Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75 min mid-LAD balloon occlusion followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45 µg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated the treatment effect at 8 w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4 w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14 days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

A patient-specific echogenic soft robotic left ventricle embedded into a closed-loop cardiovascular simulator for advanced device testing.

Cardiovascular medical devices undergo a large number of pre- and post-market tests before their approval for clinical practice use. Sophisticated cardiovascular simulators can significantly expedite the evaluation process by providing a safe and controlled environment and representing clinically relevant case scenarios. The complex nature of the cardiovascular system affected by severe pathologies and the inherently intricate patient-device interaction creates a need for high-fidelity test benches able to reproduce intra- and inter-patient variability of disease states. Therefore, we propose an innovative cardiovascular simulator that combines in silico and in vitro modeling techniques with a soft robotic left ventricle. The simulator leverages patient-specific and echogenic soft robotic phantoms used to recreate the intracardiac pressure and volume waveforms, combined with an in silico lumped parameter model of the remaining cardiovascular system. Three different patient-specific profiles were recreated, to assess the capability of the simulator to represent a variety of working conditions and mechanical properties of the left ventricle. The simulator is shown to provide a realistic physiological and anatomical representation thanks to the use of soft robotics combined with in silico modeling. This tool proves valuable for optimizing and validating medical devices and delineating specific indications and boundary conditions.

Radiomics-based detection of acute myocardial infarction on noncontrast enhanced midventricular short-axis cine CMR images.

Cardiac magnetic resonance cine images are primarily used to evaluate functional consequences, whereas limited information is extracted from the noncontrast pixel-wise myocardial signal intensity pattern. In this study we want to assess whether characterizing this inherent contrast pattern of noncontrast-enhanced short axis (SAX) cine images via radiomics is sufficient to distinguish subjects with acute myocardial infarction (AMI) from controls. Cine balanced steady-state free-precession images acquired at 1.5 T from 99 AMI and 49 control patients were included. First, radiomic feature extraction of the left ventricular myocardium of end-diastolic (ED) and end-systolic (ES) frames was performed based on automated (AUTO) or manually corrected (MAN) segmentations. Next, top features were selected based on optimal classification results using a support vector machine (SVM) approach. The classification performances of the four radiomics models (using AUTO or MAN segmented ED or ES images), were measured by AUC, classification accuracy (CA), F1-score, sensitivity and specificity. The most accurate model was found when combining the features RunLengthNonUniformity, ClusterShade and Median obtained from the manually segmented ES images (CA = 0.846, F1 score = 0.847). ED analysis performed worse than ES, with lower CA and F1 scores (0.769 and 0.770, respectively). Manual correction of automated contours resulted in similar model features as the automated segmentations and did not improve classification results. A radiomics analysis can capture the inherent contrast in noncontrast mid-ventricular SAX cine images to distinguishing AMI from healthy subjects. The ES radiomics model was more accurate than the ED model. Manual correction of the autosegmentation did not provide significant classification improvements.

An interventional sheep model of severe aortic valve stenosis hemodynamics for the evaluation of alterations in coronary physiology and microvascular function.

We aimed to develop a large animal model of subcoronary aortic stenosis (AS) to study intracoronary and microcirculatory hemodynamics. A total of three surgical techniques inducing AS were evaluated in 12 sheep. Suturing the leaflets together around a dilator (n = 2) did not result in severe AS. Suturing of a pericardial patch with a variable opening just below the aortic valve (n = 5) created an AS which was poorly tolerated if the aortic valve area (AVA) was too small (0.38-1.02 cm2), but was feasible with an AVA of 1.2 cm2. However, standardization of aortic regurgitation (AR) with this technique is difficult. Therefore, we opted for implantation of an undersized AV-bioprosthesis with narrowing sutures on the leaflets (n = 5). Overall, five sheep survived the immediate postoperative period of which three had severe AS (one patch and two bioprostheses). The surviving sheep with severe AS developed left ventricular hypertrophy and signs of increased filling-pressures. Intracoronary assessment of physiological indices in these AS sheep pointed toward the development of functional microvascular dysfunction, with a significant increase in coronary resting flow and hyperemic coronary resistance, resulting in a significantly higher index of microvascular resistance (IMR) and lower myocardial resistance reserve (MRR). Microscopic analysis showed myocardial hypertrophy and signs of fibrosis without evidence of capillary rarefaction. In a large animal model of AS, microvascular changes are characterized by increased resting coronary flow and hyperemic coronary resistance resulting in increased IMR and decreased MRR. These physiological changes can influence the interpretation of regularly used coronary indices.NEW & NOTEWORTHY In an animal model of aortic valve stenosis (AS), coronary physiological changes are characterized by increased resting coronary flow and hyperemic coronary resistance. These changes can impact coronary indices frequently used to assess concomitant coronary artery disease (CAD). At this point, the best way to assess and treat CAD in AS remains unclear. Our data suggest that fractional flow reserve may underestimate CAD, and nonhyperemic pressure ratios may overestimate CAD severity before aortic valve replacement.

