Chamber Dilation Research Articles

Systemic and heart autonomous effects of sphingosine Δ4 desaturase deficiency in lipotoxic cardiac pathophysiology.

ABSTRACTLipotoxic cardiomyopathy (LCM) is characterized by cardiac steatosis, including the accumulation of fatty acids, triglycerides and ceramides. Model systems have shown the inhibition of ceramide biosynthesis to antagonize obesity and improve insulin sensitivity. Sphingosine Δ4 desaturase (encoded by ifc in Drosophila melanogaster) enzymatically converts dihydroceramide into ceramide. Here, we examine ifc mutants to study the effects of desaturase deficiency on cardiac function in Drosophila. Interestingly, ifc mutants exhibited classic hallmarks of LCM: cardiac chamber dilation, contractile defects and loss of fractional shortening. This outcome was phenocopied in global ifc RNAi-mediated knockdown flies. Surprisingly, cardiac-specific ifc knockdown flies exhibited cardiac chamber restriction with no contractile defects, suggesting heart autonomous and systemic roles for ifc activity in cardiac function. Next, we demonstrated that ifc mutants exhibit suppressed Sphingosine kinase 1 (Sk1) expression. Ectopic overexpression of Sk1 was sufficient to prevent cardiac chamber dilation and loss of fractional shortening in ifc mutants. Partial rescue was also observed with cardiac- and fat-body-specific Sk1 overexpression. Finally, we showed that cardiac-specific expression of Drosophila inhibitor of apoptosis (dIAP) also prevented cardiac dysfunction in ifc mutants, suggesting a role for caspase activity in the observed cardiac pathology. Collectively, we show that spatial regulation of sphingosine Δ4 desaturase activity differentially affects cardiac function in heart autonomous and systemic mechanisms through tissue interplay.

P1490 Congenital right coronary artery fistula into right atrium diagnosed with help of multimodality imaging

Abstract Introduction Coronary artery fistula (CAF) is an anomaly in which abnormal connections are present between the coronary artery and the cardiac chambers or a major vessel. It is an uncommon anomaly with an estimated incidence of 1 in 50,000 live births and usually occurs in isolation. We report a case of CAF into right atrium in a patient who admitted to our outpatient department with dyspnea and fatique. With help of transthoracic echocardiography (TTE), transesophageal echocardiography (TOE) and cardiac computerized tomography (CCT) we put the definite diagnosis and decided to close this fistula percutaneously with a PDA occluder. Case A 43-year- old male admitted to our outpatient department with complaints of exertional dyspnea and fatique for 5 years. His physical examination revealed a holosystolic murmur on the aortic valve area. His TTE showed enlarged right heart chambers with a high pulmonary artery systolic pressure (50 mmHg) and a suspicious flow from the aortic root into right atrium. Qp/Qs was 2.1. TOE depicted a shunt between aorta and right atrium as well, we couldn’t truly demonstrate the connection though . In order to define the defect precisely, we performed a cardiac CT. Cardiac CT clearly showed a markedly dilated and mildly tortuous and calcified fistula arising from the osteal part of right coronary artery draining into right atrium. Right coronary artery was thin and there was no stenosis. Cardiac CT helped us to exclude coronary arter disease as well. As it was suitable to close percutaneously, we decided to close it with a PDA occluder. Conclusion CAF is a rare, generally congenital anomaly and may cause right heart chamber dilatation and pulmonary hypertension if the diagnosis is missed. It is important to support and clarify the underlying pathology with help of other cardiovascular imaging modalities like cardiac CT and cardiac magnetic resonance imaging (CMR), if TTE and TOE cannot demonstrate us the exact pathology.In our case our choice of extra method was cardiac CT, as we wanted to exclude accompanying coronary artery disease at the same time. In today’s era, the use of multimodality imaging is increasing with a tremendous rate and it helps clinical cardiologists, cardiovascular imaging specialists and interventional cardiologists all. Abstract P1490 Figure. 2D,3D TOE and CCT images of CAF

Expanding the donor pool for congenital heart disease transplant candidates by implementing 3D imaging-derived total cardiac volumes.

