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BackgroundRecently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress.MethodsWe performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling.ResultsWe first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction.ConclusionsCollectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

We used transverse aortic constriction (TAC) in mice to test the hypothesis that urocortin 2 (Ucn2) gene transfer would increase left ventricular (LV) systolic and diastolic function in the pressure-stressed LV. Three groups were studied: (1) control mice (no TAC); (2) mice that received saline 6 weeks after TAC; and (3) mice that received Ucn2 gene transfer 6 weeks after TAC, using adeno-associated virus 8 encoding murine Ucn2 (AAV8.mUcn2; 2 × 1013 genome copies (gc)/kg, i.v. per mouse). Echocardiography was performed 6 and 12 weeks after TAC. In terminal studies 12 weeks after TAC, rates of LV pressure development and decay and Tau were measured, and LV cardiac myocytes (CMs) were isolated and cytosolic Ca2+ transients and sarcomere shortening rates recorded. Reverse transcription polymerase chain reaction and immunoblotting were used to measure key proteins in LV samples. A CM cell line (HL-1) was used to explore mechanisms. Concentric LV hypertrophy was evident on echocardiography 6 weeks after TAC. Twelve weeks after TAC, LV ejection fraction (EF) was higher in mice that received Ucn2 gene transfer (TAC-saline: 65% ± 3%; TAC-Ucn2: 75% ± 2%; p = 0.01), as was LV peak +dP/dt (1.9-fold increase; p = 0.001) and LV peak -dP/dt (1.7-fold increase; p = 0.017). Tau was more rapid (23% reduction, p = 0.02), indicating improved diastolic function. The peak rates of sarcomere shortening (p = 0.002) and lengthening (p = 0.002) were higher in CMs from TAC-Ucn2 mice, and Tau was reduced (p = 0.001). LV (Ser-16) phosphorylation of phospholamban (PLB) was increased in TAC-Ucn2 mice (p = 0.025), and also was increased in HL-1 cells treated with angiotensin II to induce hypertrophy and incubated with Ucn2 peptide (p = 0.001). Ucn2 gene transfer in TAC-induced heart failure with preserved ejection fraction increased cardiac function in the intact LV and provided corresponding benefits in CMs isolated from study animals, including increased myofilament Ca2+ sensitivity during contraction. The mechanism includes enhanced CM Ca2+ handling associated with increased (Ser-16)-PLB.

BACKGROUND: In ≈25% of patients with heart failure and reduced left-ventricular ejection fraction, right-ventricular (RV), and left-ventricular (LV) filling pressures are discordant (ie, one is elevated while the other is not). Whether clinical assessment allows detection of this discordance is unknown. We sought to determine the agreement of clinically versus invasively determined patterns of ventricular congestion. METHODS: In 156 heart failure and reduced LV ejection fraction subjects undergoing invasive hemodynamic assessment, we categorized patterns of ventricular congestion (no congestion, RV only, LV only, or both) based on clinical findings of RV (jugular venous distention) or LV (hepatojugular reflux, orthopnea, or bendopnea) congestion. Agreement between clinically and invasively determined (RV congestion if right atrial pressure [RAP] ≥10 mm Hg and LV congestion if pulmonary capillary wedge pressure [PCWP] ≥22 mm Hg) categorizations was the primary end point. RESULTS: The frequency of clinical patterns of congestion was: 51% no congestion, 24% both RV and LV, 21% LV only, and 4% RV only. Jugular venous distention had excellent discrimination for elevated RAP (C=0.88). However, agreement between clinical and invasive congestion patterns was poor, к=0.44 (95% CI, 0.34-0.55). While those with no clinical congestion usually had low RAP and PCWP (67/79, 85%), over one-half (24/38, 64%) with isolated LV clinical congestion had PCWP

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.

BackgroundPressure overload left ventricular (LV) hypertrophy is characterized by increased cardiomyocyte width and ventricle wall thickness, however the regional variation of this remodeling is unclear. Cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI) may provide a non-invasive, comprehensive, and geometrically accurate method to detect regional differences in structural remodeling in hypertrophy. We hypothesized that DTI parameters, such as fractional and planar anisotropy, would reflect myocyte remodeling due to pressure overload in a regionally-dependent manner.MethodsWe investigated the regional distributions of myocyte remodeling in rats with or without transverse aortic constriction (TAC) via direct measurement of myocyte dimensions with confocal imaging of thick tissue sections, and correlated myocyte cross-sectional area and other geometric features with parameters of diffusivity from ex-vivo DTI in the same regions of the same hearts.ResultsWe observed regional differences in several parameters from DTI between TAC hearts and SHAM controls. Consistent with previous studies, helix angles from DTI correlated strongly with those measured directly from histological sections (p

BACKGROUND:Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin β chain (β93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection. METHODS:To test this hypothesis, we used RBCs from mice in which the β93 cysteine had been replaced with alanine (β93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity. RESULTS:In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (β93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with β93A RBCs. Next, when human platelets were coincubated with RBCs and then deoxygenated in the presence of nitrite, export of NO bioactivity was detected as inhibition of ADP-induced platelet activation. This effect was the same in β93C and β93A RBCs. Moreover, vascular reactivity was tested in rodent aortas in the presence of RBCs pretreated with S-nitrosocysteine or with hemolysates or purified Hb treated with authentic NO to form nitrosyl(FeII)-Hb, the proposed precursor of SNO-Hb. SNO-RBCs or NO-treated Hb induced vasorelaxation, with no differences between β93C and β93A RBCs. Finally, hypoxic microvascular vasodilation was studied in vivo with a murine dorsal skin-fold window model. Exposure to acute systemic hypoxia caused vasodilatation, and the response was similar in β93C and β93A mice. CONCLUSIONS:RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the β93 cysteine of Hb.

Background: Accurate assessment of left ventricular filling pressure in patients with atrial fibrillation or flutter (AF) remains difficult. A novel 2-dimensional scoring system, visually assessing time difference between mitral valve and tricuspid valve opening (VMT) score, based on temporal analysis of early diastolic valve opening, could be applied to these patients. We aimed to determine the usefulness of the VMT score in patients with AF., Methods: We analyzed 119 consecutive patients with AF who underwent cardiac catheterization as a derivation cohort. The diagnostic performance of the VMT score was further evaluated in an external data set containing 189 patients with AF. Elevated left ventricular filling pressure was defined as a mean pulmonary arterial wedge pressure ≥15 mm Hg. The time sequence of atrioventricular valve opening was visually assessed and scored (0, tricuspid valve first; 1, simultaneous; 2, mitral valve first). When the inferior vena cava was dilated, 1 point was added, and the VMT score was finally graded as 0 to 3. Conventional Doppler parameters to estimate left ventricular filling pressure were also measured., Results: Pulmonary arterial wedge pressure was elevated with an increase in the VMT score (0: 10±3, 1: 13±5, 2: 22±7, 3: 27±6 mm Hg; P <0.001), resulting in a significant rise in pulmonary arterial wedge pressure from VMT score 1 to 2. VMT≥2 predicted elevated pulmonary arterial wedge pressure with an accuracy of 87%, and the diagnostic accuracy of the VMT score was significantly higher than that of conventional Doppler parameters ( C index, 0.88 versus 0.54-0.68; P <0.001). In addition, VMT ≥2 showed an incremental predictive value over plasma brain natriuretic peptide levels ( C index, 0.79-0.93; P <0.001). In the external validation cohort, VMT≥2 demonstrated acceptable accuracy of 72%., Conclusions: VMT scoring was a useful echocardiographic marker of elevated left ventricular filling pressure and had an incremental benefit over practical biomarkers in patients with AF., Competing Interests: None.