Biomarkers in transposition of the great arteries after arterial switch operation: A pilot trial with deep phenotyping.

INTRODUCTION: Transposition of the great arteries (TGA) is a cyanotic congenital heart defect for which the arterial switch operation (ASO) is the preferred surgical repair. This study wanted to investigate whether a panel of biomarkers could identify morphologic as well as hemodynamic changes obtained by cardiac magnetic resonance (CMR). METHODS: Forty-four adult patients were included. Blood samples were collected to measure a broad range of biomarkers (galectin-3, ST2, GDF-15, PINP, ICTP, PIIINP, IGF-1, NT-proBNP, and hs-Tn). CMR was performed at rest and during exercise to assess cardiac function and morphology. Explorative statistics were performed between biomarker levels and CMR findings. RESULTS: All patients were asymptomatic. While galectin-3, GDF-15, and NT-proBNP levels were within normal ranges, increased ST2, PINP, PIIINP, and ICTP levels were found in 20.5%, 34.1%, 45.5%, and 27.3% of patients, respectively. Moreover, 3 and 2 patients, respectively, showed elevated IGF-1 and hs-Tn levels. Although the ejection fraction of both ventricles was within normal limits, impaired cardiac reserve was found in 20 and 25% of patients for left and right ventricle, respectively. CMR revealed no evidence of diffuse interstitial fibrosis, while 4 patients showed focal ischemic scarring. However, no significant associations between serum biomarkers and CMR data could be detected. CONCLUSION: The results suggest that in asymptomatic ASO-repaired TGA patients serum level biomarkers are elevated and that this increase is not associated with morphological changes nor with a decreased cardiac reserve. Further study with larger sample sizes is required to draw conclusions with greater confidence.

Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.

BACKGROUND: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes. METHODS: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years. RESULTS: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P=0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P<0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P=0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (P=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%. CONCLUSIONS: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.

Feature-based clustering of the left ventricular strain curve for cardiovascular risk stratification in the general population.

Objective: Identifying individuals with subclinical cardiovascular (CV) disease could improve monitoring and risk stratification. While peak left ventricular (LV) systolic strain has emerged as a strong prognostic factor, few studies have analyzed the whole temporal profiles of the deformation curves during the complete cardiac cycle. Therefore, in this longitudinal study, we applied an unsupervised machine learning approach based on time-series-derived features from the LV strain curve to identify distinct strain phenogroups that might be related to the risk of adverse cardiovascular events in the general population. Method: We prospectively studied 1,185 community-dwelling individuals (mean age, 53.2 years; 51.3% women), in whom we acquired clinical and echocardiographic data including LV strain traces at baseline and collected adverse events on average 9.1 years later. A Gaussian Mixture Model (GMM) was applied to features derived from LV strain curves, including the slopes during systole, early and late diastole, peak strain, and the duration and height of diastasis. We evaluated the performance of the model using the clinical characteristics of the participants and the incidence of adverse events in the training dataset. To ascertain the validity of the trained model, we used an additional community-based cohort (n = 545) as external validation cohort. Results: The most appropriate number of clusters to separate the LV strain curves was four. In clusters 1 and 2, we observed differences in age and heart rate distributions, but they had similarly low prevalence of CV risk factors. Cluster 4 had the worst combination of CV risk factors, and a higher prevalence of LV hypertrophy and diastolic dysfunction than in other clusters. In cluster 3, the reported values were in between those of strain clusters 2 and 4. Adjusting for traditional covariables, we observed that clusters 3 and 4 had a significantly higher risk for CV (28% and 20%, P ≤ 0.038) and cardiac (57% and 43%, P ≤ 0.024) adverse events. Using SHAP values we observed that the features that incorporate temporal information, such as the slope during systole and early diastole, had a higher impact on the model's decision than peak LV systolic strain. Conclusion: Employing a GMM on features derived from the raw LV strain curves, we extracted clinically significant phenogroups which could provide additive prognostic information over the peak LV strain.

