Right Ventricular Myocardium Research Articles

CILP1 and NTproBNP in pulmonary hypertension and right ventricular pressure overload: a translational experimental study

Abstract Introduction Cartilage intermediate layer protein 1 (CILP1) has emerged as a novel marker of right ventricular (RV) dysfunction in pulmonary hypertension (PH), although there is still little evidence on its role in different scenarios of RV pressure overload. The aim of our study was to analyze CILP1 as a biomarker of RV remodeling and PH severity, and compare it with N-terminal pro-brain natriuretic peptide (NTproBNP), in different experimental models of RV pressure overload. Methods Three different experimental models of RV pressure overload compared to a sham procedure were evaluated in 24 Yucatan pigs: chronic postcapillary PH by pulmonary vein banding (M1, n=6); chronic PH by aorto-pulmonary shunting (M2, n=6); RV pressure overload by PA banding (thus without PH) (M3, n=6); and sham procedure (M0, n=6). Animals were evaluated at 8 months after surgery by right heart catheterization, cardiac magnetic resonance (CMR), and blood/histological sampling. Levels of CILP1 and NTproBNP at the RV myocardium and blood were determined with dedicated ELISA and compared among groups by Wilcoxon test with Bonferroni correction. Associations between biomarkers and RV performance indices and pulmonary arterial pressure (PAP) were assessed with Spearman correlation test. Results M1 animals developed chronic postcapillary PH with normal left ventricular (LV) performance and RV maladaptive hypertrophy (RV fibrosis and systolic dysfunction). M2 animals developed chronic precapillary PH associated with LV dilatation and RV maladaptive hypertrophy. On contrast, M3-animals developed severe RV pressure overload (without PH) and hypertrophy but maintained normal RV systolic function. CILP1 and NTproBNP levels were moderately correlated (R=0.56, p=0.002). CILP1 levels in RV myocardium and plasma were significantly higher in M1, whereas NTproBNP plasma levels were significantly higher in M2 (Figure 1). CILP1 in plasma and RV myocardium significantly correlated with PAP, while myocardial CILP1 levels also correlated with RV extracellular volume (RV-ECV) by CMR (Figure 2). NTproBNP myocardial levels correlated with RV ejection fraction and RV-ECV and plasmatic levels correlated with PAP (Figure 2). Conclusions CILP1 levels were increased in the presence of PH and isolated RV dysfunction, whereas NTproBNP levels were increased in the model of PH, RV dysfunction and LV remodeling. Myocardial levels of both peptides correlated with diffuse fibrosis, estimated by CMR, whereas plasmatic levels of both biomarkers correlated with PAP. This suggests that CILP1 may be a more specific marker of RV dysfunction in PH, being less dependent of LV parameters.CILP1 and NTproBNP levels among modelsCorrelation with PAP & RV remodeling

Effects of dopamine β-hydroxylase inhibition in pressure overload-induced right ventricular failure.

Activation of the sympathetic nervous system is observed in pulmonary arterial hypertension patients. This study investigates whether inhibiting the conversion of dopamine into noradrenaline by dopamine β-hydroxylase (DβH) inhibition with BIA 21-5337 improved right ventricular (RV) function or remodeling in pressure overload-induced RV failure. RV failure was induced in male Wistar rats by pulmonary trunk banding (PTB). Two weeks after the procedure, PTB rats were randomized to vehicle (n = 8) or BIA 21-5337 (n = 11) treatment. An additional PTB group treated with ivabradine (n = 11) was included to control for the potential heart rate-reducing effects of BIA 21-5337. A sham group (n = 6) received vehicle treatment. After 5 weeks of treatment, RV function was assessed by echocardiography, magnetic resonance imaging, and invasive pressure-volume measurements before rats were euthanized. RV myocardium was analyzed to evaluate RV remodeling. PTB caused a fourfold increase in RV afterload which led to RV dysfunction, remodeling, and failure. Treatment with BIA 21-5337 reduced adrenal gland DβH activity and 24-h urinary noradrenaline levels confirming relevant physiological response to the treatment. At end-of-study, there were no differences in RV function or RV remodeling between BIA 21-5337 and vehicle-treated rats. In conclusion, treatment with BIA 21-5337 did not have any beneficial-nor adverse-effects on the development of RV failure after PTB despite reduced adrenal gland DβH activity.

Correlation between Epsilon Wave and Late Potentials in Arrhythmogenic Right Ventricular Cardiomyopathy-Do Late Potentials Define the Epsilon Wave?