Background: Dogs with internal hydrocephalus do not necessarily have high intraventricular pressure (IVP)., Hypothesis/objectives: Not all reported MRI findings indicate high IVP and some clinical signs might be associated with elevated IVP and syringomyelia., Animals: Fifty-three dogs., Materials and Methods: Cross-sectional study. Clinical signs and MRI findings were evaluated for an association of IVP >12 mm Hg and syringomyelia., Results: High IVP was associated with obtundation OR 4.64 (95% CI 1.27-16.93) (P = .02), head tilt OR 6.42 (95% CI 1.08-37.97) (P = .04) and nystagmus OR 8.24 (95% CI 1.44-47.07) (P = .02). Pain was associated with syringomyelia OR 3.4 (95% CI 0.98-11.78) (P = .05). The number of affected ventricles was associated with high IVP OR 2.85 (95% CI 0.97-8.33) (P = .05) and syringomyelia OR 12.74 (95% CI 2.93-55.4) (P = .0007). Periventricular edema OR 24.46 (95% CI 4.54-131.77), OR 7.61 (95% CI 1.91-30.32) (P < .0002, P = .004) and signal void sign OR 17.34 (95% CI 4.01-74.95), OR 4.18 (95% CI 1.16-15.02) (P < .0001, P = .03) were associated with high IVP and syringomyelia. The probability for syringomyelia is lower with disruption of the internal capsule OR 0.19 (95% CI 0.05-0.72) (P = .01) and higher VBR OR 0.25 (95% CI 0.1-0.63) (P = .004)., Conclusions and Clinical Importance: Previously reported MRI findings are not predictive of high IVP. Clinical signs and MRI findings should be used to make a diagnosis of internal hydrocephalus in dogs with or without high IVP., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Left bundle branch area pacing (LBBAP) may be an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). We sought to compare the acute hemodynamic and ECG effects of LBBAP, BVP, and left bundle-optimized therapy CRT (LOT-CRT) in CRT candidates with advanced conduction disease., Methods: In this multicenter study, 48 patients with either nonspecific interventricular conduction delay (n=29) or left bundle branch block (n=19) underwent acute hemodynamic testing to determine the change in left ventricular pressure maximal first derivative (LV d P /d t max ) from baseline atrial pacing to BVP, LBBAP, or LOT-CRT., Results: Atrioventricular-optimized increases in LV d P /d t max for LOT-CRT (mean, 25.8% [95% CI, 20.9%-30.7%]) and BVP (26.4% [95% CI, 20.2%-32.6%]) were greater than unipolar LBBAP (19.3% [95% CI, 15.0%-23.7%]) or bipolar LBBAP (16.4% [95% CI, 12.7%-20.0%]; P ≤0.005). QRS shortening was greater in LOT-CRT (29.5 [95% CI, 23.4-35.6] ms) than unipolar LBBAP (11.9 [95% CI, 6.1-17.7] ms), bipolar LBBAP (11.7 ms [95% CI, 6.4-17.0]), or BVP (18.5 [95% CI, 11.0-25.9] ms), all P ≤0.005. Compared with patients with left bundle branch block, patients with interventricular conduction delay experienced less QRS reduction ( P =0.026) but similar improvements in LV d P /d t max ( P =0.29). Bipolar LBBAP caused anodal capture in 54% of patients and resulted in less LV d P /d t max improvement than unipolar LBBAP (18.6% versus 23.7%; P <0.001). Subclassification of LBBAP capture (European Heart Rhythm Association criteria) indicated LBBAP or LV septal pacing in 27 patients (56%) and deep septal pacing in 21 patients (44%). The hemodynamic benefit of adding left ventricular coronary vein pacing to LBBAP depended on baseline QRS duration ( P =0.031) and success of LBBAP ( P <0.004): LOT-CRT provided 14.5% (5.0%-24.1%) greater LV d P /d t max improvement and 20.8 (12.8-28.8) ms greater QRS shortening than LBBAP in subjects with QRS ≥171 ms and deep septal pacing capture type., Conclusions: In a CRT cohort with advanced conduction disease, LOT-CRT and BVP provided greater acute hemodynamic benefit than LBBAP. Subjects with wider QRS or deep septal pacing are more likely to benefit from the addition of a left ventricular coronary vein lead to implement LOT-CRT., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04905290., Competing Interests: Dr Jastrzębski: speaker/consultant honoraria from Abbott, Biotronik, Boston Scientific, and Medtronic. Dr Foley: consultant to Medtronic, proctor for Medtronic. Dr Chandrasekaran: honoraria, consultancy fees and funding support from Medtronic, Biotronik, and Abbot. Dr Whinnett: speaker honoraria, consulting fees, and institutional fellowship/research support from Abbot, Boston Scientific, and Medtronic. Dr Vijayaraman: Medtronic: honoraria, consultant, research and fellowship support Abbott: honoraria, consultant Boston Scientific/Biotronik: honoraria; patent: HBP delivery tool. Dr Upadhyay: consulting and speaker honoraria from Abbott, Biotronik, Boston Scientific, GE Healthcare, Medtronic, Philips, Rhythm Science, and Zoll Medical. R.D. Schaller: speaking honoraria for Medtronic. Dr Richardson: consulting and speaking honoraria from Medtronic, Inc. Dr Herweg: fellowship support from Medtronic, speaker for Medtronic and Abbott. Dr Stadler, D. Kudlik, R. Waxman, Dr Zimmerman, J. Burrell, and Dr Cornelussen are Medtronic employees. The other authors report no conflicts

Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV K c ) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs ( n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs ( n = 6) served as controls. LV function was measured by echocardiography and LV K c by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed ( n = 10, n = 9, respectively). LV samples from LVPO and controls ( n = 6, respectively) were subjected to RNA sequencing. LV mass and K c increased by over 40% with LVPO ( P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV K c ( P < 0.05) that mapped to functional domains relevant to K c such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold ( P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets. NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.

Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis., Competing Interests: Conflict of interest: A. Arvanitaki, M.A. Gatzoulis and C. McCabe declare no conflicts of interest relevant to this work. ​G.P. Diller has received honoraria and travel grants from Janssen Global. L.C. Price has received consultancy fees from Janssen and educational support and conference support from Janssen and Ferrer. S.J. Wort has received consultancy fees from Janssen, Acceleron, MSD, Ferrer and Bayer, honoraria from Janssen, Acceleron, MSD, Ferrer and Bayer, as well as travel and research grants from Janssen and Ferrer., (Copyright ©The authors 2024.)

Left atrium longitudinal strain (LAS) with speckle tracking method has been proposed as a non-invasive method for the assessment of left ventricular filling pressure and diastolic dysfunction. This study aimed to investigate left atrial strain compared to invasively measured left ventricular filling pressure. All Patients candidates for coronary angiography were consecutively recruited. LAS measured by transthoracic echocardiography. Left ventricular end-diastolic pressure (LVEDP) pressure was invasively measured. Current echocardiographic modalities for diastolic function evaluated. A total of 125 people were included. 45 patients had preserved ejection fraction (EF ≥ 50%) and 85 patients had reduced EF (EF < 50%) and compared two groups. LVEDP was significantly higher in reduced EF compared to preserved EF (p-value < 0.001). LA-reservoir and LA-booster strains were significantly lower in patients with reduced EF compared to preserved EF (p-value = 0.008, mean Reservoir = 16.4% ± 6.4, mean Reservoir = 19.5% ± 5.6, respectively) and (p-value = 0.009, mean Booster = 9.09% ± 4.0, mean Booster =11. 9% ± 4.3, respectively). LA 4ch-reservoir strain <14.4%, and LA 2ch-reservoir strain <14.1% were related to LVEDP≥20 mmHg (sensitivity 63.5% and specificity 75%) (sensitivity 77.9% and specificity of 60%) respectively. LAS is significantly lower in patients with elevated LVEDP (≥ 20mmHg). LAS is significantly lower in patients with reduced EF. Both LA-reservoir and LA-booster strains have a significant relation to predicting LVFP but LA-reservoir strain is more accurate. The mean LA-reservoir strain less than 12.4% is associated with LVEDP ≥ 20mmHg., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardiopulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age of 13.4 ± 2.9 yr old. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ± 25 mmHg at rest to 130 ± 40 mmHg at peak exercise ( P < 0.001), whereas RV fractional area change (RV-FAC) and RV-free wall longitudinal strain (RVFW-S l ) worsened (35.2 vs. 27%, P = 0.09 and -16.6 vs. -14.6%, P = 0.1, respectively). At low- and moderate-intensity exercise, RVsp was positively associated with stroke volume and O 2 pulse ( P < 0.1). At high-intensity exercise, RV-FAC, RVFW-S l , and left ventricular longitudinal strain were positively associated with oxygen uptake and O 2 pulse ( P < 0.1), whereas stroke volume decreased toward peak ( P = 0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV to pulmonary artery (RV-PA) uncoupling, worsening of interventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population. NEW & NOTEWORTHY In children with pulmonary arterial hypertension, there is a marked increase in pulmonary artery pressure during physical activity, but this is not the underlying mechanism that limits exercise. Instead, right ventricle-to-pulmonary artery uncoupling occurs at the transition from moderate to high-intensity exercise and correlates with lower peak oxygen uptake. This highlights the more complex underlying pathological responses and the need for multiparametric assessment of cardiac function reserve in these patients when feasible.

The prompt and precise identification of hemodynamically significant coronary artery lesions remains an ongoing challenge. This study investigated the diagnostic value of non-invasive global left ventricular myocardial work indices by echocardiography in functional status of coronary artery disease (CAD) patients with myocardial ischemia using fractional flow reserve (FFR) as the gold standard. A total of 77 consecutive patients with clinically suspected CAD were prospectively enrolled. All participants sequentially underwent echocardiography, invasive coronary angiography (ICA) and FFR measurement. According to the results of ICA, patients were divided into myocardial ischemia group (FFR ≤ 0.8, n = 27) and non-myocardial ischemia group (FFR > 0.8, n = 50). Myocardial work indices including global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE), global positive work (GPW), global negative work (GNW), global systolic constructive work (GSCW) and global systolic wasted work (GSWW) were obtained by using the non-invasive left ventricular pressure strain loop (PSL) technique. Compared with the non-myocardial ischemia group, GWI, GCW, GPW and GSCW were significantly decreased in the myocardial ischemia group at either the 18-segment level or the 12-segment level (P < 0.001). At the 18-segment level, GWI < 1783.6 mmHg%, GCW < 1945.4 mmHg%, GPW < 1788.7 mmHg% and GSCW < 1916.5 mmHg% were optimal cut-off value to detect myocardial ischemia with an FFR ≤ 0.8. Global left ventricular myocardial work indices by echocardiography exhibited a good diagnostic value in patients with CAD and may have a good clinical significance for the screening of suspected myocardial ischemia., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% ( P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction. NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

The aim of the study is to analyze ventricular-vascular properties with different ventricular-arterial coupling (VAC) ratio in the preeclamptic women. Seventy-seven pregnant women with preeclampsia and eighty-nine with normal pregnancy were performed echocardiography. VAC was defined as the ratio between aortic elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees). Using the VAC value of 0.8 as the cut-off near uncoupling, the preeclampsia cases were divided into two subgroups: VAC ratio ≥ 0.8 and <0.8. Cardiac structure and function, VAC properties, as well as four components of the LV pressure-strain loop, including global myocardial work index (GWI), constructive work (GCW), wasted work (GWW), and work efficiency (GWE) were determined. The preeclampsia with VAC ≥ 0.8 had an enlarger indexed ventricular volume and a thicker relative ventricular wall than the VAC < 0.8. The Ees significantly increased in the subgroup with VAC < 0.8 and decreased in the VAC ≥ 0.8, while the Ea increased in both of them. The preeclampsia with VAC ≥ 0.8 showed an obvious augmentation in GWI, GCW and GWE, along with a similar GWW compared to those with VAC < 0.8. There were variable relationships between the LV pressure-strain components and VAC properties. Thus, the preeclampsia with VAC ≥ 0.8 undergoes a more adverse remodeling and a greater impact on cardiac contractility. The increased stiffness of the heart and arterial system, and increased resistance of peripheral vessels net lead to the deteriorative ventricular efficiency with elevated myocardial oxygen consumption during a preeclampsia pregnancy., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Hydrocephalus is a broad term usually understood as cerebrospinal fluid (CSF) accumulation resulting in cerebral ventricular system expansion. The production of CSF is by the choroid plexus in lateral ventricles, flowing between the third and fourth ventricles and eventually to the subarachnoid space. It is critical for proper neuronal function. Hydrocephalus is a neurological pathology linked to high morbidity from neurocognitive and motor impairment. It is classified as either communicating or non-communicating. Communicating hydrocephalus is understood as a deficit at cranial arachnoid villi and granulation absorption sites. However, there has been evidence that extracranial lymphatic vessels in the ethmoid bone region also play a role, as indicated by decreased lymphatic absorption in rat models of hydrocephalus. Treatment typically involves surgical shunt placement or endoscopic third ventriculostomy (ETV) technique with or without choroid plexus cauterization (CPC). These surgical interventions have high failure risks and complications that require re-intervention, further increasing morbidity and mortality risks. To date, there are few nonsurgical treatment strategies, but many have proved limited benefit, and many patients still require surgery. This analysis lays out the typical treatments and explores new, innovative interventions by highlighting the active role of brain parenchymal tissue in the pathogenesis of hydrocephalus., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mirkhaef et al.)

