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Poor response to PTSD treatment and the disorder's chronicity among combat veterans may at least partly be due to ambivalence about the need to change PTSD symptoms and related problems. The PTSD Motivation Enhancement (ME) Group described in this article was developed to address problem acknowledgement among veterans in treatment for PTSD. This manualized, brief therapy intervention is conceptually based on the Stages of Change and draws on Motivational Interviewing techniques. The goal of the PTSD ME Group is to help patients make decisions about the need to change any behaviors and coping styles not previously recognized as problematic so that patients will perceive PTSD intervention components as more relevant, thereby fostering greater engagement in treatment and more adaptive post-treatment coping. The authors discuss theory and research findings related to the group, the structure and content of the intervention, and important clinical issues to consider when implementing the group. [ABSTRACT FROM AUTHOR]

BACKGROUND: In elite athletes left ventricular (LV) morphological changes are predicted to alter passive pressure/volume characteristics by reducing myocardial stiffness and increasing compliance. OBJECTIVE: To investigate the utility of a new Doppler tissue index based on the pressure volume relation ((E/Ea)/LVEDD), which provides a measure of myocardial stiffness, and to assess its usefulness in detecting cardiac adaptation in elite rowers. METHODS: Thirty-six international rowers who had trained intensively and a control group of 30 sedentary subjects, matched for age and sex, were enrolled in the study. LV septal and posterior wall thickness, mass, chamber size, transmitral Doppler peak early (E) and late (A) diastolic filling velocities and isovolumic relaxation times were measured. Early diastolic myocardial velocities (Ea) were averaged from four sites at the mitral annulus; diastolic stiffness was assessed with the use of three indices E, Ea and the LV end-diastolic diameter in diastole (LVEDD). The ratio, (E/Ea)/LVEDD, provides a new index of diastolic stiffness. Rowers were further divided into two groups based on the presence or absence of left ventricular hypertrophy (LVH) 12 mm. RESULTS: No significant difference in Ea was found between the two groups, but there was a difference in the stiffness index, which remained after adjustment for body surface area and heart rate (controls 1.48 (0.3) vs athletes 1.17 (0.34), p = 0.016). No difference in stiffness index was found between the groups with LVH 12 mm (1.11 (0.32) vs 1.17 (0.34), respectively, p = 0.68) CONCLUSIONS: Intense training reduces myocardial stiffness despite the development of LVH. [ABSTRACT FROM AUTHOR]

The author presents the importance of defense policy in the present scenario. He is critical about several threats to Europe which includes terrorism to climate change, nuclear proliferation and cyberattack. Also investigated are the expenses, complications and unpredictable scenario of defense in the present global era.

Background: Myocardial strain-change in myocardial fibre length over the cardiac cycle-is a measure of cardiac muscle function. It is obtained using conventional techniques such as echocardiography and magnetic resonance imaging, adding additional clinical information to augment the current techniques., Methods: A narrative review of the current relevant literature with respect to myocardial strain, with a focus on strain measured by echocardiography., Results: Myocardial strain identifies global and regional abnormalities in myocardial function and differentiates types of cardiomyopathy. It is an earlier marker of myocardial disease than ejection fraction and is predictive of cardiovascular adverse events. Accurate measurement requires high-quality images and experienced practitioners., Conclusion: This review explains advantages and disadvantages of myocardial strain imaging and explains why, through adding increased precision without additional burden, it should be a standard part of cardiac assessment., (© 2022. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Background: This systematic review and meta-analysis compares long-term outcomes follow-up data comparing drug-eluting balloons (DEBs) and drug-eluting stents (DESs) in interventional treatment of small coronary artery disease (<3 mm). Methods: A systematic review was undertaken along with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was 1-3-year performance of DEB versus DES in major adverse cardiac events. Secondary outcomes include all-cause mortality, MI, cardiac death, vessel thrombosis, major bleeding, target vessel revascularisation and target lesion revascularisation. Two independent reviewers extracted data. All outcomes used the Mantel-Haenszel and random effects models. ORs are presented with a 95% CI. Results: Of 4,661 articles, four randomised control trials were included (1,414 patients). DEBs demonstrated reduced rates of non-fatal MI at 1 year (OR 0.44; 95% CI [0.2-0.94]), and BASKET-SMALL 2 reported a significant reduction in 2-year bleeding rates (OR 0.3; 95% CI [0.1-0.91]). There was no significant difference in all other outcomes. Conclusion: Long-term follow-up of DEB and DES use in small coronary arteries demonstrates DEBs be comparable with DESs in all outcomes at 1, 2 and 3 years of follow-up. A significant reduction was found in rates of non-fatal MI at 1 year in the DEB arm, and a reduction in major bleeding episodes at 2 years in the BASKET-SMALL 2 trial. These data highlight the potential long-term utility of novel DEBs in small coronary artery disease revascularisation., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2023, Radcliffe Cardiology.)