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterised by progressive fibrosis predominantly of the right ventricular (RV) myocardium, resulting in life-threatening arrhythmias and heart failure. The diagnosis is challenging due to a wide spectrum of clinical symptoms. The important role of ECG was covered in the current diagnostic criteria. The role of the epsilon wave (EW) is still under discussion. Aim: The aim of the study was to examine a potential association between the EW and late ventricular potentials (LPs) in ARVC patients (pts). The correlation between RV dilatation or dysfunction and LPs/EW was also analysed. Methods: The ARVC group consisted of 81 pts (53 men, aged 20-78 years) fulfilling 2010 International Task Force Criteria. 12-lead ECG, LPs, Holter, and ECHO were performed in all pts. The presence of EW was analysed in ECG by 3 investigators. LPs were detected by signal-averaged ECG (SAECG). SAECG was considered positive for LPs when at least two of the three following criteria were met: (1) the filtered QRS duration (fQRS) ≥ 114 msec; (2) the duration of the final QRS fragment in which low-amplitude signals lower than 40 μV are recorded (LAS-40 > 38 msec); and (3) the root mean square amplitude of the last 40 milliseconds of the fQRS complex (RMS-40 < 20 μV). The results were compared with a reference group consisting of 53 patients with RV damage in the course of atrial septum defect (ASD) or Ebstein's Anomaly (EA). Results: In the ARVC group, a significant relationship was observed between the occurrence of EW and the presence of LPs. EW was more common in the LP+ than in the LP- patients (48.1% vs. 6.9%, p < 0001; OR 12.5; 95% CI [2.691-58.063]). In ARVC pts, RVOT > 36 mm, RVIT > 41 mm, and RV S' < 9 cm/s were observed significantly more often in the LPs+ than in the LPs- group (OR [95% CI]: 8.3 [2.9-1.5], 6.4 [2.2-19.0] and 3.6 [1.1-12.2], respectively). In the ARVC group, any of fQRS > 114 ms, LAS > 38 ms, and RMS < 20 μV were significantly more frequent in EW+ pts. In multivariate analysis, the independent factors of the EW were LAS-40 and RV S'. In the LPs- subgroup, RVOT > 36 mm was more frequent in ASD/EA than in ARVC (70.4% vs. 25%, p = 0.002). Similarly, in the LPs- subgroup, RVIT > 41 mm was encountered more frequently in ASD/EA than in ARVC (85.2% vs. 48.3%, p = 0.004). Conclusions: In ARVC, there is an association between EW and LPs, with both probably resulting from the same process of fibrofatty substitution of the RV myocardium. Although RV dilatation is common in ASD and EA, it does not correlate with LPs.

Quantitative analysis of the impact of respiratory state on the heartbeat-induced movements of the heart and its substructures

PurposeThis study seeks to examine the influence of the heartbeat on the position, volume, and shape of the heart and its substructures during various breathing states. The findings of this study will serve as a valuable reference for dose-volume evaluation of the heart and its substructures in radiotherapy for treating thoracic tumors.MethodsTwenty-three healthy volunteers were enrolled in this study, and cine four-dimensional magnetic resonance images were acquired during periods of end-inspiration breath holding (EIBH), end-expiration breath holding (EEBH), and deep end-inspiration breath holding (DIBH). The MR images were used to delineate the heart and its substructures, including the heart, pericardium, left ventricle (LV), left ventricular myocardium, right ventricle (RV), right ventricular myocardium (RVM), ventricular septum (VS), atrial septum (AS), proximal and middle portions of the left anterior descending branch (pmLAD), and proximal portion of the left circumflex coronary branch (pLCX). The changes in each structure with heartbeat were compared among different respiratory states.ResultsCompared with EIBH, EEBH increased the volume of the heart and its substructures by 0.25–3.66%, while the average Dice similarity coefficient (DSC) increased by − 0.25 to 8.7%; however, the differences were not statistically significant. Conversely, the VS decreased by 0.89 mm in the left–right (LR) direction, and the displacement of the RV in the anterior–posterior (AP) direction significantly decreased by 0.76 mm (p < 0.05). Compared with EIBH and EEBH, the average volume of the heart and its substructures decreased by 3.08–17.57% and 4.09–20.43%, respectively, during DIBH. Accordingly, statistically significant differences (p < 0.05) were observed in the volume of the heart, pericardium, LV, RV, RVM, and AS. The average DSC increased by 0–37.04% and − 2.6 to 32.14%, respectively, with statistically significant differences (p < 0.05) found in the right ventricular myocardium and interatrial septum. Furthermore, the displacements under DIBH decreased in the three directions (i.e.,− 1.73 to 3.47 mm and − 0.36 to 2.51 mm). In this regard, the AP displacement of the heart, LV, RV, RVM, LR direction, LV, RV, and AS showed statistically significant differences (p < 0.05). The Hausdorff distance (HD) of the heart and its substructures under the three breathing states are all greater than 11 mm.ConclusionThe variations in the displacement and shape alterations of the heart and its substructures during cardiac motion under various respiratory states are significant. When assessing the dose-volume index of the heart and its substructures during radiotherapy for thoracic tumors, it is essential to account for the combined impacts of cardiac motion and respiration.