Right ventricular (RV) diastolic function has been associated with outcomes for patients with pulmonary hypertension; however, the relationship between biomechanics and hemodynamics in the right ventricle has not been studied. Rat models of RV pressure overload were obtained via pulmonary artery banding (PAB; control, n=7; PAB, n=5). At 3 weeks after banding, RV hemodynamics were measured using a conductance catheter. Biaxial mechanical properties of the RV free wall myocardium were obtained to extrapolate longitudinal and circumferential elastic modulus in low and high strain regions (E1 and E2, respectively). Hemodynamic analysis revealed significantly increased end-diastolic elastance (Eed) in PAB (control: 55.1 mm Hg/mL [interquartile range: 44.7-85.4 mm Hg/mL]; PAB: 146.6 mm Hg/mL [interquartile range: 105.8-155.0 mm Hg/mL]; P=0.010). Longitudinal E1 was increased in PAB (control: 7.2 kPa [interquartile range: 6.7-18.1 kPa]; PAB: 34.2 kPa [interquartile range: 18.1-44.6 kPa]; P=0.018), whereas there were no significant changes in longitudinal E2 or circumferential E1 and E2. Last, wall stress was calculated from hemodynamic data by modeling the right ventricle as a sphere: stress=Pressure×radius2×thickness. RV pressure overload in PAB rats resulted in an increase in diastolic myocardial stiffness reflected both hemodynamically, by an increase in Eed, and biomechanically, by an increase in longitudinal E1. Modest increases in tissue biomechanical stiffness are associated with large increases in Eed. Hemodynamic measurements of RV diastolic function can be used to predict biomechanical changes in the myocardium.

Abstract Background: The cardiovascular system is one of the first systems to be affected by snake toxins; but not many toxins exert a direct effect on the heart. Cobra venom cardiotoxins are among those few toxins that attack the heart. Although the two cardiotoxin types (S and P) differ in their central-loop structure, it is not known whether they differ in their effect on the mammalian heart. We compared the effects of S- and P-type cardiotoxins, CTХ-1 and CTХ-2, respectively, from the cobra Naja oxiana, on the isolated rat heart. Methods: An isolated rat heart perfused according to the Langendorff technique was used in this study to investigate the activity of cardiotoxins CTX-1 and CTX-2. The following parameters were registered: the left ventricular developed pressure, calculated as the difference between systolic and diastolic pressure in the left ventricle, the end-diastolic pressure, the heart rate, time to maximal end-diastolic pressure (heart contracture), and time to depression of the heart contraction. Results: Both cardiotoxins at the concentration of 5 μg/mL initially produce a slight increase in systolic intraventricular pressure, followed by its rapid decrease with a simultaneous increase in diastolic intraventricular pressure until reaching contracture. CTX-2 blocks cardiac contractions faster than CTX-1; in its presence the maximum diastolic pressure is reached faster and the magnitude of the developed contracture is higher. Conclusion: The P-type cardiotoxin CTX-2 more strongly impairs rat heart functional activity than the S-type cardiotoxin CTX-1, as expressed in its faster blockage of cardiac contractions as well as in more rapid development and greater magnitude of contracture in its presence.

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

Aim: To study the relaxation structure of the left ventricle (LV) in patients who underwent ventriculography., Material and Methods: LV ventriculography was performed in 37 patients. Before catheterization, echocardiography was performed in each patient. In 6 patients, the LV ejection fraction (EF) was below 40%; these patients with systolic dysfunction were not included in the study. In 31 patients, the LV EF was higher than 50%. In this group, 13 patients had NYHA functional class (FC) 2-3 chronic heart failure (CHF); the rest of the patients had FC 1 CHF. Eighteen of 31 patients had stable ischemic heart disease; 50% of these patients had a history of myocardial infarction; the rest of the patients had hypertension and atrial and ventricular arrhythmias. The dynamics of the LV pressure decrease was analyzed from the moment of the maximum rate of pressure drop, which usually coincides with the closure of the aortic valves. The pressure drop curve was logarithmized with natural logarithms and divided into 4-5 sections with different degrees of curve slope. The relaxation time constant was calculated for each section. Its inverse value characterizes the relaxation time constant (tau)., Results: In 31 patients with LV EF 52-60%, three types of the dynamics of the relaxation rate constant were identified during the pressure decrease in the isovolumic phase: in 9 patients, the isovolumic relaxation constant (IRC) steadily increased as the pressure decreased; in 13 patients, it continuously decreased; and in 9 patients, the dynamics of IRC change was intermediate, with an initial increase followed by a decrease., Conclusion: In diastolic dysfunction, one group of patients had an adaptation type associated with an increase in the LV wall elasticity, while the other group had a different type of adaptation associated with its decrease. Each type has advantages and disadvantages. This is probably due to changes in the structure of the sarcomeric protein connectin (titin).

Ex situ heart perfusion (ESHP) has emerged as an important strategy to preserve donation after brain death (DBD) and donation after circulatory death (DCD) donor hearts. Clinically, both DBD and DCD hearts are successfully preserved using ESHP. Viability assessment is currently based on biochemical values, while a reliable method for graft function assessment in a physiologic working mode is unavailable. As functional assessment during ESHP has demonstrated the highest predictive value of outcome post-transplantation, this is an important area for improvement. In this study, a novel method for ex situ assessment of left ventricular function with pressure-volume loop analyses is evaluated. Ovine hearts were functionally evaluated during normothermic ESHP with the novel pressure-volume loop system. This system provides an afterload and adjustable preload to the left ventricle. By increasing the preload and measuring end-systolic elastance, the system could successfully assess the left ventricular function. End-systolic elastance at 60 min and 120 min was 2.8 ± 1.8 mmHg/mL and 2.7 ± 0.7 mmHg/mL, respectively. In this study we show a novel method for functional graft assessment with ex situ pressure-loop analyses during ESHP. When further validated, this method for pressure-volume assessments, could be used for better graft selection in both DBD and DCD donor hearts., Competing Interests: Authors BW, AvP, and FN were employed by XVIVO. ME holds a patent with XVIVO. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ertugrul, Puspitarani, Wijntjes, Vervoorn, Ballan, van der Kaaij, van Goor, Westenbrink, van der Plaats, Nijhuis, van Suylen and Erasmus.)