The hemodynamic interplay between pulmonary ischemia-reperfusion injury and right ventricular function in lung transplantation: a translational porcine model.

Lung transplantation (LTx) is a challenging procedure. Following the process of ischemia-reperfusion injury, the transplanted pulmonary graft might become severely damaged, resulting in primary graft dysfunction. In addition, during the intraoperative window, the right ventricle (RV) is at risk of acute failure. The interaction of right ventricular function with lung injury is, however, poorly understood. We aimed to address this interaction in a translational porcine model of pulmonary ischemia-reperfusion injury. Advanced pulmonary and hemodynamic assessment was used, including right ventricular pressure-volume loop analysis. The acute model was based on clamping and unclamping of the left lung hilus, respecting the different hemodynamic phases of a clinical lung transplantation. We found that forcing entire right ventricular cardiac output through a lung suffering from ischemia-reperfusion injury increased afterload (pulmonary vascular resistance from baseline to end experiment P < 0.0001) and induced right ventricular failure (RVF) in 5/9 animals. Notably, we identified different compensation patterns in failing versus nonfailing ventricles (arterial elastance P = 0.0008; stroke volume P < 0.0001). Furthermore, increased vascular pressure and flow produced by the right ventricle resulted in higher pulmonary injury, as measured by ex vivo CT density (correlation: pressure r = 0.8; flow r = 0.85). Finally, RV ischemia as measured by troponin-T was negatively correlated with pulmonary injury (r = -0.76); however, troponin-T values did not determine RVF in all animals. In conclusion, we demonstrate a delicate balance between development of pulmonary ischemia-reperfusion injury and right ventricular function during lung transplantation. Furthermore, we provide a physiological basis for potential benefit of extracorporeal life support technology.NEW & NOTEWORTHY In contrast to the abundant literature of mechanical pulmonary artery clamping to increase right ventricular afterload, we developed a model adding a biological factor of pulmonary ischemia-reperfusion injury. We did not only focus on the right ventricular behavior, but also on the interaction with the injured lung. We are the first to describe this interaction while addressing the hemodynamic intraoperative phases of clinical lung transplantation.

Electric Field-Based Spatial Analysis of Noncontact Unipolar Electrograms to Map Regional Activation-Repolarization Intervals.

BACKGROUND: Spatial heterogeneity in repolarization plays an important role in generating and sustaining cardiac arrhythmias. Reliable determination of repolarization times remains challenging. OBJECTIVES: The goal of this study was to improve processing of densely sampled noncontact unipolar electrograms to yield reliable high-resolution activation and repolarization maps. METHODS: Endocardial noncontact unipolar electrograms were both simulated and recorded in pig left ventricle. Electrical activity on the endocardial surface was processed in terms of a pseudo-electric field. Activation and repolarization times were calculated by using an amplitude-weighted average on QRS and T waves (ie, the E-field method). This was compared vs the conventional Wyatt method on unipolar electrograms. Timing maps were validated against timing on endocardial action potentials in a simulation study. In vivo, activation and repolarization times determined by using this alternative E-field method were validated against simultaneously recorded endocardial monophasic action potentials (MAPs). RESULTS: Simulation showed that the E-field method provides viable measurements of local endocardial action potential activation and repolarization times. In vivo, correlation of E-field activation times with MAP activation times (rE = 0.76; P < 0.001) was similar to those of Wyatt (rWyatt = 0.80, P < 0.001; P[h1:rE > rWyatt] = 0.82); for repolarization times, correlation improved significantly (rE = 0.96, P < 0.001; rWyatt = 0.82, P < 0.001; P[h1:rE > rWyatt] < 0.00001). This resulted in improved correlations of activation-repolarization intervals to endocardial action potential duration on MAP (rE = 0.96, P < 0.001; rWyatt = 0.86, P < 0.001; P[h1:rE > rWyatt] < 0.00001). Spatial beat-to-beat variation of repolarization could only be calculated by using the E-field methodology and correlated well with the MAP beat-to-beat variation of repolarization (rE = 0.76; P = 0.001). CONCLUSIONS: The E-field method substantially enhances information from endocardial noncontact electrogram data, allowing for dense maps of activation and repolarization times and derived parameters.