Correlation between epsilon wave and late potentials in arrythmogenic right ventricular cardiomyopathy. Do late potentials define the epsilon wave?

Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterised by progressive fibrosis predominantly of the right ventricular (RV) myocardium resulting in life-threatening arrhythmias and heart failure. The diagnosis is challenging due to a wide spectrum of clinical symptoms. The important role of ECG was covered in the current diagnostic criteria. The role of epsilon wave (EW) is still under discussion. Aim The aim of the study was to correlate the presence of EW with late ventricular potentials (LPs) in ARVC patients (pts). The correlation between RV dilatation /dysfunction and LPs/EW was also analysed. Methods The ARVC group consisted of 81 pts (53 men, aged 20-78 years) fulfilling 2010 International Task Force Criteria. 12-lead ECG, LPs, Holter, ECHO were performed in all pts. The presence of EW, defined as low-amplitude deflection observed between the end of the QRS complex and the onset of the T wave was analysed in ECG by 3 investigators. LPs were defined as low-amplitude, high-frequency waveforms at the end of the QRS complex on signal-averaged ECG (SAECG). SAECG was considered positive for LPs when at least two of the three following criteria were met: filtered QRS duration (fQRS) &amp;gt;114 ms, root-mean-square voltage in the terminal 40 ms (RMS 40) &amp;lt;20 uV, or low amplitude (&amp;lt;40 µV) signal (LAS 40) duration &amp;gt;38 ms. The results were compared with a reference group consisting of 53 pts with RV damage in the course of atrial septum defect (ASD) (29 pts, 8 men, aged 22-80 years) or Ebstein Anomaly (EA) (24 pts, 11 men, aged 23-55 years). Results In the ARVC group, a significant relationship was observed between the occurrence of EW and the presence of LPs. EW was more common in LP+ than in LP- patients (48.1% vs 6.9%, p&amp;lt;0001; OR 12.5). In ARVC a relationship was also found between the presence of LPs and increased RV inflow tract (RVIT) and RV outflow tract (RVOT) dimensions, as well as a reduced RV S' wave value. RVOT &amp;gt;36 mm, RVIT &amp;gt;41 mm and RV S’ &amp;lt;9 cm/s were observed significantly more often in the LPs+ than in LPs- group (OR: 8.3, 6.4 and 3.6, respectively). In the ARVC group, any of fQRS &amp;gt;114 ms, LAS &amp;gt;38 ms, and RMS &amp;lt;20 uV were significantly more frequent in EW+ pts. In multivariate analysis, the only independent factor of the EW was fQRS (OR: 1.043 [1.020-1.067], p&amp;lt;0.001; AUC: 0.852). In the LPs- subgroup, RVOT &amp;gt;36 mm was more frequent in ASD/EA than in ARVC (70.4% vs 25%, p=0.002). Similarly, in the LPs- subgroup, RVIT &amp;gt;41 mm was encountered more frequently in ASD/EA than in ARVC (85.2% vs 48.3%, p=0.004). Conclusions In ARVC, there is an association between EW and LPs, with both probably resulting from the same process of fibrofatty substitution of the RV myocardium. Although RV dilatation is common in ASD and EA, it does not correlate with LPs, possibly due to a lower degree of fibrosis in ASD/EA compared to ARVC.

Chronic hypoxia-induced alterations of the right ventricular myocardium are not aggravated by alimentary obesity in the mouse

Background and aimsObesity is a risk factor of cardiopulmonary disorders including left and right ventricular dysfunction and pulmonary hypertension (PH), and PH is associated with right ventricular (RV) hypertrophy and failure. Here, we tested the hypothesis that alterations of the RV capillary network under PH induced by chronic hypoxia are aggravated by alimentary obesity, thereby representing a predisposition for subsequent RV dysfunction. Methods and resultsMale, 6-week-old C57BL/6N mice were assigned to one of the following groups: control diet (CD), CD/hypoxia (CD-Hyp), high-fat diet (HFD), HFD/hypoxia (HFD-Hyp). Mice were fed CD or HFD for 30 weeks, CD-Hyp and HFD-Hyp mice were exposed to normobaric hypoxia (13 % O2) during the last 3 weeks of the experiments. Hearts were prepared for light and electron microscopy and right atria and RVs were analyzed by design-based stereology. HFD and hypoxia independently increased RV and cardiomyocyte volume. These changes were further enhanced in HFD-Hyp. The ratio between RV and body weights was similar in CD and HFD but enhanced in both hypoxia groups to a similar extent. The total length of capillaries was elevated in proportion with the RV hypertrophy, thus the area of myocardium supplied by an average capillary was similar in all groups. Similarly, the thickness of the capillary endothelium was not altered by HFD or hypoxia. ConclusionIn conclusion, in experimental PH capillaries of the RV myocardium showed similar adaptations in lean and obese mice. Thus, under chronic hypoxic conditions, obesity had no adverse effect on the capillarization of the right ventricle.

Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot.

Arrhythmias may originate from surgically unaffected right ventricular (RV) regions in patients with tetralogy of Fallot (TOF). We aimed to investigate action potential (AP) remodelling and arrhythmia susceptibility in RV myocardium of patientswith repaired and with unrepaired TOF, identify possible correlations with clinical phenotype and myocardial fibrosis, and compare findings with data from patients with atrial septal defect (ASD), a less severe congenital heart disease. Intracellular AP were recorded ex vivo in RV outflow tract samples from 22 TOF and three ASD patients. Arrhythmias were provoked by superfusion with solutions containing reduced potassium and barium chloride, or isoprenaline. Myocardial fibrosis was quantified histologically and associations between clinical phenotype, AP shape, tissue arrhythmia propensity, and fibrosis were examined. Electrophysiological abnormalities (arrhythmias, AP duration [APD] alternans, impaired APD shortening at increased stimulation frequencies) were generally present in TOF tissue, even from infants, but rare or absent in ASD samples. More severely diseased and acyanotic patients, pronounced tissue susceptibility to arrhythmogenesis, and greater fibrosis extent were associated with longer APD. In contrast, APD was shorter in tissue from patients with pre-operative cyanosis. Increased fibrosis and repaired-TOF status were linked to tissue arrhythmia inducibility. Functional and structural tissue remodelling may explain arrhythmic activity in TOF patients, even at a very young age. Surprisingly, clinical acyanosis appears to be associated with more severe arrhythmogenic remodelling. Further research into the clinical drivers of structural and electrical myocardial alterations, and the relation between them, is needed to identify predictive factors for patients at risk.

Right ventricular global dysfunction score: a new concept of right ventricular function assessment in patients with heart failure with reduced ejection fraction (HFrEF).

Right ventricular (RV) function is currently being evaluated solely according to the properties of RV myocardium. We have tested a concept that in patients with heart failure with reduced ejection fraction (HFrEF), RV assessment should integrate the information about both RV function as well as size. A total of 836 stable patients with HFrEF (LVEF 23.6 ± 5.8%, 82.8% males, 68% NYHA III/IV) underwent echocardiographic evaluation and were prospectively followed for a median of 3.07 (IQRs 1.11; 4.89) years for the occurrence of death, urgent heart transplantation or implantation of mechanical circulatory support. RV size (measured as RV-basal diameter, RVD1) was significantly associated with an adverse outcome independent of RV dysfunction grade (p = 0.0002). The prognostic power of RVD1 was further improved by indexing to body surface area (RVD1i, p < 0.05 compared to non-indexed value). A novel parameter named RV global dysfunction score (RVGDs) was calculated as a product of RVD1i and the degree of RV dysfunction (1-4 for preserved RV function, mild, moderate and severe dysfunction, respectively). RVGDs showed a superior prognostic role compared to RV dysfunction grade alone (ΔAUC >0.03, p < 0.0001). In every subgroup of RVGDs (<20, 20-40, 40-60, >60), patients with milder degree of RV dysfunction but more dilated RV had similar outcome as those with more severe degree of RV dysfunction but smaller RV size (all p > 0.50), independent of tricuspid regurgitation severity and degree of pulmonary hypertension. RV dilatation is a manifestation of RV dysfunction. The evaluation of RV performance should integrate the information about both RV size and function.

Combined Right and Left Ventricular Reperfusion Injury following Percutaneous Coronary Intervention: Role of Myocardial Contrast Echocardiography

Right ventricular myocardial infarction (RVMI) occurs in up to half of the patients of inferior wall myocardial infarction. RVMI results in edema and increased right ventricular (RV) mass, and hence, it should be possible to visualize microvascular obstruction as a manifestation of reperfusion injury. Reperfusion injury of the RV myocardium following primary percutaneous coronary intervention has been rarely reported. This report describes a patient with the left ventricular inferior and RVMI who showed echocardiographically detected reperfusion injury of the RV-free wall and left ventricular basal inferolateral wall and conformed by myocardial contrast perfusion study despite successful percutaneous revascularization of the right coronary artery.

Establishment and Confirmation of a Postnatal Right Ventricular Volume Overload Mouse Model.

