor [3]. Mortality from CHD is expected to increase in developing countries from an estimated 9 million in 1990 to a projected 19 million by 2020 [4].

Congestive heart failure (CHF) is the inability of the heart to pump blood effectively throughout the body. Such dysfunction may concern myocardial contractility, the ventricular preload, the end-diastolic volume, an obstacle to cardiac ejection, or excessive afterload and heart rate. The main causes of heart failure are long-term hypertension, previous myocardial infarction, disorders of the heart valves, cardiomyopathies, and chronic lung disease. A condition of compensation can be precipitated by some aggravating factors such as increased metabolic demand, as in the case of thyrotoxicosis, anemia, arteriovenous shunt, fever, fluid overload, increased sodium intake, environmental temperature that is too high or too low, renal or hepatic failure, respiratory insufficiency, emotional stress, pregnancy, obesity, arrhythmias, pulmonary embolism, alcohol ingestion, nutrient deficiency, uncontrolled hypertensive states, and beta-blockers, anti-arrhythmic drugs, and sodium-retaining drugs such as steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) [1].

Hypertension, usually defined as persistent blood pressure (BP) at 140/90 mmHg or higher, affects about a quarter of the adult population in many countries and particularly in industrialized societies. Hypertension is a risk factor for most, if not all, cardiovascular diseases (coronary artery disease, myocardial infarction, thoracic and abdominal aneurysms, heart failure, and stroke) and renal failure. Hypertension is also associated with cognitive dysfunction, erectile dysfunction, and loss of vision. The higher the pressure is, the greater is the risk of complications [1].

BACKGROUND The aim of this study was to assess the significance of positive C4d capillary immunostaining of endomyocardial biopsies and its correlation to clinical outcome in adult heart transplant recipients. METHODS Nine hundred eighty-five endomyocardial biopsies from 107 heart transplant recipients were evaluated. Immunostaining for detection of intragraft C4d capillary deposition was performed on paraffin-embedded tissue using anti-human C4d polyclonal antibody. RESULTS Positive staining of C4d was present in 36 patients (34%) and antibody-mediated rejection in eight patients (7%). The patients were subdivided into four groups on the basis of their C4d, circulating antidonor antibodies (donor-specific antibodies [DSAs]), and graft function: group 1=C4d positive, DSA negative, and no graft dysfunction; group 2=C4d positive, DSA positive, and no graft dysfunction; group 3=C4d positive, DSA positive, and signs of graft dysfunction, and group 0 (control)=all negative. An higher mortality risk was found in C4d-positive patients, when compared with negative ones (unadjusted hazard ratios: group 1: 18, group 2: 61, and group 3: 32-fold risk; P

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS)or =0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 +/- 4 years post-HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 +/- 0.1 mm (range 0.03-1.8). MIT was higher in group A (1.16 +/- 0.3 mm vs. 0.34 +/- 0.07 mm, p0.0001). CFR was 3.1 +/- 0.8 in all patients and lower in group A (2.5 +/- 0.6 vs. 3.7 +/- 0.3, p0.0001). CFR was inversely related with MIT (r =-0.774, p0.0001). A cut point ofor =2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE-TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MITor =0.5 mm. CFR by CE-TTE may reduce the need for routine IVUS in HT.

Determination of coronary flow reserve (CFR) is increasingly being used in cardiac allograft vasculopathy (CAV). We aimed to identify determinants of CFR in heart transplantation (HT).CFR was measured by transthoracic echocardiography in 119 HT recipients (97 men, 22 women; 50 +/- 12 years of age at HT and 8 +/- 5 years post-HT). CFR was expressed as the ratio of hyperemic (adenosine infusion at a rate of 0.14 mg/kg) to basal diastolic flow velocity. Rejection scores (RS) on endomyocardial biopsy were calculated. Angiographic CAV was analyzed using a qualitative grading system. The coronary tree was divided into 17 traits and a CAV severity/diffusion index (SDI) was calculated for each patient, summing the scores assigned to all lesions.Upon multivariate analysis, CFR was related to CAV (p = 0.001), interventricular septum thickness (p = 0.01), ischemic heart disease pre-HT (p = 0.02) and SDI and SDI/segment number (p0.0001 and p = 0.003, respectively). In patients without CAV, CFR was related only to RS for severe grades (p = 0.01).Left ventricular hypertrophy, CAV and its severity/diffusion independently contribute to reduced CFR. In patients without angiographic CAV, CFR was only independently related to RS. Because a high rejection burden is associated with increased risk of CAV, CFR reduction may be an early marker of CAV. Microvascular dysfunction may contribute to the late morbidity and mortality seen in HT.