Background: High-sensitivity troponin-T (HS-cTnT) levels are often measured in patients presenting with atrial fibrillation (AF), with many subjected to unnecessary invasive assessments. The significance of a normal or mildly raised HS-cTnT in this context is poorly understood. This study aimed to determine the predictive value of HS-cTnT for significant coronary artery disease (CAD) in new AF with rapid ventricular response. We also compared the discriminative ability of HS-cTnT to suspected angina for significant CAD., Methods: We examined patients presenting with new AF to two tertiary Irish centers in a defined period. Those included had HS-cTnT taken at presentation and subsequent ischemic evaluation., Results: Of 5350 cases screened for inclusion, 281 were deemed eligible. Of these, 148 and 133 patients had a positive and negative index HS-cTnT, respectively. Of those with negative HS-cTnT, 13 (9.8%) had significant CAD versus 51 (34.5%) with positive HS-cTnT (P < 0.001). Positive Hs-cTnT status remained significant upon multivariate analysis (OR, 2.9; 95% CI, 1.37-6.14; P = 0.005). A similar model where HS-cTnT was replaced with suspected angina produced an OR of 1.64 (95% CI, 0.75-3.59; P = 0.213). A logistic model determined optimal cutoff value for HS-cTnT to be less than 30 ng/l, producing a negative predictive value of 91.8% and area under the receiver operative curve of 83.36., Conclusion: HS-cTnT exhibits potential as an effective screening biomarker to predict nonsignificant CAD in new rapid AF, allowing more targeted and rationalized ischemic testing. HS-cTnT may also be a more accurate predictor of significant CAD than clinically suspected stable angina.Graphical abstract: http://links.lww.com/MCA/A540., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Deformation imaging represents a method of measuring myocardial function, including global longitudinal strain (GLS), peak atrial longitudinal strain (PALS) and radial strain. This study aimed to assess subclinical improvements in left ventricular function in patients undergoing transcatheter aortic valve implantation (TAVI) by comparing GLS, PALS and radial strain pre and post procedure., Methods: We conducted a single site prospective observational study of 25 patients undergoing TAVI, comparing baseline and post-TAVI echocardiograms. Individual participants were assessed for differences in GLS, PALS and radial strain in addition to changes in left ventricular ejection fraction (LVEF) (%)., Results: Our results revealed a significant improvement in GLS (mean change pre-post of 2.14% [95% CI 1.08, 3.20] p = 0.0003) with no significant change in LVEF (0.96% [95% CI - 2.30, 4.22], p = 0.55). There was a statistically significant improvement in radial strain pre and post TAVI (mean 9.68% [95% CI 3.10, 16.25] p = 0.0058). There was positive trend towards improvements in PALS pre and post TAVI (mean change of 2.30% [95% CI - 0.19, 4.80] p = 0.068)., Conclusion: In patients undergoing TAVI, measuring GLS and radial strain provided statistically significant information regarding subclinical improvements in LV function, which may have prognostic implications. The incorporation of deformation imaging in addition to standard echocardiographic measurements may have an important role in guiding future management in patients undergoing TAVI and assessing response., (© 2023. The Author(s).)

