Right Atrial Enlargement on Electrocardiogram in Previously Healthy Young Patients.

OBJECTIVES: To assess whether right atrial enlargement (RAE) on electrocardiogram (ECG) correlates with true RAE on echocardiogram in previously healthy young patients and to understand which patients with RAE on ECG may warrant additional testing. STUDY DESIGN: A single-center, retrospective review of previously healthy young patients with (1) ECGs that were read as RAE by a pediatric cardiologist and (2) echocardiograms obtained within 90 days of the ECG. ECGs were reviewed to confirm RAE and determine which leads met criteria. The echocardiograms were then reviewed and RA measurements with z scores obtained. A z score >2 was considered positive for RAE on echocardiogram. RESULTS: In total, 162 patients with median age 10.8 years were included in the study. A total of 23 patients had true RAE on echocardiogram, giving a positive predictive value (PPV) of 14%. In patients <1 year of age, the PPV increased to 35%. In patients older than 1 year, the PPV was low at 7%. Patients with true RAE were more likely to meet criteria for RAE in the anterior precordial leads (V1-V3) (48% vs 5%, P < .001) and meet criteria for right ventricular hypertrophy (22% vs 6%, P = .023). CONCLUSION: Our findings show that RAE on ECG has a low PPV for RAE on echocardiogram in previously healthy young patients. The highest yield for RAE on echocardiogram was observed in patients who were <1 year of age, had RAE in the anterior precordial leads, or displayed right ventricular hypertrophy on ECG.

Multi-omic and multispecies analysis of right ventricular dysfunction.

BACKGROUND: Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. METHODS: Transcriptomics and proteomics analyses defined the pathways associated with cardiac magnetic resonance imaging (MRI)-derived values of RV hypertrophy, dilation, and dysfunction in control and pulmonary artery banded (PAB) pigs. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare molecular responses across species. RESULTS: PAB pigs displayed significant right ventricle/ventricular (RV) hypertrophy, dilation, and dysfunction as quantified by cardiac magnetic resonance imaging. Transcriptomic and proteomic analyses identified pathways associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the 3 species. FAO and ETC proteins and transcripts were mostly downregulated in rats but were predominately upregulated in PAB pigs, which more closely matched the human response. All species exhibited similar dysregulation of the dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy pathways. CONCLUSIONS: The porcine metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and pigs may more accurately recapitulate metabolic aspects of human RVF.

Establishment of a canine model of pulmonary arterial hypertension induced by dehydromonocrotaline and ultrasonographic study of right ventricular remodeling.

OBJECTIVE: Pulmonary arterial hypertension (PAH) means high blood pressure in the lungs. We aimed to observe the right ventricular size, wall thickness and characteristic functional changes and their associations with PAH in an established model of beagle dogs, and to explore convenient, reliable and sensitive ultrasound indicators for assessing right ventricular remodeling. METHODS: Twenty healthy beagle dogs (8-10 kg) were randomly divided into control group (N-dimethylformamide, n = 10) and dehydromonocrotaline (DHMCT) group (DHMCT, n = 10). N-dimethylformamide or DHMCT was injected through a catheter into the right atrium, and then right heart catheterization, routine echocardiography and two-dimensional speckle tracking imaging (2D-STI) were performed before modeling (0 weeks) and 8, 14 weeks after modeling. Hemodynamic parameters and right ventricular function-related ultrasound data were acquired. At the end of the experiment, the animals were killed and the lung tissues were taken for HE staining. Left and right ventricular walls were separated and weighed respectively, and right ventricular hypertrophy index (RVHI) was measured. The associations of the routine ultrasound data and 2D-STI data at each time point with hemodynamic parameters and RVHI were analyzed. RESULTS: At 0, 8 and 14 weeks, gradual decreases in the right ventricular global longitudinal strain (RVLS) were found in DHMCT group. RVH occurred in DHMCT group, and DHMCT group had a significantly higher RVHI than that of control group (49.83 ± 4.83% vs. 39.80 ± 1.40%, P < .001) and larger pulmonary artery media thickness. RVLS had significant positive correlations with RVSP (r = 0.74, P < .001), mRVP (r = 0.72, P < .001), PASP (r = 0.75, P < .001), mPAP (r = 0.72, P < .001) and PVR (r = 0.68, P < .001). There was a significant positive correlation between RVLS and RVHI (r = 0.74, P < .001). CONCLUSION: The right ventricular function in PAH can be effectively assessed by echocardiography, and RVLS measured by 2D-STI sensitively reflects right ventricular remodeling following PAH.