Heart transplant waitlist mortality remains high in infants <1year of age and among those with CHD. Currently, the median accepted donor-to-recipient weight percentage is approximately 130% of the recipient's weight. We hypothesized that patients with CHD may accept a larger organ using novel 3D-derived imaging data to estimate donor and recipient TCV. A single-center, retrospective study was performed using CT data for 13 patients with CHD and 94 control patients. 3D visualization software was used to create digital 3D heart models that provide an estimate of TCV. In addition, echocardiograms obtained prior to cross-sectional imaging were reviewed for presence of ventricular chamber dilation. Sixty-two percent (8/13) of patients with CHD had 3D-derived TCV resulting in a weight that was >130% larger than their actual weight. This was seen in single-ventricle patients following Blalock-Taussig shunt and Fontan palliation, and patients with biventricular repair. Of those, 75% (6/8) had reported moderate-to-severe ventricular chamber dilation by echocardiogram or cardiac magnetic resonance imaging. In a large portion of patients with CHD, 3D-derived TCV place the recipient at a higher listing weight than their actual weight. We propose obtaining cross-sectional imaging to better assess TCV in a recipient, which may increase the donor range for CHD recipients and improve organ utilization in pediatrics.

Persistent Severe Bradycardia During Liver Transplantation

Abstract Background Cardiac electrophysiological disturbances are common in end-stage liver disease (ESLD) patients. It is challenging for anesthesiologists to detect and manage cardiac abnormalities during orthotopic liver transplantation (OLT). Case report A 58-year-old male patient, diagnosed with hepatitis B cirrhosis with hepatocellular carcinoma (MELD score 24) and chronic kidney disease stage V (no hemodialysis requirement), was scheduled for combined OLT with kidney transplantation. He had mild anemia, thrombocytopenia, normal electrolytes, and INR 1.47. CXR showed cardiomegaly with blunting of the bilateral costophrenic angle. ECG presented sinus bradycardia (rate, 45/min) with prolonged QT interval. Echocardiography revealed dilatation of all cardiac chambers with ejection fraction of 65%, good RV function, and mild pulmonary hypertension (mPAP, 29 mmHg) without significant valvular abnormality. After uneventful induction and intubation, noninvasive cardiac output monitoring and central venous catheter were applied. During surgery, his heart rate was 35–40 bpm with no response to high-dose inotropic agents. External cardiac pacing pads were attached. ABG showed mild acidosis without electrolyte abnormality. Reperfusion went successfully despite persistent severe bradycardia. He remained intubated and was transferred to the ICU. Twelve-lead ECG was performed. A cardiologist diagnosed cirrhotic cardiomyopathy with high vagal tone. Transvenous pacing was inserted at a rate of 80/min for 48 hours; his heart rate subsequently rose to 50–60 bpm without treatment. Extubation was 36 hours after surgery, and discharge on postoperative day 10 Conclusions Cardiac abnormalities in ESLD patients present in various forms. Proper preoperative assessment, adequate monitoring, and good team communication result in good patient outcomes

Diagnostic methods for the canine idiopathic dilated cardiomyopathy: A narrative evidence-based rapid review

Idiopathic dilated cardiomyopathy (DCM) is an important etiology of mortality and morbidity in dogs and its diagnosis relies on systolic dysfunction, chambers dilation, electrical instability and congestion. During the last decades veterinary cardiologists have been joining efforts to obtain diagnostic resources to correctly identify canine DCM in the preclinical stage. Unfortunately, most diagnostic resources have been used with the support of research with weak evidence, without high quality methodologies such as systematic reviews or meta-analysis. Therefore, the support of evidence-based medicine is tailored by empiricism and diagnostic criteria lose'out the ability to properly classify dogs suffering DCM. The presentation of the evidence in medicine is established by multiple sources and the most reliable source has been the presentation of evidence-based medicine from systematic reviews and meta-analysis. Rapid reviews can be interpreted as a pragmatic approach to systematic reviews and although a rapid review follows most of the critical steps of a systematic review to provide timely evidence, some components of a systematic review process are either simplified or omitted. The objective of this narrative evidence-based rapid review is twofold. First: To recognize and to stratify the level of evidence offered by rigorous selected papers about the diagnosis of DCM. Second: To classify the degree of clinical recommendation of the diagnostic resources available.