Objective.To evaluate plasma markers of endothelial cell activity in patients with pulmonary arterial hypertension (PAH) induced by connective tissue diseases (CTD) before and after 3-month administration of bosentan.Methods.We quantified E, L and P-selectin (sE-S, sL-S, sP-S), thrombomodulin (TM), monocyte-chemotactic protein 1 (MCP-1), human soluble CD40 ligand (sCD40L), and nitric oxide (NO) in 18 patients and 18 controls. We evaluated right ventricular systolic pressure (RVSP) and the 6-minute walk test (6-MWT).Results.All plasma markers but sL-S and TM at Time 0 were significantly higher in patients compared with controls. After 3 months of therapy, decreased levels were noted in NO (Time 0 24.05 ± 6.01 mmol/l, Time 1 13.92 ± 3.40 mmol/l; p < 0.001) and sCD40L (Time 0 1685.33 ± 866 pg/ml, Time 1 1055.11 ± 630.6 pg/ml; p = 0.017). In contrast, sP-S was significantly increased (Time 0 88.36 ± 47.76 ng/ml, Time 1 147.21 ± 94.43 ng/ml; p = 0.021). All patients remained stable in WHO class III, and in 9 patients we noted an improvement in 6-MWT. A correlation was found between Δ of RVSP and 6-MWT (r2= 0.5355, p < 0.001) as well as between Δ-sP-S and both Δ-6-MWT and Δ-RVSP. An increase sP-S level was found in 89% of nonresponder patients, whereas 55% of responders showed a stable or reduced sP-S level (p = 0.016 responder vs nonresponder).Conclusion.Treatment with bosentan for 3 months induced a beneficial effect by restoring endothelial function through a decrease in the markers of endothelial cell activity, leading to stabilization or improvement of severe PAH.

Cardiac allograft vasculopathy (CAV) is a complex disease of the vasculature of the grafted heart. It is the major cause of graft loss and mortality 1 year posttransplantation. Imaging techniques are the main tools for detecting and classifying CAV. The disease typically involves the epicardial coronary arteries and spreads into the intramyocardial branches. Pathologic features are heterogeneous and include concentric proliferative intimal lesions and vascular inflammation, which can be associated with conventional atherosclerotic plaques. The involvement of the small arteries and the microcirculation, the microvasculopathy, is responsible for structural and functional changes. Among the multiple risk factors associated with CAV, antibody-mediated rejection is currently recognized as the principle.

Patients with diabetes are at increased cardiovascular risk. Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice in patients with type 1 diabetes mellitus and diabetic nephropathy. We assessed coronary flow reserve (CFR) by transthoracic echocardiography as a marker of major adverse cardiac events (MACE) in SPKT patients.We studied 48 consecutive SPKT patients (28 male, age at SPKT 54 ± 8 years). Time from transplantation was 8.5 ± 3 years. Follow-up was 4.6 ± 1.8 years. Coronary flow velocity in the left anterior descending coronary artery was detected by Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤ 2 was considered abnormal and a sign of coronary microvascular dysfunction. MACE were cardiac death, myocardial infarction, and heart failure.CFR was 2.55 ± 0.8. CFR was ≤2 in 13 (27%) patients. CFR was lower in SPKT patients with MACE (2.1 ± 0.7 vs 2.7 ± 0.8, P = .03) and patients with MACE had a higher incidence of CFR ≤ 2 (P = .03). Time from transplantation was shorter in patients with MACE (P .0001). Patients with CFR ≤ 2 had a lower MACE-free survival (P = .03). CFR ≤ 2 predicted the risk of MACE (P = .007) independently from coronary artery disease and metabolic control. However, this predicted role is lost when adjusted for the time from transplantation, which plays a protective role (P = .001).In SPKT, CFR ≤ 2 may be a reliable marker for MACE, independent of coronary artery disease diagnosis. However, this role seems to be reduced over time. This finding suggests a gradual reduction of cardiovascular risk in SPKT patients.

Despite optimal medical therapy, a significant proportion of patients with heart failure (HF) do not improve and experience a recurrence of symptoms (such as breathlessness at rest or for minimal exertion) requiring repeated and prolonged hospitalizations for intensive management. Heart transplantation can improve both survival and quality of life in selected patients with severe HF. Referral for heart transplantation is recommended for potentially eligible patients with refractory end-stage HF. A practical overview of the prognostic assessment, clinical selection criteria, comorbidities, and contraindications is presented.