Background: Wild-type transthyretin amyloid (ATTRwt) cardiomyopathy is increasingly recognized in the development of heart failure. The link between cardiac performance, hemodynamics, and mitochondrial function in disease stages of ATTRwt has not previously been studied but may provide new insights into the pathophysiology and clinical performance of the patients., Methods and Results: The study investigated 47 patients diagnosed with ATTRwt at Aarhus University Hospital, Denmark. Patients were stratified according to the disease stages of the National Amyloidosis Centre (NAC) as NAC I with low levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (NAC I-L, n=14), NAC I with high levels NT-proBNP (NAC I-H, n=20), and NAC II-III (n=13). Exercise testing with simultaneous right heart catheterization was performed in all patients. Endomyocardial biopsies were collected from the patients and the mitochondrial oxidative phosphorylation capacity was assessed. All NAC disease groups, even in the NAC I-L group, a significant abnormal increase in biventricular filling pressures were noted during exercise while the filling pressures was normal or near normal at rest. The inotropic response to exercise was reduced with diminished increase in cardiac output which was significantly more pronounced in the NAC I-H (Diff. -2.4, 95% CI (-4.2: -0.7), P =0.00) and the NAC II-III group (Diff: -3.1 L/min, 95% CI (-5.2: -1.1), P =0.00) compared with the NAC I-L group. The pulmonary artery wedge pressure to cardiac output ratio at peak exercise was significantly different between NAC I-L and NAC II-III (Diff: 1.6 mm Hg*min/L, 95% CI (0.01:3.3, P =0.04)). Patients with ATTRwt had a reduced oxidative phosphorylation capacity which correlated to left ventricular mass but not to cardiac output capacity., Conclusions: An abnormal restrictive left ventricle and right ventricle response to exercise was demonstrated, even present in patients with early-stage ATTRwt. In more advanced disease stages a progressive impairment of the pressure-flow relationship was noted. The myocyte energetics is deranged but not associated to the contractile reserve or restrictive filling characteristics in ATTRwt.

To investigate noninvasive pressure-strain loop (PSL) combined with two-dimensional speck tracking imaging and left ventricular pressure measurement in the evaluation of cardiac function changes in anemia of prematurity (AOP) with different modes of respiratory support, and to explore its value in detecting subclinical myocardial injury in preterm infants. This retrospective study included 79 preterm infants with anemia, according to different modes of respiratory support, who were divided into invasive respiratory support group (39 cases) and noninvasive respiratory support group (40 cases). A control group of 40 nonanemic preterm infants with matched age, sex, and gestational age were also included. Complete echocardiography was performed for each included infant. There are PSL parameters that used to evaluate cardiac function, including global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) among the three groups were compared. Compared with the control group, the value of GWI, GCW, and GWE were significantly lower and GWW was higher in the AOP groups (P < 0.05), and GWI, GCW and GWE were much significantly lower in the invasive respiratory support group than in the noninvasive respiratory support group (P < 0.05). There was no significant difference in GLS among the three groups (P > 0.05). Noninvasive PSL analysis can quantitatively assess myocardial work in AOP with different respiratory support, which is more sensitive than other conventional echocardiographic indices. This technique may provide a new method for monitoring subclinical myocardial injury with AOP., (© 2024. The Author(s).)

ObjectivePrognosis in pulmonary hypertension (PH) is largely determined by RV function. However, uncertainty remains about what metrics of RV function might be most clinically relevant. The purpose of this study was to assess the clinical relevance of metrics of RV functional adaptation to increased afterload.MethodsPatients referred for PH underwent right heart catheterisation and RV volumetric assessment within 48 h. A RV maximum pressure (Pmax) was calculated from the RV pressure curve. The adequacy of RV systolic functional adaptation to increased afterload was estimated either by a stroke volume (SV)/end-systolic volume (ESV) ratio, a Pmax/mean pulmonary artery pressure (mPAP) ratio, or by EF (RVEF). Diastolic function of the RV was estimated by a diastolic elastance coefficient β. Survival analysis was via Cox proportional HR, and Kaplan-Meier with the primary outcome of time to death or lung transplant.ResultsPatients (n=50; age 58±13 yrs) covered a range of mPAP (13-79 mm Hg) with an average RVEF of 39±17% and ESV of 143±89 mL. Average estimates of the ratio of end-systolic ventricular to arterial elastance were 0.79±0.67 (SV/ESV) and 2.3±0.65 (Pmax/mPAP-1). Transplantation-free survival was predicted by right atrial pressure, mPAP, pulmonary vascular resistance, β, SV, ESV, SV/ESV and RVEF, but after controlling for right atrial pressure, mPAP, and SV, SV/ESV was the only independent predictor.ConclusionsThe adequacy of RV functional adaptation to afterload predicts survival in patients referred for PH. Whether this can simply be evaluated using RV volumetric imaging will require additional confirmation.

Right ventricular (RV) failure in response to pulmonary hypertension (PH) is a severe disease that remains poorly understood. PH-induced pressure overload leads to changes in the RV free wall (RVFW) that eventually results in RV failure. While the development of computational models can benefit our understanding of the onset and progression of PH-induced pressure overload, detailed knowledge of the underlying structural and biomechanical events remains limited. The goal of the present study was to elucidate the structural and biomechanical adaptations of RV myocardium subjected to sustained pressure overload in a rat model. Hemodynamically confirmed severe chronic RV pressure overload was induced in Sprague-Dawley rats via pulmonary artery banding. Extensive tissue-level biaxial mechanical and histomorphological analyses were conducted to assess the remodeling response in the RV free wall. Simultaneous myofiber hypertrophy and longitudinal re-orientation of myo- and collagen fibers were observed, with both fiber types becoming more highly aligned. Transmural myo- and collagen fiber orientations were co-aligned in both the normal and diseased state. The overall tissue stiffness increased, with larger increases in longitudinal vs. circumferential stiffness. The latter was attributed to longitudinal fiber re-orientation, which increased the degree of anisotropy. Increased mechanical coupling between the two axes was attributed to the increased fiber alignment. Interestingly, estimated myofiber stiffness increased while the collagen fiber stiffness remained unchanged. The increased myofiber stiffness was consistent with clinical results showing titin-associated increased sarcomeric stiffening observed in PH patients. These results further our understanding of the underlying adaptive and maladaptive remodeling mechanisms and may lead to improved techniques for prognosis, diagnosis, and treatment for PH.