Decreased cardiac reserve in asymptomatic patients after arterial switch operation for transposition of the great arteries.

BACKGROUND: Exercise capacity is impaired in patients after arterial switch operation (ASO) for complete transposition of the great arteries. Maximal oxygen consumption is related with outcome. OBJECTIVES: This study assessed ventricular function by advanced echocardiography and cardiac magnetic resonance (CMR) imaging at rest and during exercise, to determine exercise capacity in ASO patients, and to correlate exercise capacity with ventricular function as potential early marker of subclinical impairment. METHODS: Forty-four patients (71% male, mean age 25 ± 4 years - range 18-40 years) were included during routine clinical follow-up. Assessment involved physical examination, 12­lead ECG, echocardiography, and cardiopulmonary exercise test (CPET) (day 1). On day 2 CMR imaging at rest and during exercise was performed. Blood was sampled for biomarkers. RESULTS: All patients reported New York Heart Association class I, the overall cohort had an impaired exercise capacity (80 ± 14% of predicted peak oxygen consumption). Fragmented QRS was present in 27%. Exercise CMR showed that 20% of patients had abnormal contractile reserve (CR) of the left ventricle (LV) and 25% had reduced CR of the right ventricle (RV). CR LV and CR RV were significantly associated with impaired exercise capacity. Pathological patterns on myocardial delayed enhancement and hinge point fibrosis were detected. Biomarkers were normal. CONCLUSION: This study found that in some asymptomatic ASO patients electrical, LV and RV changes at rest, and signs of fibrosis are present. Maximal exercise capacity is impaired and seems to be linearly related to the CR of the LV and the RV. Therefore, exercise CMR might play a role in detecting subclinical deterioration of ASO patients.

Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility.

BACKGROUND: After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling. METHODS: Myocardial infarction was induced in domestic pigs by 120-minute ischemia followed by reperfusion. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-ANEPPS, stimulation at 1 Hz, 37 °C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing. RESULTS: In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5±1.3 ms versus remote: 2.0±0.5 ms, P=0.036, npigs=5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (ncells=635-862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9±17.0 ms versus remote: 73.9±8.6 ms; P=0.001; npigs=6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2-15.0] versus 10.6 [7.5-11.6] in remote; P<0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel-related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote. CONCLUSIONS: Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo.

Regional beat-to-beat variability of repolarization increases during ischemia and predicts imminent arrhythmias in a pig model of myocardial infarction.

Ventricular arrhythmia (VT/VF) can complicate acute myocardial ischemia (AMI). Regional instability of repolarization during AMI contributes to the substrate for VT/VF. Beat-to-beat variability of repolarization (BVR), a measure of repolarization lability increases during AMI. We hypothesized that its surge precedes VT/VF. We studied the spatial and temporal changes in BVR in relation to VT/VF during AMI. In 24 pigs, BVR was quantified on 12-lead electrocardiogram recorded at a sampling rate of 1 kHz. AMI was induced in 16 pigs by percutaneous coronary artery occlusion (MI), whereas 8 underwent sham operation (sham). Changes in BVR were assessed at 5 min after occlusion, 5 and 1 min pre-VF in animals that developed VF, and matched time points in pigs without VF. Serum troponin and ST deviation were measured. After 1 mo, magnetic resonance imaging and VT induction by programmed electrical stimulation were performed. During AMI, BVR increased significantly in inferior-lateral leads correlating with ST deviation and troponin increase. BVR was maximal 1 min pre-VF (3.78 ± 1.36 vs. 5 min pre-VF, 1.67 ± 1.56, P < 0.0001). After 1 mo, BVR was higher in MI than in sham and correlated with the infarct size (1.43 ± 0.50 vs. 0.57 ± 0.30, P = 0.009). VT was inducible in all MI animals and the ease of induction correlated with BVR. BVR increased during AMI and temporal BVR changes predicted imminent VT/VF, supporting a possible role in monitoring and early warning systems. BVR correlated to arrhythmia vulnerability suggesting utility in risk stratification post-AMI.NEW & NOTEWORTHY The key finding of this study is that BVR increases during AMI and surges before ventricular arrhythmia onset. This suggests that monitoring BVR may be useful for monitoring the risk of VF during and after AMI in the coronary care unit settings. Beyond this, monitoring BVR may have value in cardiac implantable devices or wearables.