Nicotinamide riboside kinase-2 alleviates ischemia-induced heart failure through P38 signaling

Nicotinamide riboside kinase-2 (NRK-2), a muscle-specific β1 integrin binding protein, predominantly expresses in skeletal muscle with a trace amount expressed in healthy cardiac tissue. NRK-2 expression dramatically increases in mouse and human ischemic heart however, the specific role of NRK-2 in the pathophysiology of ischemic cardiac diseases is unknown.We employed NRK2 knockout (KO) mice to identify the role of NRK-2 in ischemia-induced cardiac remodeling and dysfunction. Following myocardial infarction (MI), or sham surgeries, serial echocardiography was performed in the KO and littermate control mice. Cardiac contractile function rapidly declined and left ventricular interior dimension (LVID) was significantly increased in the ischemic KO vs. control mice at 2 weeks post-MI. An increase in mortality was observed in the KO vs. control group. The KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric analysis. Consistently, histological assessment revealed an extensive and thin scar and dilated LV chamber accompanied with elevated fibrosis in the KOs post-MI. Mechanistically, we observed that loss of NRK-2 enhanced p38α activation following ischemic injury. Consistently, ex vivo studies demonstrated that the gain of NRK-2 function suppresses the p38α as well as fibroblast activation (α-SMA expression) upon TGF-β stimulation, and limits cardiomyocytes death upon hypoxia/re‑oxygenation.Collectively our findings show, for the first time, that NRK-2 plays a critical role in heart failure progression following ischemic injury. NRK-2 deficiency promotes post-MI scar expansion, rapid LV chamber dilatation, cardiac dysfunction and fibrosis possibly due to increased p38α activation.

ECHOCARDIOGRAPHIC STUDY OF RIGHT VENTRICLE CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS OF DIFFERENT SEVERITY

Chronic obstructive pulmonary disease (COPD) characterized by interminable air flow limitation that is not fully reversible COPD includes chronic bronchitis, emphysema, and chronic asthmatic bronchitis. Chronic obstructive pulmonary disease as a complex disease with various systemic manifestations and one of the co-morbidity linked with COPD is cardiovascular disease. Hypoxic vasoconstriction and alterations in pulmonary microvasculature, which are both observed in COPD patients, leads to an increase in pulmonary vascular resistance. As a result, this increase in right ventricular (RV) after load causes right ventricular remodeling, including chamber dilatation and wall hypertrophy and ultimately to functional deterioration. The aim of this study to evaluate the right ventricular changes that develop secondary to COPD using GOLD guidelines and echocardiographic findings .This cross-sectional study involved 134 patients who presented to the pulmonary disease outpatient clinic with COPD. We assessed the right ventricular changes in COPD patients of different severity using echocardiography .COPD patients shown change in the right ventricular dimensions as the severity of COPD increases and right ventricular function as well. It is also observed that frequency of pulmonary hypertension also increased as the severity of COPD increases. The study shows high prevalence of cardiac co-morbidities such as RV dysfunction and pulmonary hypertension in COPD patients. The severity of complications increases with severity of COPD and makes a linear relation.&#x0D; Keywords: Echocardiography, ECG, COPD

Effect of hydroethanolic extract of Piper betle in isoproterenol induced cardiac hypertrophy

Cardiac hypertrophy (CH) is a condition in which myocardial mass is increased beyond the normal range due to irreversible fibrotic events that lead to various complication like ventricular chamber dilation, thinning of the internal walls and extensive myocardial damage. In this study, the cardioprotective potential of the hydro-ethanolic extract of Piper betle (P. betle) was evaluated against cardiac hypertrophy induced by isoproterenol in male albino Wistar rats. Isoproterenol (10 mg/kg b.w., i.p., 7 days) induced cardiac hypertrophy in experimental rats which were simultaneously treated with the standard drug losartan (50 mg/ kg b.w., oral., 7 days) and hydro-ethanolic extract of P. betle (200 mg/kg b.w., oral., 7 days). Biochemical estimations revealed increased levels of glucose, protein, cholesterol, serum creatinine, cardiac maker enzymes (SGOT; SGPT and LDH), reduced enzymic antioxidants (SOD, CAT, GPx) and serum were observed during CH which were reciprocated to normal when treated with plant extract. Histopathological analysis of the heart tissue (left ventricles) showed repairment of cellular architecture with reduced stiffened cell layers and necrosis in plant extract administered rats thereby indicating the anti-hypertrophic potential of P. betle.