Individual monitoring of radiation workers is essential to ensure compliance with legal dose limits and to ensure that doses are As Low As Reasonably Achievable. However, large uncertainties still exist in personal dosimetry and there are issues with compliance and incorrect wearing of dosimeters. The objective of the PODIUM (Personal Online Dosimetry Using Computational Methods) project was to improve personal dosimetry by an innovative approach: the development of an online dosimetry application based on computer simulations without the use of physical dosimeters. Occupational doses were calculated based on the use of camera tracking devices, flexible individualised phantoms and data from the radiation source. When combined with fast Monte Carlo simulation codes, the aim was to perform personal dosimetry in real-time. A key component of the PODIUM project was to assess and validate the methodology in interventional radiology workplaces where improvements in dosimetry are needed. This paper describes the feasibility of implementing the PODIUM approach in a clinical setting. Validation was carried out using dosimeters worn by Vascular Surgeons and Interventional Cardiologists during patient procedures at a hospital in Ireland. Our preliminary results from this feasibility study show acceptable differences of the order of 40% between calculated and measured staff doses, in terms of the personal dose equivalent quantity H p (10), however there is a greater deviation for more complex cases and improvements are needed. The challenges of using the system in busy interventional rooms have informed the future needs and applicability of PODIUM. The availability of an online personal dosimetry application has the potential to overcome problems that arise from the use of current dosimeters. In addition, it should increase awareness of radiation protection among staff. Some limitations remain and a second phase of development would be required to bring the PODIUM method into operation in a hospital setting. However, an early prototype system has been tested in a clinical setting and the results from this two-year proof-of-concept PODIUM project are very promising for future development., (Creative Commons Attribution license.)