Background: The diagnostic value of natriuretic peptides in uremic cardiomyopathy has not been defined, nor has the effect of a hemodialysis (HD) session on peptides.Methods: We performed an observational study of 100 white adult outpatients in New York Heart Association class I–II, with neither diabetes nor ischemic heart disease, 50 of whom had idiopathic dilated cardiomyopathy (DCM) and 50 of whom had uremic cardiomyopathy and were undergoing HD. We measured plasma N-terminal proB-type natriuretic peptide (NT-proBNP), BNP, and atrial natriuretic peptide (ANP) both before and after a dialysis session. Doppler echocardiograms were evaluated. We performed multiple regression analysis on the logarithm of peptide concentrations using clinical, laboratory, and echocardio-Doppler data as explanatory variables.Results: Mean peptide concentrations were higher in the HD group, with an HD:DCM ratio of 25 for NT-proBNP and 5 for BNP and ANP. Peptides were correlated with each other (r > 0.85). After HD, NT-proBNP significantly increased by 14%, BNP decreased by 17%, and ANP decreased by 56%. Predialysis concentrations correlated with postdialysis values (r > 0.85). A multiple regression equation significantly fitted the observed peptide concentrations, both pre- and postdialysis, using the same set of 4 variables: disease group (DCM or HD), diastolic pattern, left atrial volume, and body mass index.Conclusions: Renal dysfunction was a confounder for natriuretic peptides, which were present in higher concentrations in the uremic patients with milder cardiac dysfunction than in those with idiopathic DCM without renal dysfunction. Left diastolic function pattern and atrial volume were cardiac determinants of peptide concentrations in DCM and HD.

Background— In autoimmune disorders, circulating autoantibodies identify healthy relatives at risk years before clinical presentation. Healthy relatives of patients with dilated cardiomyopathy (DCM) who have echocardiographic changes, including left ventricular enlargement or depressed fractional shortening at baseline, have increased medium-term risk for DCM development. Approximately one third of relatives have serum anti-heart autoantibodies (AHAs) at baseline; we intended to assess their potential role in predicting DCM development. Methods and Results— Baseline evaluation, including electrocardiography, echocardiography, and AHA, was performed in 592 asymptomatic relatives of 169 consecutive DCM patients (291 males and 301 females; mean age 36±16 years). Relatives were classified in accordance with published echocardiographic criteria; those who did not have DCM were followed up (median of 58 months). DCM among relatives was diagnosed by echocardiography at follow-up. Of the 592 individuals evaluated, 77% were assessed as normal, 4.4% as having DCM, and 19% as possibly affected on the basis of depressed fractional shortening without ventricular dilatation in 17 and left ventricular enlargement without systolic dysfunction in 94. Five-year follow-up of 311 relatives revealed that 26 had progressed (13 to DCM, 11 to left ventricular enlargement, and 2 to depressed fractional shortening). Relatives who developed DCM were more frequently AHA-positive than those who did not (69% versus 37%, P =0.02). Five-year probability of progression to DCM, among normal or possibly affected relatives, was higher in AHA-positive cases ( P =0.03). By Cox regression, positive AHAs at baseline were independent predictors of progression (RR 2.26, CI 1 to 5.1, P =0.03). Conclusions— Among healthy relatives of DCM patients, AHAs are independent predictors of disease development within 5 years.

Pheochromocytoma is a catecholamine-secreting tumor, with highly variable clinical expression leading to its designation as the great mimicker. A given patient may be completely asymptomatic or present with abdominal, metabolic, and cardiovascular manifestations because of catecholamine excess, such as paroxysmal or sustained hypertension and heart failure or life-threatening arrhythmias. Drugs interfering with adrenergic stimuli may worsen a patient’s condition. In our case report, a patient with a pheochromocytoma presented with acute and sudden heart failure and the delay in diagnosis led to a progression of catecolaminergic myocardial injury until mass resection. A 54-year-old woman with no significant past medical history went to the hospital because of nausea and prolonged vomit. On admission, she was treated with antiemetic drugs (metoclopramide) and suddenly developed acute heart failure that progressed to cardiogenic shock. She clinically improved with initiation of inotrope support. Serum laboratory testing was notable for leukocytosis and troponin I elevation (62.5ng/mL). The ECG showed no evidence of ischemia or prior infarct. Echocardiogram and cardiac MRI showed normal left ventricular dimensions and mild systolic dysfunction (left ventricular ejection …