P826Peri-procedural treatment with high dose Rosuvastatin reduces soluble TNF receptor 1 in patients treated with primary percutaneous coronary intervention for ST elevation myocardial infarction

Abstract Background The extent of cardiac injury in ST elevation myocardial infarction (STEMI) depends on the level of inflammation and subsequent immune cell recruitment. An inflammatory phase that is disproportionately prolonged, of excessive magnitude, or insufficiently suppressed, can lead to sustained tissue damage and improper healing, promoting infarct expansion, adverse remodelling and chamber dilatation. Soluble TNF receptor 1 (sTNFR-1) is believed to mirror systemic pan-inflammatory status more closely than a single cytokine antigenic level. sTNFR-1 levels might give prognostic information, independent from and, at the same time, additive with some well-recognized outcome predictors such as left ventricular ejection fraction. Purpose We hypothesised that sTNFR-1 and other inflammatory markers could be modulated by statins. Methods Plasma levels of inflammatory markers were measured at baseline, 2 days, 7 days and 2 months in consecutive patients with first time STEMI with single vessel disease. Twenty-five patients (treatment group (TG)) were treated with 80 mg Rosuvastatin daily with first dose before primary percutaneous coronary intervention (PCI) whereas the control group (CG) consisted of 34 patients in whom treatment with 20 mg simvastatin daily were initiated the day after PPCI. Results sTNFR1 increased during the first 48 hours following PCI and this increase was larger in the CG compared with the TG (0.22±0.30 ng/mL vs 0.08±0.19 ng/nmL, p=0.025). The difference in increase during one week was only borderline statistically significant (0.21±0.30 ng/mL vs 0.08±0.26 ng/mL, p=0.081). These differences in the kinetics of sTNRF-1 were mirrored by changes in Pentraxin 3 (PTX3) between groups from baseline to 1 week, CG vs TG. (0.28±0.70 μmol/l vs 0.10±0.05 ng/mL, p=0.014) and at 2 months (−0.42±0.56 ng/mL vs 0.08±0.60 μmol/l, p=0.032) Conclusion High dose Rosuvastatin therapy initiated peri-procedural during PPCI for STEMI reduces pan inflammation as reflected by sTNFR1 and is associated with a less abrupt fall in PTX3 at 1 week and 2 months supporting recent research suggesting that PTX3 plays a cardiovascular protective effect in cardiovascular disease and healing. Acknowledgement/Funding Western Norway Regional Health Authority

A genetic mouse model of severe iron deficiency anemia reveals tissue-specific transcriptional stress responses and cardiac remodeling

Iron is a micronutrient fundamental for life. Iron homeostasis in mammals requires sustained postnatal intestinal iron absorption that maintains intracellular iron concentrations for central and systemic metabolism as well as for erythropoiesis and oxygen transport. More than 1 billion people worldwide suffer from iron deficiency anemia (IDA), a state of systemic iron insufficiency that limits the production of red blood cells and leads to tissue hypoxia and intracellular iron stress. Despite this tremendous public health concern, very few genetic models of IDA are available to study its progression. Here we developed and characterized a novel genetic mouse model of IDA. We found that tamoxifen-inducible deletion of the mammalian iron exporter ferroportin exclusively in intestinal epithelial cells leads to loss of intestinal iron absorption. Ferroportin ablation yielded a robust phenotype of progressive IDA that develops in as little as 3 months following disruption of intestinal iron absorption. We noted that, at end-stage IDA, tissue-specific transcriptional stress responses occur in which the heart shows little to no hypoxic and iron stress compared with other peripheral organs. However, morphometric and echocardiographic analysis revealed massive cardiac hypertrophy and chamber dilation, albeit with increased cardiac output at very low basal heart rates. We propose that our intestine-specific ferroportin knockout mouse model of end-stage IDA could be used in future studies to investigate IDA progression and cell-specific responses to hypoxic and iron stress.