Right ventricular (RV) volume overload (VO) is common in children with congenital heart disease. In view of distinct developmental stages,the RV myocardium may respond differently to VO in children compared to adults. The present study aims to establish a postnatal RV VO model in mice using a modified abdominal arteriovenous fistula. To confirm the creation of VO and the following morphological and hemodynamic changes of the RV, abdominal ultrasound, echocardiography, and histochemical staining were performed for 3 months. As a result, the procedure in postnatal mice showed an acceptable survival and fistula success rate. In VO mice, the RV cavity was enlarged with a thickened free wall, and the stroke volume was increased by about 30%-40% within 2 months after surgery. Thereafter, the RV systolic pressure increased, corresponding pulmonary valve regurgitation was observed, and small pulmonary artery remodeling appeared. In conclusion, modified arteriovenous fistula (AVF) surgery is feasible to establish the RV VO model in postnatal mice. Considering the probability of fistula closure and elevated pulmonary artery resistance, abdominal ultrasound and echocardiography must be performed to confirm the model status before application.

Fetal pulmonary valvuloplasty for pulmonary atresia with intact ventricular septum: a single-center clinical experience.

Fetal pulmonary valvuloplasty for pulmonary atresia with intact ventricular septum: a single-center clinical experience.

β3 adrenoceptor agonist mirabegron protects against right ventricular remodeling and drives Drp1 inhibition.

The right ventricular (RV) function determines the prognosis of patients with pulmonary hypertension (PH). Metabolic disorders have been observed in the RV myocardium in PH. Activation of the β3 adrenoceptor improves cardiac function and restores cardiac metabolic efficiency in rodents with heart failure; however, its role in the RV remains uncertain. Experimental PH was induced by monocrotaline (MCT) in rats. Mirabegron, a selective β3 adrenoceptor agonist, was given to MCT rats daily from the day after MCT injection at the dose of 10 mg/kg. In vivo echocardiography and RV catheterization were performed to assess RV hemodynamics, structure, and function. RV fibrosis and hypertrophy were assessed by Sirius Red (SR) and wheat germ agglutinin (WGA) staining respectively. Western blotting was performed to examine the markers of RV fibrosis and hypertrophy, as well as the levels of the key molecules and their phosphorylated forms. The molecular changes were confirmed in the cardiac hypertrophy model of angiotensin II (Ang II) treated H9c2 cardiomyocytes using western blotting. The overloaded RV had increased β3 adrenoceptor expression, which was further increased by mirabegron. Mirabegron reduced RV pressure and reduced RV structural and functional deterioration in MCT rats. Mirabegron decreased cardiac fibrosis and hypertrophy in the overloaded RV. Mirabegron suppressed dynaminrelated protein 1 (Drp1) and promoted AMP-activated protein kinase (AMPK) signaling in the overloaded RV and Ang II treated cardiomyocytes. The β3 adrenoceptor agonist mirabegron reduced RV hypertrophy and fibrosis in PH rats. The treatment effect involved Drp1 inhibition and AMPK activation.

Abstract 11637: Myocardial Metabolic Dysregulation and Right Ventricular Outcomes After Surgery for Advanced Heart Failure

Introduction: Inhaled pulmonary vasodilators (iPVD) help prevent right heart failure (RHF) by lowering PVR after surgery. However, variable change in PVR is seen in response to iPVD. As metabolism is central to cardiomyocyte function, we evaluated the role of right ventricular (RV) myocardial metabolism in iPVD response heterogeneity. Hypothesis: We previously identified plasma metabolic biomarkers as potential reporters of response heterogeneity and posited here that these key metabolites change in parallel with changes in RV phenotypes. Methods: We evaluated 63 LVAD or heart transplant recipients with precapillary pulmonary hypertension before surgery from a recent randomized trial (INSPIRE-FLO, NCT03081052). All participants received iPVD after heart-lung bypass through postoperative day 1 (pod 1). Targeted profiling of &gt; 500 metabolites (MxP® Quant 500, Biocrates) was performed in baseline and pod 1 plasma, and in RV free-wall full-thickness biopsies from LVAD recipients. Principal components analysis (PCA) was used for metabolite dimensionality reduction. Generalized linear models were used to assess the association of percent change (%Δ) in metabolite factors with (1) %Δ PVR (baseline to pod1); (2) responder, PVR &lt; 3 Wood U vs. non-responder, PVR ≥ 3 Wood U, on pod 1); (3) RHF after surgery. Results: PCA identified 21 factors with 204 metabolites clustering in biologically consistent pathways. Of these, %Δ in factor 8 (glycine and eight glycerophospholipids, GPs) were positively correlated with %Δ PVR (P &lt; 0.05). There was a trend for association in %Δ in factors 1 and 12 (ceramides, other GPs, amino acids: glutamate, aspartate, alanine, glutamine) and %Δ PVR (both P &lt; 0.10, negatively correlated). There was a trend for association in %Δ in factor 7 (long chain acylcarnitines) and subsequent RHF (P = 0.08, positively correlated). No metabolites were associated with responder status. Plasma levels of select metabolites in factors 1 and 12 were positively correlated with RV myocardial levels (P &lt; 0.05), suggesting a myocardial source. Conclusions: Leveraging a unique clinical trial cohort, we identified substrates of amino acid and fatty acid mitochondrial ß-oxidation metabolism in RV myocardium that may serve as biomarkers of metabolism in RHF.