Reversal of Right Ventricular Remodeling After Correction of Pulmonary Regurgitation in Tetralogy of Fallot.

In the sheep model with pathophysiologic changes similar to patients with repaired TOF, severe PR leads to fibrotic changes in the RV. Pulmonary valve replacement reverses these fibrotic changes. Early valve replacement led to a quick RV recovery, and in time there was no difference in outcome between early and late valve replacement. These data support the benefit of valve replacement for RV function and suggest that there is a margin in the timing of the surgery. The fibrotic changes correlated well with the circulating biomarker PICP, which can have an added value in the clinical follow-up of patients with repaired TOF.

InsP3R-RyR channel crosstalk augments sarcoplasmic reticulum Ca2+ release and arrhythmogenic activity in post-MI pig cardiomyocytes.

Ca2+ transients (CaT) underlying cardiomyocyte (CM) contraction require efficient Ca2+ coupling between sarcolemmal Ca2+ channels and sarcoplasmic reticulum (SR) ryanodine receptor Ca2+ channels (RyR) for their generation; reduced coupling in disease contributes to diminished CaT and arrhythmogenic Ca2+ events. SR Ca2+ release also occurs via inositol 1,4,5-trisphosphate receptors (InsP3R) in CM. While this pathway contributes negligeably to Ca2+ handling in healthy CM, rodent studies support a role in altered Ca2+ dynamics and arrhythmogenic Ca2+ release involving InsP3R crosstalk with RyRs in disease. Whether this mechanism persists in larger mammals with lower T-tubular density and coupling of RyRs is not fully resolved. We have recently shown an arrhythmogenic action of InsP3-induced Ca2+ release (IICR) in end stage human heart failure (HF), often associated with underlying ischemic heart disease (IHD). How IICR contributes to early stages of disease is however not determined but highly relevant. To access this stage, we chose a porcine model of IHD, which shows substantial remodelling of the area adjacent to the infarct. In cells from this region, IICR preferentially augmented Ca2+ release from non-coupled RyR clusters that otherwise showed delayed activation during the CaT. IICR in turn synchronised Ca2+ release during the CaT but also induced arrhythmogenic delayed afterdepolarizations and action potentials. Nanoscale imaging identified co-clustering of InsP3Rs and RyRs, thereby allowing Ca2+-mediated channel crosstalk. Mathematical modelling supported and further delineated this mechanism of enhanced InsP3R-RyRs coupling in MI. Our findings highlight the role of InsP3R-RyR channel crosstalk in Ca2+ release and arrhythmia during post-MI remodelling.

Lifelong endurance exercise and its relation with coronary atherosclerosis.