SEX-DIFFERENCES IN FETAL PROGRAMMING OF CARDIOMYOPATHY INDUCED BY HYPERTENSIVE DISORDERS OF PREGNANCY IN MICE

Hypertensive disorders can reach one in ten pregnancies worldwide. They account for a quarter of all preterm births and low birth weight, significantly increasing rates of maternal and neonatal morbidity and mortality Children born to hypertensive pregnancies can develop special clinical features that are consistent with a preterm or accelerated aging process with signs of cardiac remodeling as early as childhood. Significant heart shape and ventricular geometrical alterations have been described in growth-restricted fetuses of hypertensive pregnancies suggesting an extended impact on fetal heart development and programming of heart diseases. The aim of this study was to develop a new ultrasound imaging protocol to describe, for the first time in a genetic mice model of maternal hypertension and superposed preeclampsia, sex-differences in the fetal programming of cardiomyopathy. We have performed echocardiography imaging in fetuses of n=4/group transgenic pregnant mice overexpressing human renin and angiotensinogen and controls (C57BL/6) at 18.5 gestational days. Fetal images were adjusted by intracranial diameter as a surrogate intrauterine marker of fetal growth. Genotype-negative offspring were followed up to 40-day postnatal, when echocardiography was performed in male and female offspring (n=8/group) of control and transgenic mothers. Data are presented as average±SD of control vs hypertensive-pregnancies, compared using student t-test. Fetuses of hypertensive mothers have larger LV mass (3.2±0.4 vs 4.3±0.3 mg, P < .001) with thicker LV walls (0.32±0.02 vs 0.45±0.04 mm, P < .01) and dilated chamber (0.82±0.02 vs 0.97±0.07 mm, P < .01) compared to fetuses of control mothers, these parameters remaining significant after adjusting by intracranial diameter. Into adulthood, both male and female offspring to hypertensive mothers have greater LV mass (male: 88±19 vs 139±62 mg P < .01; female: 74±21 vs 104±27 P < .05) and wall thickness (male: 0.70±0.03 vs 0.95±0.22 mm P < .05; female: 0.63±0.15 vs 0.91±0.17 mm P < .05) compared to control offspring. However, in females only, these changes were added by an important LV chamber dilation (3.3±0.3 vs 3.9±0.4 mm P < .05) and reduced fraction of shortening (48±9 vs 33±4 % P < .01), indicating systolic ventricular dysfunction only in female offspring in comparison to controls. Our findings demonstrate for the first time, the feasibility of using fetal and postnatal echocardiography to assess the programming of cardiomyopathy in mice exposed to hypertensive pregnancies. Further, we have described that the transgenic model of maternal hypertension and preeclampsia can induce significant fetal heart remodeling changes that can persist into adulthood in offspring, and in females only, into an accelerated programming of cardiomyopathy.

Abstract 148: Sex-Differences in Fetal Programming of Cardiomyopathy Induced by Hypertensive Disorders of Pregnancy in Mice

Background: Hypertensive disorders reach one in ten pregnancies worldwide, significantly increasing rates of maternal and neonatal morbidity and mortality. Children born to hypertensive pregnancies can develop special clinical features that are consistent with a preterm or accelerated aging process with signs of cardiac remodeling as early as childhood. The aim of this study was to develop a new ultrasound imaging protocol to describe sex-differences in the fetal programming of cardiomyopathy in a genetic mice model of maternal hypertension and superposed pre-eclampsia. Methods and Results: We have performed fetal echocardiography imaging in n=4/group transgenic mice overexpressing human renin+angiotensinogen versus controls (C57BL/6) at 18.5 gestational days. Fetal images were adjusted by intracranial diameter as an intrauterine marker of fetal growth. Male and female offspring (n=8/group/sex) were followed by echocardiography up to 40 postnatal days. Data are average±SD. Fetuses of hypertensive mothers had thicker left ventricular (LV) walls (0.32±0.02 vs 0.45±0.04mm, P&lt;.01) and more dilated chamber (0.82±0.02 vs 0.97±0.07mm, P&lt;.01), with larger LV mass (3.2±0.4 vs 4.3±0.3mg, P&lt;.001) compared to controls, which remained significant after adjusting for intracranial diameters. Into adulthood, male and female offspring of hypertensive mothers had greater LV mass (male: 88±19 vs 139±62mg, P&lt;.01; female: 74±21 vs 104±27, P&lt;.05) and wall thickness (male: 0.70±0.03 vs 0.95±0.22mm, P&lt;.05; female: 0.63±0.15 vs 0.91±0.17mm, P&lt;.05) compared to control offspring. However, females had additional LV chamber dilation (3.3±0.3 vs 3.9±0.4mm, P&lt;.05) and reduced fraction of shortening (48±9 vs 33±4%, P&lt;.01) compared to controls, indicating LV systolic dysfunction and cardiomyopathy only in in this offspring group but not in males. Conclusion: Our results demonstrate the feasibility of using fetal and postnatal echocardiography to evaluate the programming of cardiomyopathy in mice exposed to hypertensive pregnancy. In addition, we showed that fetal cardiac remodeling changes persisted into adulthood in offspring of hypertensive mothers, which in females has further progressed to an accelerated cardiomyopathy programming.