Abstract 15182: Recruiting Super-Relaxed Myosin to Restore Contractility in Human Right Heart Failure

Intro: Right ventricular (RV) dysfunction worsens outcomes in pulmonary hypertension (PH) due to heart failure with reduced ejection fraction (HF), yet underlying mechanisms are unknown. We previously reported RV myofilament max calcium-activated tension (T max ) is reduced in human PH-HF. Here, we reveal that this decline is due to more myosin heads in the super-relaxed (SRX) state which lack force-production due to low ATP turnover. Methods: Frozen RV myocardium from 25 PH-HF and 9 control patients were permeabilized and myocyte mechanics and small angle X-ray diffraction measured. Results: RV T max (16±4 vs. 23±3 mN/mm 2 , p&lt;1x10 -15 ) and peak power (0.06±0.01 vs. 0.11±0.03, p=7.9x10 -5 ) were 50% lower in HF. Unsupervised machine learning (infinite mixture Dirichlet process) using mechanics identified two HF subgroups distinguished by RV T max : Group 1 with slightly reduced T max (19±1 mN/mm 2 , p=3.8x10 -6 ) and Group 2 with 40% reduced T max (14±3 mN/mm 2 , p&lt;1x10 -15 ), with Group 2 exhibiting clinically overt RV failure vs. Group 1 (right atrial pressure, RAP 14±6 vs. 9±4, p=0.01; RAP/pulmonary capillary wedge ratio 0.7±0.3 vs. 0.4±0.2, p=0.047). To test if low RV T max was associated with more SRX myosin, X-ray diffraction patterns from RV myofibers were used to determine the equatorial intensity ratio (I 1,1 /I 1,0 ), an indicator of myosin proximity to the thick filament backbone. The ratio was lower (more SRX), which was associated with reduced myosin ATP turnover in Group 2 vs. both 1 (p=9.0x10 -7 ) and controls (p=1.8x10 -9 ). We then tested the effect of SRX on T max by perturbing the proportion of SRX myosin using mavacamten (M), a myosin inhibitor that stabilizes the SRX state, and deoxy-ATP (dATP), a nucleotide that destabilizes SRX. In group 2, dATP augmented T max by 30% (p=0.0002) while M had no effect (p=0.1); meanwhile in group 1, M suppressed T max by 30% (p=0.0002) while dATP had no effect (p=0.9). Finally, a myosin activator EMD-57033, which increases probability of actin-myosin binding, augmented T max (correlation between ΔSRX-ΔT max r=-0.55, p=0.01). Conclusion: We find increased SRX myosin contributes to RV myofilament and chamber-level failure in PH-HF. Small molecules that recruit SRX myosin may have therapeutic benefit in patients with RV dysfunction.

High-resolution systolic T1 mapping with compressed sensing for the evaluation of the right ventricle: a phantom and volunteer study.

To investigate the usefulness of high-resolution systolic T1 mapping using compressed sensing for right ventricular (RV) evaluation. Phantoms and normal volunteers were scanned at 3T by using a high-resolution (HR) modified look-locker inversion recovery (MOLLI) pulse sequence and a conventional MOLLI pulse sequence. The T1 values of the left ventricular (LV) and RV myocardium and blood pool were measured for each sequence. T1 values of HR-MOLLI and MOLLI sequences were compared in the LV myocardium, blood pool, and RV myocardium. The T1 values of HR-MOLLI and MOLLI showed good agreement in both phantoms and the LV myocardium and blood pool of volunteers. However, there was a significant difference between HR-MOLLI and MOLLI in the RV myocardium (1258 ± 52ms vs. 1327 ± 73ms; P = 0.0005). No significant difference was observed between the T1 value of RV and that of LV (1217 ± 32ms) in HR-MOLLI, whereas the T1 value of RV was significantly higher than that of LV in MOLLI (P < 0.0001). The interclass correlation coefficients of intraobserver variabilities from HR-MOLLI and MOLLI were 0.919 and 0.804, respectively, and the interobserver variabilities from HR-MOLLI and MOLLI were 0.838 and 0.848, respectively. Assessment of RV myocardium by using HR systolic T1 mapping was superior to the conventional MOLLI sequence in terms of accuracy and reproducibility.