Background: Iron-overload cardiomyopathy initially manifests with diastolic dysfunction and can progress to dilated cardiomyopathy if untreated. Previous studies have shown that patients with primary and secondary hemochromatosis can have subclinical left ventricle dysfunction with abnormalities on strain imaging. This study aimed to evaluate the relationship between cardiac T2* values and myocardial-wall strain in patients with hereditary hemochromatosis (HH) at the time of diagnosis and after a course of venesection treatment., Materials and Methods: Baseline cardiac magnetic resonance (CMR) at 3 T was performed in 19 patients with newly diagnosed HH with elevated serum ferritin levels and repeated after a course of treatment with venesection. Quantitative T2* mapping and strain analysis were performed offline using dedicated relaxometry fitting and feature-tracking software., Results: The majority (84%) of patients had normal baseline myocardial T2* values (mean 19.3 ms, range 8.9 to 31.2 ms), which improved significantly after venesection (mean 24.1 ms, range 11 to 38.1 ms) ( P =0.021). Mean global radial strain significantly improved from 25.0 (range: 15.6 to 32.9) to 28.3 (range: 19.8 to 35.8) ( P =0.001) and mean global circumferential strain improved, decreasing from -15.7 (range: -11.1 to -19.2) to -17.1 (range: -13.0 to -20.1) ( P =0.001)., Conclusion: Patients with HH may have normal T2* values in the presence of subclinical left ventricle dysfunction, which can be detected by abnormal radial and circumferential strain. As strain imaging improves following venesection in HH, it may serve as a useful biomarker to guide treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Studying variability in the care provided to secondary prevention coronary heart disease (CHD) outpatients can identify interventions to improve their outcomes., Methods: We studied outpatients who had an index CHD event in the preceding 6-24 months. Eligible CHD events included acute coronary syndrome (ACS) and coronary revascularisation for stable chronic coronary syndrome (CCS). Site training was provided by a core team and data were collected using standardised methods., Results: Between 2017 and 2019, we enrolled 721 outpatients at nine Irish study sites; 81% were men and mean age was 63.9 (SD ±8.9) years. The study examination occurred a median of 1.16 years after the index CHD event, which was ACS in 399 participants (55%) and stable-CCS in 322. On examination, 42.5% had blood pressure (BP) >140/90 mm Hg, 63.7% had low-density lipoprotein cholesterol (LDL-C) >1.8 mmol/L and 44.1% of known diabetics had an HbA1c >7%. There was marked variability in risk factor control, both by study site and, in particular, by index presentation type. For example, 82% of outpatients with prior-ACS had attended cardiac rehabilitation versus 59% outpatients with prior-CCS (p<0.001) and there were also large differences in control of traditional risk factors like LDL-C (p=0.002) and systolic BP (p<0.001) among outpatients with prior-ACS versus prior-CCS as the index presentation., Conclusions: Despite international secondary prevention guidelines broadly recommending the same risk factor targets for all adults with CHD, we found marked differences in outpatient risk factor control and management on the basis of hospital location and index CHD presentation type (acute vs chronic). These findings highlight the need to reduce hospital-level and patient-level variability in preventive care to improve outcomes; a lesson that should inform CHD prevention programmes in Ireland and around the world., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: CT coronary angiography (CTCA) is a well-validated clinical tool in the evaluation of chest pain. In our institution, CTCA availability was increased in January 2020, and subsequently, expanded further to replace all exercise testing during the COVID-19 pandemic. Our objective was to assess the impact of increased utilisation of CTCA on length of stay in patients presenting with chest pain in the prepandemic era and during the COVID-19 pandemic., Methods: Study design was retrospective. Patients referred for cardiology review between October 2019 and May 2020 with chest pain and/or dyspnoea were broken into three cohorts: a baseline cohort, a cohort with increased CTCA availability and a cohort with increased CTCA availability, but after the national lockdown due to COVID-19. Coronary angiography and revascularisation, length of stay and 30-day adverse outcomes were assessed., Results: 513 patients (35.3% female) presented over cohorts 1 (n=179), 2 (n=182), and 3 (n=153). CTCA use increased from 7.8% overall in cohort 1% to 20.4% in cohort 3. Overall length of stay for the patients undergoing CTCA decreased from a median of 4.2 days in cohort 1 to 2.5 days in cohort 3, with no increase in 30 days adverse outcomes. Invasive coronary angiogram rates were 45.8%, 39% and 34.2% across the cohorts. 29.6% underwent revascularisation in cohort 1, 15.9% in cohort 2 and to 16.4% in cohort 3., Conclusions: Increased CTCA availability was associated with a significantly reduced length of stay both pre-COVID-19 and post-COVID-19 lockdown, without any increase in 30-day adverse outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hereditary haemochromatosis is often not diagnosed until adulthood. Iron overload cardiomyopathy initially results in diastolic dysfunction and can result in arrhythmias and irreversible cardiac failure if untreated. The aim of this study was to investigate whether patients with newly diagnosed hereditary haemochromatosis without signs of heart failure exhibit subclinical alterations of cardiac function and to determine if cardiac function improved after 1 year of venesection., Methods: Baseline echocardiography was performed on 25 patients with newly diagnosed hereditary haemochromatosis with elevated serum ferritin levels. The test was repeated after 1 year of treatment with venesection. Tissue Doppler imaging (TDI) and deformation (strain) imaging using speckle tracking were performed. Left atrial force was measured according to the Newtonian principle, in which force (dynes) = mass × acceleration. Left atrial force was calculated by the Manning method expressed as ρ × 0.53 × mitral annular orifice area × (peak A velocity) 2 ., Results: Radial strain showed a significant improvement after 1 year of venesection (increase from 38.8 to 52.6). The LAF showed a significant decrease after 1 year of venesection (median decrease = 0.6 (IQR 0, 1.60), p = 0.0004). Iso-volumetric relaxation time (IVRT) decreased significantly in patients after 1 year of venesection (decrease from 107.4 ± 16.2 to 97.68 ± 15.4 ms, p (0.0187))., Conclusion: Among all measurements, radial strain, IVRT and left atrial force were shown to significantly improve following a 1-year course of venesection, suggesting that these parameters could be used to identify subclinical cardiac dysfunction in patients with iron overload secondary to hereditary haemochromatosis and to guide intensification of venesection therapy.