High-echoic line tracing of transthoracic echocardiography accurately assesses right ventricular enlargement in adult patients with atrial septal defect.

Accurate measurement of right ventricular (RV) size using transthoracic echocardiography (TTE) is important for evaluating the severity of congenital heart diseases. The RV end-diastolic area index (RVEDAi) determined using TTE is used to assess RV dilatation; however, the tracing line of the RVEDAi has not been clearly defined by the guidelines. This study aimed to determine the exact tracing method for RVEDAi using TTE. We retrospectively studied 107 patients with atrial septal defects who underwent cardiac magnetic resonance imaging (CMR) and TTE. We measured the RVEDAi according to isoechoic and high-echoic lines, and compared it with the RVEDAi measured using CMR. The isoechoic line was defined as the isoechoic endocardial border of the RV free wall, whereas the high-echoic line was defined as the high-echoic endocardial border of the RV free wall more outside than the isoechoic line. RVEDAi measured using high-echoic line (high-RVEDAi) was more accurately related to RVEDAi measured using CMR than that measured using isoechoic line (iso-RVEDAi). The difference in the high-RVEDAi was 0.3 cm2/m2, and the limit of agreement (LOA) was - 3.7 to 4.3 cm2/m2. With regard to inter-observer variability, high-RVEDAi was superior to iso-RVEDAi. High-RVEDAi had greater agreement with CMR-RVEDAi than with iso-RVEDAi. High-RVEDAi can become the standard measurement of RV size using two-dimensional TTE.

Reporte de caso: enfermedad de Fabry en un adulto con enfermedad renal crónica y síntomas sistémicos característicos / A case report: Fabry disease in an adult with chronic kidney disease and characteristic systemic symptoms / Relato de um caso: doença de Fabry em um adulto com doença renal crônica e sintomas sistémicos característicos

Se presenta el caso de un paciente de sexo masculino, de 62 años, con antecedentes familiares de cardiopatía y enfermedad renal, y antecedentes personales de enfermedad renal crónica severa, por la que recibió trasplante renal. Es enviado a consulta cardiológica por dolores torácicos atípicos y episodios de hipotensión sintomática, se constata en el ecocardiograma: hipertrofia ventricular izquierda concéntrica y deformación miocárdica longitudinal del ventrículo izquierdo patológica. La resonancia magnética cardíaca encuentra un patrón de realce tardío sugestivo de enfermedad de Fabry, diagnóstico que se confirma con dosificación enzimática y estudio genético. Recibe tratamiento específico con una buena respuesta inicial. Esta es una enfermedad sistémica metabólica congénita en la que el diagnóstico y el tratamiento específico se realiza en la edad adulta.

It is presented a 62-year-old male patient with a family history of heart and kidney disease, and a personal history of chronic kidney disease, for which he received a kidney transplant. He was sent to the cardiology department due to atypical chest pain and episodes of symptomatic hypotension. The echocardiogram revealed: concentric left ventricular hypertrophy and pathological longitudinal myocardial deformation of the left ventricle. Cardiac magnetic resonance finds a pattern of late enhancement suggestive of Fabry disease, a diagnosis that is confirmed with enzyme dosage and genetic study. He receives specific treatment with a good initial response. This is a congenital metabolic systemic disease in which the diagnosis and specific treatment is carried out in adulthood.

Se apresenta o caso de um paciente do sexo masculino, 62 anos, com histórico familiar de cardiopatia e doença renal e histórico pessoal de doença renal crônica grave, para o qual recebeu transplante de rim. Foi encaminhado ao serviço de cardiologia por dor torácica atípica e episódios de hipotensão sintomática. O ecocardiograma revelou: hipertrofia ventricular esquerda concêntrica e deformação miocárdica longitudinal patológica do ventrículo esquerdo. A ressonância magnética cardíaca encontra um padrão de realce tardio sugestivo de doença de Fabry, diagnóstico confirmado com dosagem enzimática e estudo genético. Recebe tratamento específico com boa resposta inicial. Tratase de uma doença sistêmica metabólica congênita em que o diagnóstico e o tratamento específico são realizados na idade adulta.

