Pacing-induced regional differences in adenosine receptors mRNA expression in a Swine model of dilated cardiomyopathy.

The adenosinergic system is essential in the mediation of intrinsic protection and myocardial resistance to insult; it may be considered a cardioprotective molecule and adenosine receptors (ARs) represent potential therapeutic targets in the setting of heart failure (HF). The aim of the study was to test whether differences exist between mRNA expression of ARs in the anterior left ventricle (LV) wall (pacing site: PS) compared to the infero septal wall (opposite region: OS) in an experimental model of dilated cardiomyopathy. Cardiac tissue was collected from LV PS and OS of adult male minipigs with pacing-induced HF (n = 10) and from a control group (C, n = 4). ARs and TNF-α mRNA expression was measured by Real Time-PCR and the results were normalized with the three most stably expressed genes (GAPDH, HPRT1, TBP). Immunohistochemistry analysis was also performed. After 3 weeks of pacing higher levels of expression for each analyzed AR were observed in PS except for A1R (A1R: C = 0.6±0.2, PS = 0.1±0.04, OS = 0.04±0.01, p<0.0001 C vs. PS and OS respectively; A2AR: C = 1.04±0.59, PS = 2.62±0.79, OS = 2.99±0.79; A2BR: C = 1.2±0.1, PS = 5.59±2.3, OS = 1.59±0.46; A3R: C = 0.76±0.18, PS = 8.40±3.38, OS = 4.40±0.83). Significant contractile impairment and myocardial hypoperfusion were observed at PS after three weeks of pacing as compared to OS. TNF-α mRNA expression resulted similar in PS (6.3±2.4) and in OS (5.9±2.7) although higher than in control group (3.4±1.5). ARs expression was mainly detected in cardiomyocytes. This study provided new information on ARs local changes in the setting of LV dysfunction and on the role of these receptors in relation to pacing-induced abnormalities of myocardial perfusion and contraction. These results suggest a possible therapeutic role of adenosine in patients with HF and dyssynchronous LV contraction

Cardiac magnetic resonance findings in patients with type 1 myotonic dystrophy

Abstract Funding Acknowledgements Type of funding sources: None. Background Heart disease is a major determinant of prognosis in type 1 myotonic dystrophy (DM1), second only to respiratory complications. Cardiac imaging, possibly including cardiac magnetic resonance (CMR), is recommended in patients with DM1. However, limited information is available on CMR findings and their prognostic significance in DM1. Methods We identified all patients with DM1 evaluated from 2009 to 2020 in a CMR laboratory with an established collaboration with a Neuromuscular Disorder Unit. Results Thirty-four patients were retrieved (21 males, aged 45 ± 12). At the time of CMR examination, 97% had neuromuscular symptoms (mean duration 16 ± 13 years), 12 (35%) presented with atrioventricular block (n = 11 1st degree, n = 1 2nd degree type 1), 15 (44%) with intraventricular conduction disturbances (n = 5 left bundle branch block, n = 5 right bundle branch block, n = 3 left anterior fascicular block, n = 2 other non-specific intraventricular conduction delay), 4 (12%) with atrial fibrillation or flutter. No patient had a device. At CMR, 5 (15%) patients had left ventricular (LV) systolic dysfunction (LV ejection fraction [LVEF] &lt;50%) and 5 (15%) a depressed right ventricular (RV) function (RVEF &lt;50%). Compared to age- and sex-specific reference values for our laboratory, 12 (35%) patients showed a decreased LV end-diastolic volume index (LVEDVi), 7 (21%) a decreased LV mass index (LVMi), and 29 (83%) a decreased LVMi/LVEDVi ratio. Nine (26%) patients had mid-wall late gadolinium enhancement (LGE, mean extent 4.5 ± 2.0% of LVM; n = 8 septal, n = 4 inferolateral, n = 2 inferior, n = 1 anterolateral), and 14 (40%) some areas of fatty infiltration (n = 9 involving the LV, n = 13 the RV). Native T1 in the interventricular septum (1,041 ± 53 ms) approached the upper reference limit (1,089 ms), and the extracellular volume was slightly increased (33 ± 2%, reference values &lt;30%). Over a median follow-up of 3.3 years (interquartile interval 1.6-4.7), 2 (6%) patients died, one for infectious and respiratory complications and the other for unknown causes, 5 (15%) patients underwent pacemaker implantation for conduction disturbances, and 4 (12%) had a documentation of high-risk (Lown class ≥4) ventricular ectopic beats (VEBs). Among all CMR variables collected, higher values of LVMi/LVEDVi ratio emerged as univariate predictor of all-cause death (p = 0.044). At logistic regression analysis, anteroseptal wall thickness was associated with the need for pacemaker implantation (p = 0.028), while LGE mass was associated with high-risk VEBs (p = 0.026). Conclusions Patients with DM1 display several structural and functional cardiac abnormalities, with variable degrees of cardiac muscle hypotrophy, fibrosis and fatty infiltration. The possibility to predict the need for pacemaker implantation, ventricular arrhythmias and all-cause or cardiovascular mortality should be verified in larger cohorts

High concentration of C-type natriuretic peptide promotes VEGF-dependent vasculogenesis in the remodeled region of infarcted swine heart with preserved left ventricular ejection fraction.