Background: TAVI is a percutaneous approach to aortic valve replacement in high surgical risk patients deemed inoperable., Aim: To evaluate the early and mid-term outcomes for an Irish TAVI cohort over a six-year period at St James's Hospital and Blackrock Clinic, Dublin, Ireland., Results: In total 147 patients, 56% male with an average age of 82 underwent TAVI between December 2008 and December 2014. Thirty day, one year and two year survival was 90.5%, 83% and 71% respectively. Major vascular complications and renal failure were the biggest predictors of mortality at 30 days (p = 0.02). We observed a pacing rate of 13.5%, the majority in patients who had Medtronic Corevalve implants (p < 0.05). With increasing procedural experience there was a reduction in length of stay from 10 days to 7.5 days., Conclusion: This review, the first of its kind in Ireland showed favorable rates of 30 day and one year and two year survival post TAVI with procedural success and complication rates similar to international registry data.

Genetic variation along the length of a chromosome can influence the transcription of a gene. In a heterozygous individual, this may lead to one chromosome producing different levels of RNA, compared to its paired chromosome, for a given gene. Allelic differences in gene expression can offer insight into the role of variation in transcription, and subsequently infer a route to conferring disease risk. This phenomenon is known as allele expression imbalance or AEI, which may be assayed using a PCR-based method that includes the quantification of the relative dosage of each allele (e.g., 5' exonuclease assays, TaqMan™). Importantly, in heterozygous individuals the resolution of expression imbalance is performed within a controlled system; the comparison of the alternate allele is reported relative to the wild-type, as the experiment can be performed within a single sample, controlled for background genetic information. Alternative methods for the detection of AEI include Primer-extension MALDI-TOF (Sequenom MassARRAY(®)), Next-Generation Sequencing, and SNP genotyping arrays. Here we present the methods used for the TaqMan™ approach and include a description of the SNP identification, allele-specific PCR, and analytic methods to convert allele amplification metrics to relative allele dosage.

Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterized by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic phenomena are a focus of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.

Background: Multiple studies in adults have shown that osteochondral allograft transplantation is an effective treatment option for large chondral and osteochondral defects of the knee. Limited outcome data are available on osteochondral allografts in the pediatric and adolescent patient populations., Purpose: To describe a 28-year experience with osteochondral allograft transplantation in patients younger than 18 years with a focus on subjective outcome measures, return to activities, and allograft survivorship., Study Design: Case series; Level of evidence, 4., Methods: A total of 39 patients (43 knees) underwent fresh osteochondral allograft transplantation for treatment of chondral and osteochondral lesions. Twenty-six male and 17 female knees with a mean age of 16.4 years (range, 11.0-17.9 years) at index surgery were followed-up at a mean of 8.4 years (range, 1.7-27.1 years). Thirty-four knees (79%) had at least 1 previous surgery. The most common underlying causes of the lesions were osteochondritis dissecans (61%), avascular necrosis (16%), and traumatic chondral injury (14%). Mean allograft size was 8.4 cm(2). The most common allograft location was the medial femoral condyle (41.9%), followed by the lateral femoral condyle (35%). Each patient was evaluated with the International Knee Documentation Committee pain, function, and total scores; a modified Merle d'Aubigné-Postel (18-point) scale; and Knee Society function score. Failure was defined as revision osteochondral allograft or conversion to arthroplasty., Results: Five knees experienced clinical failure at a median of 2.7 years (range, 1.0-14.7 years). Four failures were salvaged successfully with another osteochondral allograft transplant. One patient underwent prosthetic arthroplasty 8.6 years after revision allograft. Graft survivorship was 90% at 10 years. Of the knees whose grafts were in situ at latest follow-up, 88% were rated good/excellent (18-point scale). The mean International Knee Documentation Committee scores improved from 42 preoperatively to 75 postoperatively, and the Knee Society function score improved from 69 to 89 (both P < .05). Eighty-nine percent of patients reported "extremely satisfied" or "satisfied.", Conclusion: With 88% good/excellent results and 80% salvage rate of clinical failures with an additional allograft, osteochondral allograft transplantation is a useful treatment option in pediatric and adolescent patients.