Contribution of DNA methylation in chronic stress-induced cardiac remodeling and arrhythmias in mice.

It is recognized that stress can induce cardiac dysfunction, but the underlying mechanisms are not well understood. The present study aimed to test the hypothesis that chronic negative stress leads to alterations in DNA methylation of certain cardiac genes, which in turn contribute to pathologic remodeling of the heart. We found that mice that were exposed to chronic restraint stress (CRS) for 4 wk exhibited cardiac remodeling toward heart failure, as characterized by ventricular chamber dilatation, wall thinning, and decreased contractility. CRS also induced cardiac arrhythmias, including intermittent sinus tachycardia and bradycardia, frequent premature ventricular contraction, and sporadic atrioventricular conduction block. Circulating levels of stress hormones were elevated, and the cardiac expression of tyrosine hydroxylase, a marker of sympathetic innervation, was increased in CRS mice. Using reduced representation bisulfite sequencing, we found that although CRS did not lead to global changes in DNA methylation in the murine heart, it nevertheless altered methylation at specific genes that are associated with the dilated cardiomyopathy (DCM) (e.g., desmin) and adrenergic signaling of cardiomyocytes (ASPC) (e.g., adrenergic receptor-α1) pathways. We conclude that CRS induces cardiac remodeling and arrhythmias, potentially through altered methylation of myocardial genes associated with the DCM and ASPC pathways.-Zhang, P., Li, T., Liu, Y.-Q., Zhang, H., Xue, S.-M., Li, G., Cheng, H.-Y.M., Cao, J.-M. Contribution of DNA methylation in chronic stress-induced cardiac remodeling and arrhythmias in mice.

Natural History of Cardiomyopathy in Adult Dogs With Golden Retriever Muscular Dystrophy.

BackgroundDuchenne muscular dystrophy (DMD) is an X‐linked disease that causes progressive muscle weakness. Affected boys typically die from respiratory or cardiac failure. Golden retriever muscular dystrophy (GRMD) is genetically homologous with DMD and causes analogous skeletal and cardiac muscle disease. Previous studies have detailed features of GRMD cardiomyopathy in mostly young dogs. Cardiac disease is not well characterized in adult GRMD dogs, and cardiac magnetic resonance (CMR) imaging studies have not been completed.Methods and ResultsWe evaluated echocardiography and CMR in 24 adult GRMD dogs at different ages. Left ventricular systolic and diastolic functions, wall thickness, and myocardial strain were assessed with echocardiography. Features evaluated with CMR included left ventricular function, chamber size, myocardial mass, and late gadolinium enhancement. Our results largely paralleled those of DMD cardiomyopathy. Ejection fraction and fractional shortening correlated well with age, with systolic dysfunction occurring at ≈30 to 45 months. Circumferential strain was more sensitive than ejection fraction in early disease detection. Evidence of left ventricular chamber dilatation provided proof of dilated cardiomyopathy. Late gadolinium enhancement imaging showed DMD‐like left ventricular lateral wall lesions and earlier involvement of the anterior septum. Multiple functional indexes were graded objectively and added, with and without late gadolinium enhancement, to give cardiac and cardiomyopathy scores of disease severity. Consistent with DMD, there was parallel skeletal muscle involvement, as tibiotarsal joint flexion torque declined in tandem with cardiac function.ConclusionsThis study established parallels of progressive cardiomyopathy between dystrophic dogs and boys, further validating GRMD as a model of DMD cardiac disease.