Abstract BACKGROUND: Vasculogenesis is a hallmark of myocardial restoration. Post-ischemic late remodeling is associated with pathology and function worsening. At the same time, neo-vasculogenesis helps function improving and requires the release of vascular endothelial growth factor type A (VEGF-A). The vasculogenic role of C-type natriuretic peptide (CNP), a cardiac paracrine hormone, is unknown in infarcted hearts with preserved left ventricular (LV) ejection fraction (EF). We explored whether myocardial VEGF-dependent vasculogenesis is affected by CNP. METHODS AND RESULTS: To this end, infarcted swine hearts were investigated by magnetic resonance imaging (MRI), histological and molecular assays. At the fourth week, MRI showed that transmural myocardial infarction (MI) affected approximately 13% of the LV wall mass without impairing global function (LVEF>50%, n=9). Increased fibrosis, metalloproteases and capillary density were localized to the infarct border zone (BZ), and were associated with increased expression of CNP (p=0.03 vs. remote zone (RZ)), VEGF-A (p<0.001 vs. RZ), BNP, a marker of myocardial dysfunction (p<0.01 vs. RZ) and the endothelial marker, factor VIII-related antigen (p<0.01 vs. RZ). In vitro, CNP 1000 nM promoted VEGF-dependent vasculogenesis without affecting the cell growth and survival, although CNP 100 nM or a high concentration of VEGF-A halted vascular growth. CONCLUSIONS: CNP expression is locally increased in infarct remodeled myocardium in the presence of dense capillary network. The vasculogenic response requires the co-exposure to high concentration of CNP and VEGF-A. Our data will be helpful to develop combined myocardial delivery of CNP and VEGF-A genes in order to reverse the remodeling process

Implementation of an epicardial implantable MEMS sensor for continuous and real-time postoperative assessment of left ventricular activity in adult minipigs over a short- and long-term period

The sensing of left ventricular (LV) activity is fundamental in the diagnosis and monitoring of cardiovascular health in high-risk patients after cardiac surgery to achieve better short- and long-term outcome. Conventional approaches rely on noninvasive measurements even if, in the latest years, invasive microelectromechanical systems (MEMS) sensors have emerged as a valuable approach for precise and continuous monitoring of cardiac activity. The main challenges in designing cardiac MEMS sensors are represented by miniaturization, biocompatibility, and long-term stability. Here, we present a MEMS piezoresistive cardiac sensor capable of continuous monitoring of LV activity over time following epicardial implantation with a pericardial patch graft in adult minipigs. In acute and chronic scenarios, the sensor was able to compute heart rate with a root mean square error lower than 2 BPM. Early after up to 1 month of implantation, the device was able to record the heart activity during the most important phases of the cardiac cycle (systole and diastole peaks). The sensor signal waveform, in addition, closely reflected the typical waveforms of pressure signal obtained via intraventricular catheters, offering a safer alternative to heart catheterization. Furthermore, histological analysis of the LV implantation site following sensor retrieval revealed no evidence of myocardial fibrosis. Our results suggest that the epicardial LV implantation of an MEMS sensor is a suitable and reliable approach for direct continuous monitoring of cardiac activity. This work envisions the use of this sensor as a cardiac sensing device in closed-loop applications for patients undergoing heart surgery

Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention.Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV- partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of approximately 12% from the true vaccine efficacy.CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs

Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions

Mapping of the longitudinal relaxation time (T1) and extracellular volume (ECV) offers a means of identifying pathological changes in myocardial tissue, including diffuse changes that may be invisible to existing T1-weighted methods. This technique has recently shown strong clinical utility for pathologies such as Anderson- Fabry disease and amyloidosis and has generated clinical interest as a possible means of detecting small changes in diffuse fibrosis; however, scatter in T1 and ECV estimates offers challenges for detecting these changes, and bias limits comparisons between sites and vendors. There are several technical and physiological pitfalls that influence the accuracy (bias) and precision (repeatability) of T1 and ECV mapping methods. The goal of this review is to describe the most significant of these, and detail current solutions, in order to aid scientists and clinicians to maximise the utility of T1 mapping in their clinical or research setting. A detailed summary of technical and physiological factors, issues relating to contrast agents, and specific disease-related issues is provided, along with some considerations on the future directions of the field. Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions. Available from: https://www.researchgate.net/publication/317548806_Towards_accurate_and_precise_T1_and_extracellular_volume_mapping_in_the_myocardium_a_guide_to_current_pitfalls_and_their_solutions [accessed Jun 13, 2017]