Résumé: La circulation extracorporelle avec oxygénateur à membrane veino-artérielle (ECMO-VA) est de plus en plus utilisée pour la prise en charge des chocs cardiogéniques réfractaires, mais reste associée à une mortalité élevée et à de nombreuses complications. La réinjection par une canule artérielle fémorale entraîne un flux rétrograde dans l'aorte descendante qui s'oppose au débit cardiaque propre du patient. Ceci est à l'origine d'une augmentation de la post-charge du ventricule gauche et favorise la survenue de dilatation ventriculaire gauche, la formation de thrombus intracavitaires et l'œdème pulmonaire. Ces complications constituent une problématique centrale lors de la prise charge des patients sous ECMO-VA et leur prévention et prise en charge ont un impact sur le pronostic des patients. Les principales stratégies préventives consistent en la baisse du débit d'ECMO, la mise en place d'une réinjection antérograde, d'un ballon de contre-pulsion intra-aortique ou encore d'une Impella®. La prise en charge curative repose sur la décharge du ventricule gauche par voie chirurgicale ou percutanée. The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for refractory cardiogenic choc keeps growing but its mortality and complication rates remains high. Reinjection through a femoral artery cannula causes retrograde flow in the descending aorta that opposes the patient's own cardiac output. It leads to an increased left ventricular afterload and favors the occurrence of left ventricular dilation, the formation of intracavitary thrombi and pulmonary edema. These complications are a central issue in the management of patients assisted by VA-ECMO and their prevention and management has an impact on patient's prognosis. The main preventive strategies are based on reducing ECMO flow, setting up an antegrade reinjection flow, an intra-aortic balloon pump or an Impella®. The curative management is based on the discharge of the left ventricle by surgical or percutaneous methods. [ABSTRACT FROM AUTHOR]

Mechanical stretch of cardiac muscle modulates action potential propagation velocity, causing potentially arrhythmogenic conduction slowing. The mechanisms by which stretch alters cardiac conduction remain unknown, but previous studies suggest that stretch can affect the conformation of caveolae in myocytes and other cell types. We tested the hypothesis that slowing of action potential conduction due to cardiac myocyte stretch is dependent on caveolae. Cardiac action potential propagation velocities, measured by optical mapping in isolated mouse hearts and in micropatterned mouse cardiomyocyte cultures, decreased reversibly with volume loading or stretch, respectively (by 19±5% and 26±4%). Stretch-dependent conduction slowing was not altered by stretch-activated channel blockade with gadolinium or by GsMTx-4 peptide, but was inhibited when caveolae were disrupted via genetic deletion of caveolin-3 (Cav3 KO) or membrane cholesterol depletion by methyl-β-cyclodextrin. In wild-type mouse hearts, stretch coincided with recruitment of caveolae to the sarcolemma, as observed by electron microscopy. In myocytes from wild-type but not Cav3 KO mice, stretch significantly increased cell membrane capacitance (by 98±64%), electrical time constant (by 285±149%), and lipid recruitment to the bilayer (by 84±39%). Recruitment of caveolae to the sarcolemma during physiologic cardiomyocyte stretch slows ventricular action potential propagation by increasing cell membrane capacitance.

BackgroundRapid determination of the left ventricular (LV) pressure-volume (PV) relationship as loading conditions are varied is the gold standard for assessment of LV function. Cine magnetic resonance imaging (MRI) does not have sufficient spatiotemporal resolution to assess beat-to-beat changes of the LV PV relationship required to measure the LV end-systolic elastance (EES) or preload-recruitable stroke work (PRSW). Our aim was to investigate real-time MRI and semiautomated LV measurement of LV volume to measure PV relations in large animals under normal and inotropically stressed physiologic conditions.MethodsWe determined that PV relationships could be accurately measured using an image exposure time Tex less than 100 ms and frame rate Tfr less than 50 ms at elevated heart rates (∼140 beats per minute) using a golden angle radial MRI k-space trajectory and active contour segmentation.ResultsWith an optimized exposure time (Tex=95 ms and frame rate Tfr=2.8 ms), we found that there was no significant difference between cine and real-time MRI at rest in end-diastolic volume, end-systolic volume, ejection fraction, stroke volume, or cardiac output (n=5, p

Patients with pulmonary hypertension associated with congenital heart disease survive longer with preserved right ventricular (RV) function compared with those with primary pulmonary hypertension. The purpose of this study was to test the hypothesis that superior RV performance can be demonstrated, at baseline and when challenged with increased RV afterload, in lambs with chronic left-to-right cardiac shunts compared with control lambs. A shunt was placed between the pulmonary artery and the aorta in fetal lambs (shunt). RV pressure-volume loops were obtained 4 wk after delivery in shunt and control lambs, before and after increased afterload was applied using pulmonary artery banding (PAB). Baseline stroke volume (8.7 ± 1.8 vs. 15.8 ± 2.7 ml, P = 0.04) and cardiac index (73.0 ± 4.0 vs. 159.2 ± 25.1 ml·min(-1)·kg(-1), P = 0.02) were greater in shunts. After PAB, there was no difference in the change in cardiac index (relative to baseline) between groups; however, heart rate (HR) was greater in controls (168 ± 7.3 vs. 138 ± 6.6 beats/min, P = 0.01), and end-systolic elastance (Ees) was greater in shunts (2.63 vs. 1.31 × baseline, P = 0.02). Control lambs showed decreased mechanical efficiency (71% baseline) compared with shunts. With acute afterload challenge, both controls and shunts maintained cardiac output; however, this was via maladaptive responses in controls, while shunts maintained mechanical efficiency and increased contractility via a proposed enhanced Anrep effect-the second, slow inotropic response in the biphasic ventricular response to increased afterload, a novel finding in the RV. The mechanisms related to these physiological differences may have important therapeutic implications.