Abstract 825: Attenuation of Cardiac Fibrosis by Scleraxis Gene Deletion Improves Pressure Overload-Induced Cardiac Remodeling

Cardiac fibrosis is a significant independent risk factor for heart failure with increasing incidence. The fibrotic myocardium shows increased arrhythmogenesis, and poor pumping and relaxation due to greater tissue stiffness. A critical step in this process is the conversion of fibroblasts to myofibroblasts, which are responsible for excessive extracellular matrix (ECM) production; limiting this conversion may reduce fibrosis and restore cardiac function. We previously reported that the transcription factor scleraxis, following mechanical stretch or TGFβ signaling, is both sufficient and necessary to convert fibroblasts to myofibroblasts by direct transcriptional control of myofibroblast genes including collagens, α-smooth muscle actin and fibronectin. In a pressure overload transverse aorta constriction (TAC) mouse model analyzed by echocardiography, we found that fibroblast-specific scleraxis gene deletion prior to TAC using a tamoxifen-inducible TCF21-Cre/loxP approach attenuated both systolic (LV ejection fraction, fractional shortening) and diastolic (early and late filling velocity) dysfunction, as well as chamber dilation, despite persistent hypertrophy. Functional improvement was matched by an almost complete attenuation of cardiac fibrosis (Masson’s trichrome; qPCR and western blots for fibrillar collagens and ED-A fibronectin). Scleraxis deletion also prevented induction of the myofibroblast marker periostin, suggesting a failure of scleraxis-null fibroblasts to convert to myofibroblasts. We next tested if scleraxis deletion 4 weeks post-TAC could reverse subsequent remodeling at 8 weeks post-TAC. Adverse remodeling occurred in all animals 4 weeks post-TAC (prior to scleraxis deletion), but cardiac function and chamber dimensions subsequently declined further in scleraxis-intact animals, while scleraxis-deleted animals showed preserved or improved cardiac function and morphology. Our results demonstrate that scleraxis is required for the initiation and progression of cardiac fibrosis, and that reducing fibrosis alone improves cardiac performance and morphology even in the presence of persistent pressure overload. Scleraxis is thus an important target for anti-fibrotic therapy development.

Adaptive Reductions in Left Ventricular Diastolic Compliance Protect the Heart From Stretch-Induced Stunning

Swine subjected to 2weeks of repetitive pressure overload (RPO) exhibited significant myocyte loss, but leftventricular (LV) systolic function was preserved, and chamber dilatation did not occur. Instead, myocardialremodeling characterized by myocyte hypertrophy and interstitial fibrosis led to a marked reduction in LV diastolic compliance, which protected the heart from stretch-induced myocyte injury and preserved LVejection fraction without anatomic LV hypertrophy. These results support a novel paradigm that links cardiacadaptations to RPO with the pathogenesis of reduced LV diastolic compliance and may explain howLVstiffening can occur in the absence of sustained hypertension or anatomic hypertrophy.

New formula for cardiothoracic ratio for the diagnosis of cardiomegaly on post-mortem CT.

The cardiothoracic ratio (CTR) is considered to be a reliable detector of cardiomegaly on computed tomography for livings, with a threshold of 0.5. Our study aimed to establish an adjusted CTR-based score to predict cardiac hypertrophy at PMCT. We selected adult's autopsy cases examined between 2009 and 2016. Two groups were considered, a normal heart weight group and an overweighed heart group. The CTR was measured on axial images. Logistic regression analysis was performed to investigate the discriminating power of the CTR between groups when adjusted to the confounding factors. Sixty-six cases with normal heart weight and 94 cases with overweighed heart were analyzed. The factors associated to the cardiac hypertrophy are CTR (p value 0.003, OR 3.57), BMI (p value 0.055, OR 1.09), age (p value < 0.001, OR 1.67), and gender (p value 0.002, OR 4.85). The area under the ROC curve (receiver operating characteristic curve) was 0.77 when using CTR alone and 0.88 when considering BMI, age, and gender. In conclusion, CTR alone cannot be used to discriminate between normal heart weight and overweighed heart at PMCT. A new formula has been developed, including age, gender, and BMI. Dilatation of the cardiac chambers, which is a subjective evaluation, influences the CTR measure and could be not related to a pre-existing cardiac hypertrophy. This new score formula allows to overpasses this subjective step. We proposed a cut-off value of the score of 32 for the diagnosis of cardiac hypertrophy. The Internet/smartphone application (http://calc.chuv.ch/CTR) facilitates its routine application.