The lateral habenula (LHb) is activated by aversive stimuli and the omission of reward, inhibited by rewarding stimuli and is hyperactive in helpless rats-an animal model of depression. Here we test the hypothesis that congenital learned helpless (cLH) rats are more sensitive to decreases in reward size and/or less sensitive to increases in reward than wild-type (WT) control rats. Consistent with the hypothesis, we found that cLH rats were slower to switch preference between two responses after a small upshift in reward size on one of the responses but faster to switch their preference after a small downshift in reward size. cLH rats were also more risk-averse than WT rats-they chose a response delivering a constant amount of reward ("safe" response) more often than a response delivering a variable amount of reward ("risky" response) compared to WT rats. Interestingly, the level of bias toward negative events was associated with the rat's level of risk aversion when compared across individual rats. cLH rats also showed impaired appetitive Pavlovian conditioning but more accurate responding in a two-choice sensory discrimination task. These results are consistent with a negative learning bias and risk aversion in cLH rats, suggesting abnormal processing of rewarding and aversive events in the LHb of cLH rats.

Background: Latest research shows that the lower resting values of right ventricular (RV) myocardial % strain may represent a physiologic change rather than subclinical myocardial damage. Therefore, we assessed load-independent changes to the RV as a consequence of high intensity training by measuring the Isovolumic acceleration (IVA) of the free wall of the RV in conjunction with NT pro-BNP measured by an electrochemiluminescence assay., Methods: Seventeen controls (mean age 27 ± 4), 24 soccer footballers (mean age 24 ± 4), and 18 elite rowers (mean age 22 ± 4) were studied. Left ventricular (LV) and RV % strain were measured using two-dimensional (2D) speckle based automated functional imaging (AFI) software. RV free wall IVA was measured using pulsed-wave tissue Doppler at the lateral tricuspid annulus. Standard 2D echo were used to measured RV parameters including the Tei index (systolic and diastolic function) and the total annular plane systolic excursion (TAPSE) of the RV annulus. NT pro-BNP was measured by an electrochemiluminescence assay., Results: The RV diameter was increased in the footballers and elite rowers compared with controls (P < 0.001). RV wall size was greater in the elite rowers compared with controls and footballers (P = 0.002). The peak IVA of the RV was higher in the rowers, compared with the footballers and to controls (P < 0.001). The mean LV and RV % myocardial strain were lower in the elite athletes and the footballers compared with controls (P < 0.001). There was no difference in RV Tei index, levels of BNP, and TAPSE across all subjects., Conclusions: This study showed a significant increase in IVA of the RV of athletes despite reduced myocardial % strain and normal levels in NT-proBNP. This suggests that the decrease in % strain is not a consequence of myocardial damage, but may represents a part of the physiological response to endurance exercise. Therefore, a reduced IVA in a remodeled RV could herald a pathological response., (© 2013, Wiley Periodicals, Inc.)

Therapeutic hypothermia (TH) is a process of cooling a patient post ventricular tachycardia/ventricular fibrillation (VT/VF) cardiac arrest to 32-34 degrees C for 24 hours. This improves neurological outcome and is part of current guidelines. Hypothermia prolongs QT interval, which can precipitate torsades de pointes (TdP). We performed a retrospective review of all patients who received TH in our hospital over a period of 2 years to assess the effect of TH on the corrected OT interval (QTc) and any possible pro-arrhythmia. A total of 13 patients received TH. QTc prolonged in all patients with an average of 80.3 + 57.2 ms., and up to 109.8 + 80.4 ms in patients who received Amiodarone concurrently. No TdP was seen in any patient. We conclude that TH is safe, though careful monitoring of the OTc interval is advisable especially with concurrent use of QT prolonging drugs.