Lack of right ventricular hypertrophy is associated with right heart failure in patients with left ventricular failure.

Presence of right heart failure (RHF) is associated with a worse prognosis in patients with left ventricular failure (LVF). While the cause of RHF secondary to LVF is multifactorial, an increased right ventricular (RV) afterload is believed as the major cause of RHF. However, data are scarce on the adaptive responses of the RV in patients with LVF. Our aim was to understand the relationship of right ventricular hypertrophy (RVH) with RHF and RV systolic and diastolic properties in patients with LVF. 55 patients with a left ventricular ejection fraction of 40% or less were included in the present study. A comprehensive two-dimensional transthoracic echocardiographic examination was done to all participants. 12 patients (21.8%) had RHF, and patients with RHF had a significantly lower right ventricular free wall thickness (RVFWT) as compared to patients without RHF (5.3 ± 1.7 mm vs. 6.6 ± 0.9 mm, p = 0.02) and the difference remained statistically significant after adjusting for confounders (Δx̅:1.34 mm, p = 0.002). RVFWT had a statistically significant correlation with tricuspid annular plane systolic excursion (r = 0.479, p < 0.001) and tricuspid annular lateral systolic velocity (r = 0.360, p = 0.007), but not with the indices of the RV diastolic function. None of the patients with concentric RVH had RHF, while 22.2% of patients with eccentric RVH and 66.7% of patients without RVH had RHF (p < 0.01 as compared to patients with concentric RVH). In patients with left ventricular systolic dysfunction, absence of RVH was associated with worse RV systolic performance and a significantly higher incidence of RHF.

Severe right ventricular hypertrophy in hypertrophic cardiomyopathy: Serious symptoms, complex surgical procedures, and poor prognosis in Fuwai Hospital.

OBJECTIVE: Severe right ventricular hypertrophy (SRVH) in hypertrophic cardiomyopathy (HCM) is rare. We studied the clinical characteristics and prognosis of 36 patients with HCM and SRVH in a Chinese cohort. METHODS: Patients with HCM and SRVH were enrolled between 2013 and 2017. The clinical characteristics, treatment therapies, and clinical outcomes of the 36 patients were retrospectively studied and compared with those of 128 patients without SRVH. RESULTS: Patients in the group with SRVH were younger than those in the group without SRVH (27.58±15.09 years vs 40.34±13.21 years, respectively; p<0.001). Patients with SRVH had more serious clinical symptoms and a higher New York Heart Association functional class than those without SRVH. Most patients in the group with SRVH exhibited diffuse RV hypertrophy, and 13 patients presented with biventricular outflow tract obstruction. Maximal left ventricular (LV) wall thickness (27.29±7.95 mm vs 24.33±5.85 mm, respectively; p=0.027) and LV outflow tract gradient (80.83±24.41 mm Hg vs 42.3±5.7 mm Hg, respectively; p=0.000) were significantly greater in patients with SRVH than in those without SRVH. A total of 30 patients in the group with SRVH underwent surgical correction. During a median follow-up period of 48 months, six patients with SRVH reached primary clinical endpoints (four sudden cardiac deaths, one heart failure-related death, and one heart transplantation), whereas only two deaths occurred in the patients without SRVH. CONCLUSION: We conclude that patients with HCM and SRVH exhibit serious symptoms and have complex surgical requirements and poor clinical outcomes.

An exploratory assessment of stretch-induced transmural myocardial fiber kinematics in right ventricular pressure overload.

Right ventricular (RV) remodeling and longitudinal fiber reorientation in the setting of pulmonary hypertension (PH) affects ventricular structure and function, eventually leading to RV failure. Characterizing the kinematics of myocardial fibers helps better understanding the underlying mechanisms of fiber realignment in PH. In the current work, high-frequency ultrasound imaging and structurally-informed finite element (FE) models were employed for an exploratory evaluation of the stretch-induced kinematics of RV fibers. Image-based experimental evaluation of fiber kinematics in porcine myocardium revealed the capability of affine assumptions to effectively approximate myofiber realignment in the RV free wall. The developed imaging framework provides a noninvasive modality to quantify transmural RV myofiber kinematics in large animal models. FE modeling results demonstrated that chronic pressure overload, but not solely an acute rise in pressures, results in kinematic shift of RV fibers towards the longitudinal direction. Additionally, FE simulations suggest a potential protective role for concentric hypertrophy (increased wall thickness) against fiber reorientation, while eccentric hypertrophy (RV dilation) resulted in longitudinal fiber realignment. Our study improves the current understanding of the role of different remodeling events involved in transmural myofiber reorientation in PH. Future experimentations are warranted to test the model-generated hypotheses.