Arrhythmogenic right ventricular cardiomyopathy patients with a markedly enlarged RV compressing LV to left side have an atypical distribution of epsilon waves and elevated plasma BNP

Abstract Funding Acknowledgements Type of funding sources: None. Background Epsilon waves on V1-3 leads are specific ECG findings in patients with arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC) suggesting RV conduction delay. Four dimensional (4D) cardiac CT visualizes ARVC characteristics, such as fibro-fatty invasion into RV and left ventricular (LV) myocardium (RVM, LVM), an enlarged RV, reduced RV motion, and bulging. Purpose We hypothesize that Epsilon waves in V4-6 leads suggest LV invasion in ARVC. Alternatively, extreme RV enlargement may compress the LV and cause clockwise rotation; an enlarged RV may itself cause epsilon waves in V4-6 leads. Methods Retrospective analysis of 17 patients (11 males, 57 ± 17 yrs) with suspected ARVC undergoing cardiac CT and ECG, 9 of whom met 2010 ARVC task force criteria. Results All 9 patients had epsilon waves on ECG; 5 had fibro-fatty invasion into the LVM. We divided the 9 into 5 groups by CT: 1) markedly enlarged RV compressing the LV to the left side with fibro-fatty changes exclusively in RVM (N = 1); 2) similar findings in both RVM and LVM (N = 2); 3) moderately enlarged RV without compression of the LV to the left side and fibro-fatty changes exclusively in RVM (N = 3); 4) the same in both RVM and LVM (N = 2); 5) severe mitral valve regurgitation, a markedly enlarged LV, and a fibro-fatty change in both RVM and LVM (N = 1). The patient in group (gp) 1 showed epsilon waves in V1-6 leads, patients in gp 2 had epsilon waves in V1-6 (N = 1), and V3-5 (N = 1) leads; patients in gp 3 had epsilon waves in V1-4 (N = 2), and V1-3 (N = 1) leads, patients in gp 4 had epsilon waves in V1-3 (N = 1), and V1, 2 (N = 1) leads; finally, the patient in gp 5 had epsilon waves in V4-6 leads. Plasma brain natriuretic peptide (BNP) levels were significantly greater in patients in gp 1 &amp; 2 than gp 3 &amp; 4 (1255 ± 838 vs 80 ± 52 pg/ml, P = 0.016). Conclusions ARVC patients with a markedly enlarged RV compressing the LV to the left side (gp 1,2) had a broad (V1-6) or different range (V3-5) distribution of epsilon waves and significantly elevated plasma BNP independent of fibro-fatty invasion of the LV, different from typical ARVC (gp 3,4). Additionally, structural change due to complicated heart disease, such as valvular disease (gp5), may also influence the distribution of epsilon waves in ARVC. Abstract Figure. CT and ECG in ARVC group 1

Abstract 11877: Arrhythmogenic Right Ventricular Cardiomyopathy Patients with a Markedly Enlarged RV Compressing LV to Left Side Have an Atypical Distribution of Epsilon Waves and Elevated Plasma BNP

Introduction: Epsilon waves on V1-3 leads are specific ECG findings in patients with arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC). 4D cardiac CT visualizes ARVC characteristics, such as fibro-fatty invasion into RV and left ventricular (LV) myocardium (RVM, LVM), an enlarged RV, reduced RV motion, and bulging. Hypothesis: We hypothesize that epsilon waves in V4-6 leads suggest LV invasion in ARVC. Alternatively, extreme RV enlargement may compress the LV and cause clockwise rotation; an enlarged RV may itself cause epsilon waves in V4-6 leads. Methods: Retrospective analysis of 17 patients (11 males, 57±17 yrs) with suspected ARVC undergoing cardiac CT and ECG, 9 of whom met 2010 ARVC task force criteria. Result: All 9 patients had epsilon waves ; 5 had fibro-fatty invasion into the LVM. We divided the 9 into 5 groups by CT: 1) markedly enlarged RV compressing the LV to the left side with fibro-fatty changes exclusively in RVM (N=1); 2) similar findings in both RVM and LVM (N=2); 3) moderately enlarged RV without compression of the LV to the left side and fibro-fatty changes exclusively in RVM (N=3); 4) the same in both RVM and LVM (N=2); 5) severe mitral valve regurgitation, a markedly enlarged LV, and a fibro-fatty change in both RVM and LVM (N=1). The patient in group (gp) 1 showed epsilon waves in V1-6 leads, patients in gp 2 had epsilon waves in V1-6 (N=1), and V3-5 (N=1) leads; patients in gp 3 had epsilon waves in V1-4 (N=2), and V1-3 (N=1) leads, patients in gp 4 had epsilon waves in V1-3 (N=1), and V1, 2 (N=1) leads; finally, the patient in gp 5 had epsilon waves in V4-6 leads. Plasma BNP levels were significantly greater in patients in gp 1 &amp; 2 than gp 3 &amp; 4 (1255±838 vs 80±52 pg/ml, P=0.016). Conclusions: ARVC patients with a markedly enlarged RV compressing the LV to the left side (gp 1,2) had a broad (V1-6) or different range (V3-5) distribution of epsilon waves and significantly elevated plasma BNP independent of fibro-fatty invasion of the LV, different from typical ARVC (gp 3,4).