The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic, and suppressed by serotonin. Behaviorally, activation of this pathway is aversive, consistent with its role as an "antireward" signal. Our demonstration of an excitatory projection from the basal ganglia to the LHb explains how LHb-projecting basal ganglia neurons can have similar encoding properties as LHb neurons themselves. Our results also provide a link between antireward excitatory synapses and serotonin, a neuromodulator implicated in depression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Periprosthetic valve leak can develop as a complication of valve replacement surgery and may manifest as symptomatic valvular regurgitation, heart failure, or haemolysis. We report a case of severe mitral periprosthetic valve leak requiring a two-stage percutaneous closure technique with multiple Amplatzer® III vascular plugs., (Copyright © 2011 Wiley-Liss, Inc.)

Objectives: Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing., Background: Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation., Methods: We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain., Results: We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells., Conclusions: Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the long-term effects of standard chemotherapy on myocardial function in asymptomatic breast cancer survivors using two-dimensional speckle tracking echocardiography., Methods: Seventy women (chemotherapy group) aged 54+/-8 years who had received anthracycline treatment with (n=19) or without (n=51) adjuvant trastuzumab up to 6 years previously, and 50 female controls were studied. Left ventricular systolic (ejection fraction (EF%), peak systolic myocardial excursion, (Sm)) and diastolic (peak mitral E and A velocities, six-point average of mitral annular E' velocities) function, 2D global and regional longitudinal and radial strain were determined using standard 2D Doppler and tissue Doppler echocardiographic methods and speckle tracking software., Results: Despite normal EF% (62+/-4% vs 60+/-3%, p=0.051) the chemotherapy group had reduced E/A ratios (0.9+/-0.3 vs 1.1+/-0.3, p=0.003), global E' (10.2+/-2 vs 11.2+/-2.3, p=0.036), global Sm (9.0+/-1.3 vs 9.6+/-1.3, p=0.029) and global longitudinal 2D strain (-18.1+/-2.2 vs -19.6+/-1.8, p=0.0001) in comparison with controls. In 18 (26%) of the chemotherapy group, global longitudinal strain was below the lower limit of the control group. Cigarette smoking was a negative predictor of longitudinal strain, but only in the chemotherapy group. Radial strain did not differ significantly between the two groups. There were no significant differences in EF%, global Sm and longitudinal strain between trastuzumab-treated individuals and controls., Conclusions: Subclinical systolic and diastolic myocardial abnormalities were present in asymptomatic breast cancer survivors up to 6 years after standard chemotherapy. Cigarette smoking had a negative effect on longitudinal strain in these individuals. Adjuvant trastuzumab treatment did not appear to have an additive adverse impact on myocardial function in the medium-long term.

Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high-risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high-risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high-risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow-limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high-risk but non flow-limiting plaque to establish patient-specific targeted therapy and to refine plaque stabilizing strategies in the future., (Copyright 2009 Wiley-Liss, Inc.)

Inflammation is an important element in the development and destabilization of atherosclerotic plaque. Using a high sensitivity multiplex assay, previously untested in the context of atherosclerotic disease, we determined serum concentrations of GM-CSF, IFNgamma, IL-1beta, IL-2, IL-10, IL-12p70, TNF alpha, IL-6, and IL-8 in 48 Myocardial Infarction (MI) patients, 14 Unstable Angina (UA) patients and 12 healthy controls. IFNgamma levels were significantly higher in MI compared to UA (p=0.0091) and Control groups (p=0.0014). IL-10 also showed higher expression levels between MI, UA groups and Controls (p=0.0299).This up-regulation may reflect the extent of plaque instability and/or rupture in MI patients.Our observations provide evidence that IFNgamma and IL-10 merit further investigation in atherosclerotic disease states as potential markers of disease and therapeutic targets.

Objectives: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients., Background: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction., Methods: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction., Results: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP., Conclusions: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling.