Rare case of right ventricular dilatation associated with anomalous pulmonary venous drainage, sinus venosus atrial septal defect and persistent left superior vena cava.

A 34-year-old woman was seen in the emergency department for shortness of breath and chest pain. During a pandemic, it is easy to 'think horses and not zebras', and with a patient presenting with the classic coronavirus symptoms it would have been easy to jump to that as her diagnosis. After a careful history and examination, it became clear that there was another underlying diagnosis. Chest X-ray, echocardiogram and CT scan revealed marked right ventricular dilatation and pulmonary hypertension, alongside a persistent left superior vena cava (PLSVC). Further investigation with cardiac MRI and coronary angiography at a tertiary centre demonstrated that she not only have a PLSVC but also a partial anomalous pulmonary venous drainage and sinus venosus atrial septal defect. This case highlights the importance of considering all differentials and approaching investigations in a logical manner.

Evaluation of right coronary vascular dysfunction in severe pulmonary hypertensive rats using synchrotron radiation microangiography.

Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. Coronary vascular response was assessed using microangiography with synchrotron radiation (SR) in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the nonselective endothelin-1 receptor antagonist (ERA), macitentan, was also examined. Myocardial viability was determined in SuHx model rats, using 18F-FDG Positron emission tomography (PET) and magnetic resonance imaging (MRI). Endothelium-dependent and endothelium-independent vasodilator responses were significantly attenuated in the medium and small arteries of severe PH rats. ERA treatment significantly improved RCA vascular function compared with the untreated group. ERA treatment improved both the decrease in ejection fraction and the increased glucose uptake, and reduced RV remodeling. In addition, the upregulation of inflammatory genes in the RV was almost suppressed by ERA treatment. We found impairment of vasodilator responses in the RCA of severe PH rat models. Endothelin-1 activation in the RCA plays a major role in impaired vascular function in PH rats and is partially restored by ERA treatment. Treatment of PH with ERA may improve RV function in part by indirectly attenuating right heart afterload and in part by associated improvements in right coronary endothelial function.NEW & NOTEWORTHY We demonstrated for the first time the impairment of vascular responses in the right coronary artery (RCA) of the dysfunctional right heart in pulmonary hypertensive rats in vivo. Treatment with an endothelin-1 receptor antagonist ameliorated vascular dysfunction in the RCA, enabled tissue remodeling of the right heart, and improved cardiac function. Our results suggest that impaired RCA function might also contribute to the early progression to heart failure in patients with severe pulmonary arterial hypertension (PAH). The endothelium of the coronary vasculature might be considered as a potential target in treatments to prevent heart failure in severe patients with PAH.

Early return of reflected waves increases right ventricular wall stress in chronic thromboembolic pulmonary hypertension.

Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are as follows: 1) to investigate whether reflected pressure returns sooner in proximal than in distal CTEPH and 2) to elucidate whether the timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy, and wall stress. Right heart catheterization and cardiac MRI were performed in 17 patients with proximal CTEPH and 17 patients with distal CTEPH. In addition to the determination of PVR, compliance, and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as %systole). Findings were related to RV dimensions and time-resolved RV wall stress. Proximal CTEPH was characterized by higher RV volumes, mass, and wall stress, and lower RVEF. While PVR, compliance, and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53 ± 8% vs. distal 63 ± 15%, P < 0.05). The magnitude of the reflected pressure waves did not differ. RV volumes, RVEF, RV mass, and wall stress were all related to the timing of peak reflected pressure. Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance, and characteristic impedance do not explain the differences in RV function between proximal and distal CTEPH.NEW & NOTEWORTHY In chronic thromboembolic pulmonary hypertension (CTEPH), proximal localization of vessel obstructions is associated with poor right ventricular (RV) function compared with distal localization, though pulmonary vascular resistance, vascular compliance, characteristic impedance, and the magnitude of wave reflection are similar. In proximal CTEPH, the RV is exposed to an earlier return of the reflected wave. Early wave reflection may increase RV wall stress and compromise RV function.