Background: Unilateral pulmonary artery (PA) stenosis is common in the transposition of the great arteries (TGA) after arterial switch operation (ASO) but the effects on the right ventricle (RV) remain unclear., Aims: To assess the effects of unilateral PA stenosis on RV afterload and function in pediatric patients with TGA-ASO., Methods: In this retrospective study, eight TGA patients with unilateral PA stenosis underwent heart catheterization and cardiac magnetic resonance (CMR) imaging. RV pressures, RV afterload (arterial elastance [Ea]), PA compliance, RV contractility (end-systolic elastance [Ees]), RV-to-PA (RV-PA) coupling (Ees/Ea), and RV diastolic stiffness (end-diastolic elastance [Eed]) were analyzed and compared to normal values from the literature., Results: In all TGA patients (mean age 12 ± 3 years), RV afterload (Ea) and RV pressures were increased whereas PA compliance was reduced. RV contractility (Ees) was decreased resulting in RV-PA uncoupling. RV diastolic stiffness (Eed) was increased. CMR-derived RV volumes, mass, and ejection fraction were preserved., Conclusion: Unilateral PA stenosis results in an increased RV afterload in TGA patients after ASO. RV remodeling and function remain within normal limits when analyzed by CMR but RV pressure-volume loop analysis shows impaired RV diastolic stiffness and RV contractility leading to RV-PA uncoupling., (© 2024 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Right ventricular (RV) diastolic stiffness is an independent predictor of survival and is strongly associated with disease severity in patients with precapillary pulmonary hypertension (PH). Therefore, a fully validated echocardiographic method for assessing RV diastolic stiffness needs to be established. This study aimed to compare echocardiography-derived RV diastolic stiffness and invasively measured pressure-volume loop-derived RV diastolic stiffness in patients with precapillary PH. We studied 50 consecutive patients with suspected or confirmed precapillary PH who underwent cardiac catheterization, magnetic resonance imaging, and echocardiography within a 1-week interval. Single-beat RV pressure-volume analysis was performed to determine the gold standard for RV diastolic stiffness. Elevated RV end-diastolic pressure (RVEDP) was defined as RVEDP ≥ 8 mmHg. Using continuous-wave Doppler and M-mode echocardiography, an echocardiographic index of RV diastolic stiffness was calculated as the ratio of the atrial-systolic descent of the pulmonary artery-RV pressure gradient derived from pulmonary regurgitant velocity (PRPGD AC ) to the tricuspid annular plane movement during atrial contraction (TAPM AC ). PRPGD AC /TAPM AC showed significant correlation with β (r = 0.54, p < 0.001) and RVEDP (r = 0.61, p < 0.001). A cut-off value of 0.74 mmHg/mm for PRPGD AC /TAPM AC showed 83% sensitivity and 93% specificity for identifying elevated RVEDP. Multivariate analyses indicated that PRPGD AC /TAPM AC was independently associated with disease severity in patients with precapillary PH, including substantial PH symptoms, stroke volume index, right atrial size, and pressure. PRPGD AC /TAPM AC , based on pulmonary regurgitation velocity waveform analysis, is useful for the noninvasive assessment of RV diastolic stiffness and is associated with prognostic risk factors in precapillary PH., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Sustained hemodynamic pressure overload (PO) produced by murine transverse aortic constriction (TAC) causes myocardial fibrosis; removal of TAC (unTAC) returns left ventricle (LV) hemodynamic load to normal and results in significant, but incomplete regression of myocardial fibrosis. However, the cellular mechanisms that result in these outcomes have not been defined. The objective was to determine temporal changes in myocardial macrophage phenotype in TAC and unTAC and determine whether macrophage depletion alters collagen degradation after unTAC. Myocardial macrophage abundance and phenotype were assessed by immunohistochemistry, flow cytometry, and gene expression by RT-PCR in control (non-TAC), 2 wk, 4 wk TAC, and 2 wk, 4 wk, and 6 wk unTAC. Myocardial cytokine profiles and collagen-degrading enzymes were determined by immunoassay and immunoblots. Initial collagen degradation was detected with collagen-hybridizing peptide (CHP). At unTAC, macrophages were depleted with clodronate liposomes, and endpoints were measured at 2 wk unTAC. Macrophage number had a defined temporal pattern: increased in 2 wk and 4 wk TAC, followed by increases at 2 wk unTAC (over 4 wk TAC) that then decreased at 4 wk and 6 wk unTAC. At 2 wk unTAC, macrophage area was significantly increased and was regionally associated with CHP reactivity. Cytokine profiles in unTAC reflected a proinflammatory milieu versus the TAC-induced profibrotic milieu. Single-cell sequencing analysis of 2 wk TAC versus 2 and 6 wk unTAC revealed distinct macrophage gene expression profiles at each time point demonstrating unique macrophage populations in unTAC versus TAC myocardium. Clodronate liposome depletion at unTAC reduced CHP reactivity and decreased cathepsin K and proMMP2. We conclude that temporal changes in number and phenotype of macrophages play a critical role in both TAC-induced development and unTAC-mediated partial, but incomplete, regression of myocardial fibrosis. NEW & NOTEWORTHY Our novel findings highlight the dynamic changes in myocardial macrophage populations that occur in response to PO and after alleviation of PO. Our data demonstrated, for the first time, a potential benefit of macrophages in contributing to collagen degradation and the partial regression of interstitial fibrosis following normalization of hemodynamic load.

Pathologic cardiac hypertrophy is a common consequence of many cardiovascular diseases, including aortic stenosis (AS). AS is known to increase the pressure load of the left ventricle, causing a compensative response of the cardiac muscle, which progressively will lead to dilation and heart failure. At a cellular level, this corresponds to a considerable increase in the size of cardiomyocytes, known as cardiomyocyte hypertrophy, while their proliferation capacity is attenuated upon the first developmental stages. Cardiomyocytes, in order to cope with the increased workload (overload), suffer alterations in their morphology, nuclear content, energy metabolism, intracellular homeostatic mechanisms, contractile activity, and cell death mechanisms. Moreover, modifications in the cardiomyocyte niche, involving inflammation, immune infiltration, fibrosis, and angiogenesis, contribute to the subsequent events of a pathologic hypertrophic response. Considering the emerging need for a better understanding of the condition and treatment improvement, as the only available treatment option of AS consists of surgical interventions at a late stage of the disease, when the cardiac muscle state is irreversible, large animal models have been developed to mimic the human condition, to the greatest extend. Smaller animal models lack physiological, cellular and molecular mechanisms that sufficiently resemblance humans and in vitro techniques yet fail to provide adequate complexity. Animals, such as the ferret (Mustello purtorius furo), lapine (rabbit, Oryctolagus cunigulus), feline (cat, Felis catus), canine (dog, Canis lupus familiaris), ovine (sheep, Ovis aries), and porcine (pig, Sus scrofa), have contributed to research by elucidating implicated cellular and molecular mechanisms of the condition. Essential discoveries of each model are reported and discussed briefly in this review. Results of large animal experimentation could further be interpreted aiming at prevention of the disease progress or, alternatively, at regression of the implicated pathologic mechanisms to a physiologic state. This review summarizes the important aspects of the pathophysiology of LV hypertrophy and the applied surgical large animal models that currently better mimic the condition., Competing Interests: Conflict of interest: P.D.C.M. and L.D.W. are co-founders and stockholders of Mirabilis Therapeutics BV. The remaining authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The assessment of left ventricular (LV) filling pressure (FP) is important for the management of aortic stenosis (AS) patients. Although, it is often restricted for predict LV FP in AS because of mitral annular calcification and a certain left ventricular hypertrophy. Thus, we tested the predictive ability of the algorithm for elevated LV FP in AS patients and also applied a recently-proposed echocardiographic scoring system of LV FP, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score., Methods: We enrolled consecutive 116 patients with at least moderate AS in sinus rhythm who underwent right heart catheterization and echocardiography within 7 days. Mean pulmonary artery wedge pressure (PAWP) was measured as invasive parameter of LV FP. LV diastolic dysfunction (DD) was graded according to the ASE/EACVI guidelines. The VMT score was defined as follows: time sequence of opening of mitral and tricuspid valves was scored to 0-2 (0: tricuspid valve first, 1: simultaneous, 2: mitral valve first). When the inferior vena cava was dilated, one point was added and VMT score was finally calculated as 0-3., Results: Of the 116 patients, 29 patients showed elevated PAWP. Ninety patients (93%) and 67 patients (63%) showed increased values for left atrium volume index (LAVI) and E/e', respectively when the cut-off values recommended by the guidelines were applied and thus the algorism predicted elevated PAWP with a low specificity and positive predictive value (PPV). VMT ≥ 2 predicted elevated PAWP with a sensitivity of 59%, specificity of 90%, PPV of 59%, and negative predictive value of 89%. An alternative algorithm that applied tricuspid regurgitation velocity and VMT scores was tested, and its predictive ability was markedly improved., Conclusion: VMT score was applicable for AS patients. Alternative use of VMT score improved diagnostic accuracy of guideline-recommended algorism., (© 2024 Wiley Periodicals LLC.)

Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomeric mutations which may affect myocardial mechano-energetic efficiency (MEE). We investigated the effects of sarcomeric mutations on MEE. A non-invasive pressure/volume (P/V) analysis was performed. We included 49 genetically screened HCM patients. MEEi was calculated as the ratio between stroke volume and heart rate normalized by LV mass. Fifty-seven percent (57%) HCM patients carried a sarcomeric mutation. Patients with and without sarcomeric mutations had similar LV ejection fraction, heart rate, LV mass, and LV outflow gradient. Younger age at diagnosis, family history of HCM, and lower MEEi were associated with presence of sarcomeric mutation (p = 0.017; p = 0.001 and p = 0.0001, respectively). Lower MEEi in HCM with sarcomeric mutation is not related to significant differences on filling pressure as shown on P/V analysis. Sarcomeric mutations determine a reduction of the LV pump performance as estimated by MEEi in HCM. Lower MEEi may predict a positive genetic analysis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Mitral annular calcification (MAC) poses many challenges to the evaluation of diastolic function using standard echocardiography. Left atrial (LA) strain and left ventricular early diastolic strain rate (DSr) measured by speckle-tracking echocardiography (STE) are emerging techniques in the noninvasive evaluation of diastolic function. We aim to evaluate the utility of LA strain and early DSr in predicting elevated left ventricular filling pressures (LVFP) in patients with MAC and compare their effectiveness to ratio of mitral inflow velocity in early and late diastole (E/A)., Methods: We included adult patients with MAC who presented between January 1 and December 31, 2014 and received a transthoracic echocardiogram (TTE) and cardiac catheterization with measurement of LVFP within a 24-h period. We used Spearman's rank correlation coefficient to assess associations of LA reservoir strain and average early DSr with LVFP. Receiver operating characteristic (ROC) curves were computed to assess the effectiveness of LA strain and DSr in discriminating elevated LVFP as a dichotomized variable and to compare their effectiveness with E/A ratio categorized according to grade of diastolic dysfunction., Results: Fifty-five patients were included. LA reservoir strain demonstrated poor correlation with LVFP (Spearman's rho = 0.03, p = 0.81) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.54, 95% CI 0.38-0.69). Categorical E/A ratio alone also demonstrated poor discriminatory ability (AUC = 0.53, 95% CI 0.39-0.67), and addition of LA reservoir strain did not significantly improve effectiveness (AUC = 0.58, 95% CI 0.42-0.74, p = 0.56). Average early DSr also demonstrated poor correlation with LVFP (Spearman's rho = -0.19, p = 0.16) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.59, 95% CI 0.44-0.75). Addition of average early DSr to categorical E/A ratio failed to improve effectiveness (AUC = 0.62, 95% CI 0.46-0.77 vs. AUC = 0.54, 95% CI 0.39-0.69, p = 0.38)., Conclusions: In our sample, LA reservoir strain and DSr do not accurately predict diastolic filling pressure. Further research is required before LA strain and early DSr can be routinely used in clinical practice to assess filling pressure in patients with MAC., (© 2024. The Author(s).)

Background: Despite surgical advances, children with tetralogy of Fallot/pulmonary atresia/major aortopulmonary collaterals (TOF/PA/MAPCAs) are subject to chronic right ventricular (RV) pressure and volume overload. Current diagnostic tools do not identify adverse myocardial remodeling and cannot predict progression to RV failure. We sought to identify a noninvasive, circulating signature of the systemic response to right heart stress to follow disease progression. Methods: Longitudinal data were collected from patients with TOF/PA/MAPCAs (N = 5) at the time of (1) early RV pressure overload and (2) late RV pressure and volume overload. Plasma protein and microRNA expression were evaluated using high-throughput data-independent mass spectroscopy and Agilent miR Microarray, respectively. Results: At the time of early RV pressure overload, median patient age was 0.34 years (0.02-9.37), with systemic RV pressures, moderate-severe hypertrophy, and preserved systolic function. Late RV pressure and volume overload occurred at a median age of 4.08 years (1.51-10.83), with moderate RV hypertrophy and dilation, and low normal RV function; 277 proteins were significantly dysregulated (log2FC ≥0.6/≤-0.6, FDR≤0.05), predicting downregulation in lipid transport (apolipoproteins), fibrinolytic system, and extracellular matrix structural proteins (talin 1, profilin 1); and upregulation in the respiratory burst. Increasing RV size and decreasing RV function correlated with decreasing structural protein expression. Similarly, miR expression predicted downregulation of extracellular matrix-receptor interactions and upregulation in collagen synthesis. Conclusion: To our knowledge, we show for the first time a noninvasive protein and miR signature reflecting the systemic response to adverse RV myocardial remodeling in TOF/PA/MAPCAs which could be used to follow disease progression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

RationaleHyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart.ObjectiveTo test whether amylin accumulates in the heart of obese and type 2 diabetic patients and to uncover the effects of amylin accumulation on cardiac morphology and function.Methods and resultsWe compared amylin deposition in failing and nonfailing hearts from lean, obese, and type 2 diabetic humans using immunohistochemistry and Western blots. We found significant accumulation of large amylin oligomers, fibrils, and plaques in failing hearts from obese and diabetic patients but not in normal hearts and failing hearts from lean, nondiabetic humans. Small amylin oligomers were even elevated in nonfailing hearts from overweight/obese patients, suggesting an early state of accumulation. Using a rat model of hyperamylinemia transgenic for human amylin, we observed that amylin oligomers attach to the sarcolemma, leading to myocyte Ca(2+) dysregulation, pathological myocyte remodeling, and diastolic dysfunction, starting from prediabetes. In contrast, prediabetic rats expressing the same level of wild-type rat amylin, a nonamyloidogenic isoform, exhibited normal heart structure and function.ConclusionsHyperamylinemia promotes amylin deposition in the heart, causing alterations of cardiac myocyte structure and function. We propose that detection and disruption of cardiac amylin buildup may be both a predictor of heart dysfunction and a novel therapeutic strategy in diabetic cardiomyopathy.