Depressed right ventricular systolic function in heart failure due to constrictive pericarditis.

AimsHeart failure in constrictive pericarditis (CP) is attributed to impaired biventricular diastolic filling. However, diseases that cause CP due to myocardial infiltration and fibrosis can also impair biventricular systolic function (sf) and contribute to heart failure. This study of patients with CP examined biventricular sf and the effect of myocardial infiltration by pericardial diseases and the resulting fibrosis on ventricular sf.Methods and resultsHistopathologic examinations of right ventricular (RV) and left ventricular (LV) myocardia and pericardia were performed on three autopsied hearts of patients with pericardial diseases. Additionally, in 40 adults with clinical heart failure and 40 healthy adults (controls), sf of both ventricles was examined by echocardiography, including strain measurements, and biventricular diastolic filling and pulmonary artery pressures were assessed by cardiac catheterization. Cardiac histopathology indicated thickening of the pericardium with fibrosis, disease infiltrating the myocardium, greater infiltration of the RV than the LV, and an association of pericardial thickness with myocardial infiltrations. Functional analysis indicated that RVsf was impaired on all echo indices, including strain measurement, but LVsf was preserved.ConclusionsDiseases causing CP are not restricted to the pericardium but also infiltrate the biventricular myocardium and affect the thin‐walled RV more than the thick‐walled LV, resulting in depressed RVsf. The present results help explain clinical heart failure in the presence of restricted diastolic filling in CP. Depression of RVsf due to progression of fibrosis in the RV myocardium may increase the risk of delayed pericardiectomy.

Right-ventricular dysfunction in HFpEF is linked to altered cardiomyocyte Ca2+ homeostasis and myofilament sensitivity.

AimsHeart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF.Methods and resultsHeart failure with preserved ejection fraction‐prone animals (ZSF‐1 obese) and control rats (Wistar Kyoto) were fed a high‐caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca2+) transients were assessed. ZSF‐1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end‐diastolic pressures and E/e′ ratio), and preserved LV ejection fraction. ZSF‐1 obese animals developed RV dilatation (50% increased end‐diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF‐1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca2+ transient amplitude was reduced. In addition, augmentation of cytosolic Ca2+ release with increased stimulation frequency was lost in ZSF‐1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF‐1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin‐binding protein C (Ser282 cMyBP‐C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF‐1 obese rats.ConclusionsRight ventricular dysfunction in obese ZSF‐1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca2+ amplitudes, loss of frequency‐dependent augmentation of Ca2+ release, and increased myofilament Ca2+ sensitivity.

Assessment of Right Ventricular Contractile Patterns Using Cardiac Magnetic Resonance Imaging Would Reflect the Underlying Mechanism of Right Ventricular Dysfunction

<h3>Purpose</h3> Right ventricular (RV) function has been recognized as an important prognostic factor in patients with heart failure. However, previous studies have focused on the global RV function such as RV ejection fraction (RVEF), not on RV contractile pattern. Cardiac magnetic resonance imaging (CMR) is a powerful imaging modality to assess RV morphological change together with its global systolic function.The purpose of this study is to elucidate the difference of RV contractile patterns in various heart diseases with RV dysfunction using CMR. <h3>Methods</h3> The CMR data obtained from 50 patients with RV dysfunction and 23 control subjects were analyzed.The patients with RV dysfunction were classified into 3 groups according to the etiology of RV dysfunction; RV volume-overload group (Group V, n=16, consisting of those with atrial septal defect), RV-dominant myocyte degeneration (Group M, n=17, consisting of arrhythmogenic right ventricular cardiomyopathy), and pericarditis group (Group P, n=17). The RV longitudinal contractile pattern (FLC: fractional longitudinal change) and the radial contractile pattern (FTC: fractional transverse change) were measured using a 4-chamber view of Cine-CMR. The ratio of transverse to longitudinal contraction (T/L ratio=FTC/FLC) was calculated. <h3>Results</h3> Both FLC and FTC significantly decreased in Groups M and P, while Group V showed relatively preserved FTC compared to control subjects. The T/L ratio was significantly lower in Group M than the other groups, while the value tended to be higher in Group V and P than the control (Figure). <h3>Conclusion</h3> Impaired transverse contractile pattern as reflected by the reduced T/L ratio may indicate the degeneration of RV myocardium itself, whereas this value tends to be preserved in patients with RV dysfunction due to volume overload. RV contractile pattern may help to understand the disease progression and the underlying cause of RV dysfunction.