Myocardial Adaptations to Competitive Swim Training

Swim training is performed in the prone or supine position and obligates water immersion, factors that may augment cardiac volume loading more than other endurance sports. At present, prospective data defining the cardiac responses to swim training are lacking. We therefore studied myocardial adaptations among competitive swimmers to establish a causal relationship between swim training and left ventricular (LV) remodeling. Collegiate swimmers were studied before and after a 90-d period of training intensification. Transthoracic echocardiography was used to examine LV structural and functional adaptations under resting conditions and during an acute LV afterload challenge generated by isometric handgrip testing (IHGT). A sedentary control population was identically studied with IHGT. In response to a discrete period of swim training intensification, athletes (n = 17, 47% female, 19 ± 0.4 yr old) experienced eccentric LV remodeling, characterized by proportionally more chamber dilation than wall thickening, with attendant enhancements of resting LV systolic (LV twist) and diastolic (early and late phase tissue velocities) function. Compared with baseline and controls, athletes posttraining demonstrated greater systolic twist impairment during IHGT. However, training-induced LV dilation coupled with gains in diastolic function offsets this acquired systolic susceptibility to acute afterload, resulting in the relative preservation of stroke volume during IHGT. Swim training, a sport characterized by unique cardiac loading conditions, stimulates eccentric LV remodeling with the concomitant augmentation of systolic twist and diastolic relaxation. This volume-mediated cardiac remodeling appears to result in greater systolic susceptibility to acute afterload challenge. Further work is required to establish how training-induced changes in function translate to human performance and whether these are accompanied by physiologic trade-offs with relevance to common forms of heart disease.

The developing athlete's heart: a cohort study in young athletes transitioning through adolescence.

Athlete's heart is a term used to describe physiological changes in the hearts of athletes, but its early development has not been described in longitudinal studies. This study aims to improve our understanding of the effects of endurance training on the developing heart. Cardiac morphology and function in 48 cross-country skiers were assessed at age 12 years (12.1 ± 0.2 years) and then again at age 15 years (15.3 ± 0.3 years). Echocardiography was performed in all subjects including two-dimensional speckle-tracking strain echocardiography and three-dimensional echocardiography. All participants underwent cardiopulmonary exercise testing at both ages 12 and 15 years to assess maximal oxygen uptake and exercise capacity. Thirty-one (65%) were still active endurance athletes at age 15 years and 17 (35%) were not. The active endurance athletes had greater indexed maximal oxygen uptake (62 ± 8 vs. 57 ± 6 mL/kg/min, P < 0.05) at follow-up. There were no differences in cardiac morphology at baseline. At follow-up the active endurance athletes had greater three-dimensional indexed left ventricular end-diastolic (84 ± 11 mL/m2 vs. 79 ± 10 mL/m2, P < 0.05) and end-systolic volumes (36 ± 6 mL/m2 vs. 32 ± 3 mL/m2, P < 0.05). Relative wall thickness fell in the active endurance athletes, but not in those who had quit (-0.05 ΔmL/m2 vs. 0.00 mL/m2, P = 0.01). Four active endurance athletes had relative wall thickness above the upper reference values at baseline; all had normalised at follow-up. After an initial concentric remodelling in the pre-adolescent athletes, those who continued their endurance training developed eccentric changes with chamber dilatation and little change in wall thickness. Those who ceased endurance training maintained a comparable wall thickness, but did not develop chamber dilatation.

PH Grand Rounds: A Case of Pulmonary Hypertension Associated With High Cardiac Output State from Arteriovenous Fistula–Or Is It?

PH Grand Rounds: A Case of Pulmonary Hypertension Associated With High Cardiac Output State from Arteriovenous Fistula–Or Is It?