Background: Functional and intrinsic mitral valve (MV) abnormalities are common in hypertrophic cardiomyopathy (HCM); however, morphologic characteristics constituting indications for surgical intervention are incompletely defined. This study was conducted to define the echocardiographic features of MV pathology in patients with HCM and relate these to repairability of the MV, MV procedures performed, durability of repair, and survival., Methods: From 1986 to 2003, 851 patients with HCM underwent operation, and 115 had a concomitant MV procedure. Detailed analysis of their 784 transthoracic and transesophageal echocardiograms, performed intraoperatively and postoperatively, was conducted. Outcomes were assessed by cross-sectional follow-up., Results: Sixty-seven patients (58%) underwent MV repair, and 48 (42%) had MV replacement. The mean left ventricular outflow tract peak gradient was 70 +/- 50 mm Hg. Systolic anterior motion was present in 95%. Valve abnormalities were degenerative in 36 (31%), myxomatous in 23 (20%), papillary muscle in 23 (20%), restrictive chordal in 22 (19%), restrictive leaflet in 80 (70%), and long leaflet in 64 (56%). Patients undergoing MV repair had higher prevalence of long leaflets and degenerative MV pathology. The anterior mitral leaflet was 3.0 +/- 0.49 cm in the repair group vs 2.5 +/- 0.40 cm in the replacement group (p = 0.0001). MV replacement patients were older, more symptomatic, and had more renal dysfunction and lower hematocrits. By 3 years, 91% of patients with a repair were free of reoperation., Conclusions: Intrinsic MV pathology is frequently observed in HCM patients with symptomatic obstruction who undergo myectomy. Echocardiography can identify MV features predictive of successful valve repair. Repair, although durable, is feasible in only about half of patients.

Dilated cardiomyopathy (DCM), characterized by ventricular dilation and decreased systolic function, is estimated to be of genetic origin in up to 50% of cases. In the present study, we investigated the role of two genes, encoding the Z line proteins PDZ and LIM domain protein 3 (PDLIM3) and myozenin-1 (MYOZ1), in the etiology of DCM. The coding regions of PDLIM3 and MYOZ1 were first amplified from the genomic DNA of 185 unrelated DCM patients by polymerase chain reaction (PCR), followed by denaturing high-performance liquid chromatography (DHPLC) analysis. The samples that exhibited abnormal peaks on DHPLC were re-amplified, purified and sequenced using a Big-Dye Terminator cycle sequencing system. Interestingly, a 2-bp insertion (178insCA) in exon 2 of PDLIM3 was identified in one patient who presented with DCM during pregnancy and died a year later awaiting heart transplant. No other significant mutations were found in either PDLIM3 or MYOZ1. The mutation probably resulted in an unstable protein, since no exogenous protein could be detected in transfected murine myoblastoid cells by immunohistochemical or Western blot analyses. We conclude that mutations in PDLIM3 and MYOZ1, encoding myocyte Z line proteins, do not play any significant role in the genetic etiology of idiopathic DCM. The exact mechanism by which the mutation identified in the present study is linked to DCM phenotype remains unknown. The hemodynamic burden of pregnancy and/or other genetic or environmental factors could have precipitated heart failure symptoms in an individual with defective myocardial cytoarchitecture.

Cardiac amyloidosis typically presents with diastolic heart failure, but asymmetrical septal hypertrophy with outflow tract obstruction has been described. We illustrate the case of a 71-year-old woman with biopsy-proven cardiac amyloidosis and severe medical comorbidities with refractory severe heart failure who had asymmetric septal hypertrophy, systolic anterior motion (SAM) of the mitral valve, and a resting left ventricular outflow tract gradient of 86 mm Hg, increasing to 102 mm Hg on Valsalva maneuver. She underwent percutaneous transluminal septal myocardial ablation (PTSMA) with a dramatic resolution of her SAM and outflow tract obstruction, confirmed by intracavitary pressure wire measurements. PTSMA is technically feasible in this context, and correction of outflow tract obstruction may represent a new therapeutic target in cardiac amyloidosis.