AIMS: The impact of long-term endurance sport participation (on top of a healthy lifestyle) on coronary atherosclerosis and acute cardiac events remains controversial. METHODS AND RESULTS: The Master@Heart study is a well-balanced prospective observational cohort study. Overall, 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after 30 years of age), and 176 healthy non-athletes, all male with a low cardiovascular risk profile, were included. Peak oxygen uptake quantified fitness. The primary endpoint was the prevalence of coronary plaques (calcified, mixed, and non-calcified) on computed tomography coronary angiography. Analyses were corrected for multiple cardiovascular risk factors. The median age was 55 (50-60) years in all groups. Lifelong and late-onset athletes had higher peak oxygen uptake than non-athletes [159 (143-177) vs. 155 (138-169) vs. 122 (108-138) % predicted]. Lifelong endurance sports was associated with having ≥1 coronary plaque [odds ratio (OR) 1.86, 95% confidence interval (CI) 1.17-2.94], ≥ 1 proximal plaque (OR 1.96, 95% CI 1.24-3.11), ≥ 1 calcified plaques (OR 1.58, 95% CI 1.01-2.49), ≥ 1 calcified proximal plaque (OR 2.07, 95% CI 1.28-3.35), ≥ 1 non-calcified plaque (OR 1.95, 95% CI 1.12-3.40), ≥ 1 non-calcified proximal plaque (OR 2.80, 95% CI 1.39-5.65), and ≥1 mixed plaque (OR 1.78, 95% CI 1.06-2.99) as compared to a healthy non-athletic lifestyle. CONCLUSION: Lifelong endurance sport participation is not associated with a more favourable coronary plaque composition compared to a healthy lifestyle. Lifelong endurance athletes had more coronary plaques, including more non-calcified plaques in proximal segments, than fit and healthy individuals with a similarly low cardiovascular risk profile. Longitudinal research is needed to reconcile these findings with the risk of cardiovascular events at the higher end of the endurance exercise spectrum.

Unsupervised Time-Series Clustering of Left Atrial Strain for Cardiovascular Risk Assessment.

BACKGROUND: Early identification of individuals at high risk for developing cardiovascular (CV) events is of paramount importance for efficient risk management. Here, the authors investigated whether using unsupervised machine learning methods on time-series data of left atrial (LA) strain could distinguish clinically meaningful phenogroups associated with the risk for developing adverse events. METHODS: In 929 community-dwelling individuals (mean age, 51.6 years; 52.9% women), clinical and echocardiographic data were acquired, including LA strain traces, at baseline, and cardiac events were collected on average 6.3 years later. Two unsupervised learning techniques were used: (1) an ensemble of a deep convolutional neural network autoencoder with k-medoids and (2) a self-organizing map to cluster spatiotemporal patterns within LA strain curves. Clinical characteristics and cardiac outcome were used to evaluate the validity of the k clusters using the original cohort, while an external population cohort (n = 378) was used to validate the trained models. RESULTS: In both approaches, the optimal number of clusters was five. The first three clusters had differences in sex distribution and heart rate but had a similar low CV risk profile. On the other hand, cluster 5 had the worst CV profile and a higher prevalence of left ventricular remodeling and diastolic dysfunction compared with the other clusters. The respective indexes of cluster 4 were between those of clusters 1 to 3 and 5. After adjustment for traditional risk factors, cluster 5 had the highest risk for cardiac events compared with clusters 1, 2, and 3 (hazard ratio, 1.36; 95% CI, 1.09-1.70; P = .0063). Similar LA strain patterns were obtained when the models were applied to the external validation cohort, and clinical characteristics revealed similar CV risk profiles across all clusters. CONCLUSION: Unsupervised machine learning algorithms used in time-series LA strain curves identified clinically meaningful clusters of LA deformation and provide incremental prognostic information over traditional risk factors.

Alginate sulfate-nanoparticles loaded with hepatocyte growth factor and insulin-like growth factor-1 improve left ventricular repair in a porcine model of myocardial ischemia reperfusion injury.

Nanomedicine offers great potential for the treatment of cardiovascular disease and particulate systems have the capacity to markedly improve bioavailability of therapeutics. The delivery of pro-angiogenic hepatocyte growth factor (HGF) and pro-survival and pro-myogenic insulin-like growth factor (IGF-1) encapsulated in Alginate-Sulfate nanoparticles (AlgS-NP) might improve left ventricular (LV) functional recovery after myocardial infarction (MI). In a porcine ischemia-reperfusion model, MI is induced by 75 min balloon occlusion of the mid-left anterior descending coronary artery followed by reperfusion. After 1 week, pigs (n = 12) with marked LV-dysfunction (LV ejection fraction, LVEF < 45%) are randomized to fusion imaging-guided intramyocardial injections of 8 mg AlgS-NP prepared with 200 µg HGF and IGF-1 (HGF/IGF1-NP) or PBS (Control). Intramyocardial injection is safe and pharmacokinetic studies of Cy5-labeled NP confirm superior cardiac retention compared to intracoronary infusion. Seven weeks after intramyocardial-injection of HGF/IGF1-NP, infarct size, measured using magnetic resonance imaging, is significantly smaller than in controls and is associated with increased coronary flow reserve. Importantly, HGF/IGF1-NP-treated pigs show significantly increased LVEF accompanied by improved myocardial remodeling. These findings demonstrate the feasibility and efficacy of using AlgS-NP as a delivery system for growth factors and offer the prospect of innovative treatment for refractory ischemic cardiomyopathy.