Excess Protein O-GlcNAcylation Links Metabolic Derangements to Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-GlcNAcylation. While numerous studies demonstrate increased right ventricle (RV) glucose uptake in pulmonary arterial hypertension (PAH), the relationship between O-GlcNAcylation and RV function in PAH is unexplored. Therefore, we examined how colchicine-mediated AMP-kinase activation altered HBP intermediates, O-GlcNAcylation, mitochondrial function, and RV function in pulmonary artery-banded (PAB) and monocrotaline (MCT) rats. AMPK activation induced GFAT phosphorylation and reduced HBP intermediates and O-GlcNAcylation in MCT but not PAB rats. Reduced O-GlcNAcylation partially restored the RV metabolic signature and improved RV function in MCT rats. Proteomics revealed elevated expression of O-GlcNAcylated mitochondrial proteins in MCT RVs, which fractionation studies corroborated. Seahorse micropolarimetry analysis of H9c2 cardiomyocytes demonstrated colchicine improved mitochondrial function and reduced O-GlcNAcylation. Presence of diabetes in PAH, a condition of excess O-GlcNAcylation, reduced RV contractility when compared to nondiabetics. Furthermore, there was an inverse relationship between RV contractility and HgbA1C. Finally, RV biopsy specimens from PAH patients displayed increased O-GlcNAcylation. Thus, excess O-GlcNAcylation may contribute to metabolic derangements and RV dysfunction in PAH.

Prognostic Value of Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Parameters in Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Background Cardiac right ventricular remodeling plays a substantial role in pathogenesis, progression, and prognosis of pulmonary hypertension. Cardiac magnetic resonance is considered an excellent tool for evaluation of right ventricle. However, value of right ventricular remodeling parameters derived from cardiac magnetic resonance in predicting adverse events is controversial. Methods The Pubmed (MEDLINE), Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure platform (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases were systematically searched until November 2019. Studies reporting hazard ratios (HRs) for all-cause death and composite end point of pulmonary hypertension were included. Univariate HRs were extracted from the included studies to calculate pooled HRs of each right ventricular remodeling parameter. Results Eight studies with 1120 patients examining all-cause death (female: 44%-92%, age: 40-67 years old, follow-up time: 27-48 months) and 10 studies with 604 patients examining composite end point (female: 60%-83%, age: 29-57 years old, follow-up time: 10-68 months) met the criteria. Right ventricular ejection fraction was the only parameter which could predict both all-cause death (pooled HR=0.95; P=0.014) and composite end point (pooled HR=0.95; P<0.001), although right ventricular end-diastolic volume index (pooled HR=1.01; P<0.001), right ventricular end-systolic volume index (pooled HR=1.01, P=0.045), and right ventricular mass index (pooled HR=1.03, P=0.032) only predicted composite outcome. Similar results were observed when we conducted the meta-analysis among patients with World Health Organization type I of pulmonary hypertension. Conclusions Cardiac magnetic resonance-derived right ventricular remodeling parameters have independent prognostic value for all-cause death and composite end point of patients with pulmonary hypertension. Right ventricular ejection fraction was the strongest prognostic factor among all the right ventricular remodeling parameters. Right ventricular mass index, right ventricular end-diastolic volume index, and right ventricular end-systolic volume index also demonstrated prognostic value.

Inferior Right Ventricular Wall Thickness by Echocardiogram: A Novel Method of Assessing Hypertrophy in Neonates and Infants.

An established echocardiographic (echo) standard for assessing the newborn right ventricle (RV) for hypertrophy has not been thoroughly developed. This is partially due to the RV's complex architecture, which makes quantification of RV mass by echo difficult. Here, we retrospectively evaluate the thickness of the inferior RV wall (iRVWT) by echo in neonates and infants with normal cardiopulmonary physiology. Inferior RVWT was defined at the medial portion of the inferior wall of the RV at the mid-ventricular level, collected from a subxiphoid, short axis view. iRVWT was indexed to body surface area (BSA) to the 0.5 power and normalized to iLVWT to explore the best normalization method. Ninety-eight neonates and 32 infants were included in the final analysis. Mean age for neonates and infants was 2 days and 59 days, respectively. Mean ± SD for neonate and infant end-diastole iRVWT was 2.17 ± 0.35 mm and 1.79 ± 0.28 mm, respectively. There was no residual relationship between the index iRVWT and BSA (r = 0.03, p = NS). In the infant cohort, the iRVWT was significantly lower and iLVWT was significantly higher compared to neonate, consistent with known physiologic changes of RV and LV mass. Thus, iRVWT may serve as a reliable and accurate proxy for RV mass and the parameter warrants further evaluation.

Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is the second most common etiology of PAH and carries a poor prognosis. Recently, it has been shown that female human tumor necrosis factor (TNF)-transgenic (Tg) mice die of cardiopulmonary disease by 6 months of age. This study was undertaken to characterize this pathophysiology and assess its potential as a novel model of CTD-PAH. METHODS: Histologic analysis was performed on TNF-Tg and wild-type (WT) mice to characterize pulmonary vascular and right ventricular (RV) pathology (n = 40 [4-5 mice per group per time point]). Mice underwent right-sided heart catheterization (n = 29) and micro-computed tomographic angiography (n = 8) to assess vascular disease. Bone marrow chimeric mice (n = 12), and anti-TNF-treated mice versus placebo-treated mice (n = 12), were assessed. RNA sequencing was performed on mouse lung tissue (n = 6). RESULTS: TNF-Tg mice displayed a pulmonary vasculopathy marked by collagen deposition (P < 0.001) and vascular occlusion (P < 0.001) with associated RV hypertrophy (P < 0.001) and severely increased RV systolic pressure (mean ± SD 75.1 ± 19.3 mm Hg versus 26.7 ± 1.7 mm Hg in WT animals; P < 0.0001). TNF-Tg mice had increased α-smooth muscle actin (α-SMA) staining, which corresponded to proliferation and loss of von Willebrand factor (vWF)-positive endothelial cells (P < 0.01). There was an increase in α-SMA-positive, vWF-positive cells (P < 0.01), implicating endothelial-mesenchymal transition. Bone marrow chimera experiments revealed that mesenchymal but not bone marrow-derived cells are necessary to drive this process. Treatment with anti-TNF therapy halted the progression of disease. This pathology closely mimics human CTD-PAH, in which patient lungs demonstrate increased TNF signaling and significant similarities in genomic pathway dysregulation. CONCLUSION: The TNF-Tg mouse represents a novel model of CTD-PAH, recapitulates key disease features, and can serve as a valuable tool for discovery and assessment of therapeutics.

Effects of Chronic Nicotine Inhalation on Systemic and Pulmonary Blood Pressure and Right Ventricular Remodeling in Mice.

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure was recorded weekly by radio-telemetry, and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension.

Increased systolic vorticity in the left ventricular outflow tract is associated with abnormal aortic flow formations in Tetralogy of Fallot.

Aortopathy is a recognized comorbidity of Tetralogy of Fallot (TOF). Aortic flow in children with repaired TOF is abnormal despite normal aortic valve anatomy and early surgical repair that results in aortic size normalization. The purpose of this study was to investigate the flow hemodynamics inside the left ventricle (LV) of children with repaired TOF using 4D-Flow MRI derived vorticity. Vorticity is the spatial derivative of flow velocity and is sensitive to anatomic and geometric variations. Vorticity was calculated inside the LV of children with repaired TOF having normal aortic size (n = 14) and normal controls (n = 10) during systolic ejection phase. All subjects underwent comprehensive biventricular analysis including the MRI based feature-tracking based LV strain analysis and mechanical dyssynchrony. Right ventricular (RV) volumetric indices along with LV mechanical indices were correlated with LV vorticity. All TOF patients had supraphysiologic helical flow in the ascending aorta. The generated peak systolic vorticity integrated over the LV volume was elevated in TOF group compared to control (median: 1344 vs. 858 s-1, P < 0.001). TOF patients had increased LV mechanical dyssynchrony (47 ± 11 vs. 32 ± 7 ms, P < 0.001) and reduced LV global circumferential strain (19 ± 2 vs. 21 ± 2%, P = 0.020). In the TOF group, LV systolic vorticity was independent of RV size and LV mechanical indices. Pathologic aortic flow in children with repaired TOF is associated with abnormal ejection flow patterns inside the LV. Increased systolic vorticity was not associated with LV mechanical dyssynchrony and RV dilation, suggesting that systolic flow inside the LV is independent of impaired LV contractile mechanics and inter-ventricular interactions.