Scar imaging in the dyssynchronous left ventricle: Accuracy of myocardial metabolism by positron emission tomography and function by echocardiographic strain.

PURPOSE: Response to cardiac resynchronization therapy (CRT) is reduced in patients with high left ventricular (LV) scar burden, in particular when scar is located in the LV lateral wall or septum. Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can identity scar, but is not feasible in all patients. This study investigates if myocardial metabolism by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contractile function by echocardiographic strain are alternatives to LGE-CMR. METHODS: In a prospective multicenter study, 132 CRT candidates (91% with left bundle branch block) were studied by speckle tracking strain echocardiography, and 53 of these by FDG-PET. Regional myocardial FDG metabolism and peak systolic strain were compared to LGE-CMR as reference method. RESULTS: Reduced FDG metabolism (<70% relative) precisely identified transmural scars (≥50% of myocardial volume) in the LV lateral wall, with area under the curve (AUC) 0.96 (95% confidence interval (CI) 0.90-1.00). Reduced contractile function by strain identified transmural scars in the LV lateral wall with only moderate accuracy (AUC = 0.77, CI 0.71-0.84). However, absolute peak systolic strain >10% could rule out transmural scar with high sensitivity (80%) and high negative predictive value (96%). Neither FDG-PET nor strain identified septal scars (for both, AUC < 0.80). CONCLUSIONS: In CRT candidates, FDG-PET is an excellent alternative to LGE-CMR to identify scar in the LV lateral wall. Furthermore, preserved strain in the LV lateral wall has good accuracy to rule out transmural scar. None of the modalities can identify septal scar. CLINICAL TRIAL REGISTRATION: The present study is part of the clinical study "Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy (CRID-CRT)", which was registered at clinicaltrials.gov (identifier NCT02525185).

Dynamic aspects of ventricular interaction during exercise in HFpEF and in pre-capillary pulmonary hypertension.

AIMS: The contribution of adverse ventricular interdependence remains undervalued in heart failure or pulmonary vascular disease, and not much is known about its dynamic nature during exercise and respiration. In this study, we evaluated ventricular interaction during exercise in patients with heart failure with preserved ejection fraction (HFpEF) and patients with chronic thromboembolic pulmonary hypertension (CTEPH) as compared with healthy controls. METHODS AND RESULTS: Forty-six subjects (10 controls, 19 CTEPH patients, and 17 HFpEF patients) underwent cardiac magnetic resonance imaging during exercise. Ventricular interaction was determined through analysis of the septal curvature (SC) of a mid-ventricular short-axis slice at end-diastole, end-systole, and early-diastole, both in expiration and inspiration. Exercise amplified ventricular interaction in CTEPH patients and to a lesser extent in HFpEF patients (P < 0.05 for decrease in SC with exercise). Adverse interaction was most profound in early-diastole and most pronounced in CTEPH patients (P < 0.05 interaction group * exercise) because of a disproportionate increase RV afterload (P < 0.05 to both controls and HFpEF) and diastolic pericardial restraint (P < 0.001 for interaction group * exercise) during exercise. Inspiration enhanced diastolic interdependence in CTEPH and HFpEF patients (P < 0.05 vs. expiration). Both at rest and during exercise, SC strongly correlated with RV volumes and pulmonary artery pressures (all P < 0.05). CONCLUSIONS: Exercise amplifies adverse right-left ventricular interactions in CTEPH, while a more moderate effect is observed in isolated post-capillary HFpEF. Given the strong link with RV function and pulmonary hemodynamic, assessing ventricular interaction with exCMR might be valuable from a diagnostic or therapeutic perspective.