Cardiac resynchronization therapy using bi-ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS-complex. In the absence of QRS prolongation, however, device-based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell-based approach in the setting of narrow QRS-complex HF.

Na(V)1.5 is a mechanosensitive voltage-gated Na(+) channel encoded by the gene SCN5A, expressed in cardiac myocytes and required for phase 0 of the cardiac action potential (AP). In the cardiomyocyte, ranolazine inhibits depolarizing Na(+) current and delayed rectifier (I(Kr)) currents. Recently, ranolazine was also shown to be an inhibitor of Na(V)1.5 mechanosensitivity. Stretch also accelerates the firing frequency of the SA node, and fluid shear stress increases the beating rate of cultured cardiomyocytes in vitro. However, no cultured cell platform exists currently for examination of spontaneous electrical activity in response to mechanical stimulation. In the present study, flow of solution over atrial myocyte-derived HL-1 cultured cells was used to study shear stress mechanosensitivity of Na(+) current and spontaneous, endogenous rhythmic action potentials. In voltage-clamped HL-1 cells, bath flow increased peak Na(+) current by 14 ± 5%. In current-clamped cells, bath flow increased the frequency and decay rate of AP by 27 ± 12% and 18 ± 4%, respectively. Ranolazine blocked both responses to shear stress. This study suggests that cultured HL-1 cells are a viable in vitro model for detailed study of the effects of mechanical stimulation on spontaneous cardiac action potentials. Inhibition of the frequency and decay rate of action potentials in HL-1 cells are potential mechanisms behind the antiarrhythmic effect of ranolazine.

Contractile discordance exacerbates cardiac dysfunction, aggravating heart failure outcome. Dissecting the genesis of mechanical dyssynchrony would enable an early diagnosis before advanced disease.

To investigate whether revascularisation improves prognosis compared with medical treatment among patients with stable coronary artery disease.

Embryonic stem cells possess a pluripotent transcriptional background with the developmental capacity for distinct cell fates. Simultaneous expression of genetic elements for multiple outcomes obscures cascades relevant to specific cell phenotypes. To map molecular patterns critical to cardiogenesis, we interrogated gene expression in stem cells undergoing guided differentiation, and defined a genomic paradigm responsible for confinement of pluripotency.

Cardiopoietic stem cells have reached advanced clinical testing for ischemic heart failure. To profile their molecular influence on recipient hearts, systems proteomics was here applied in a chronic model of infarction randomized with and without human cardiopoietic stem cell treatment. Multidimensional label-free tandem mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell therapy non-stochastically reversed a majority of infarction-provoked changes, remediating 85% of disease-affected protein clusters. Pathway and network analysis decoded functional reorganization, distinguished by prioritization of vasculogenesis, cardiac development, organ regeneration, and differentiation. Subproteome restoration nullified adverse ischemic effects, validated by echo-/electro-cardiographic documentation of improved cardiac chamber size, reduced QT prolongation and augmented ejection fraction post-cell therapy. Collectively, cardiopoietic stem cell intervention transitioned infarcted hearts from a cardiomyopathic trajectory towards pre-disease. Systems proteomics thus offers utility to delineate and interpret complex molecular regenerative outcomes.

Response to stem cell therapy in heart failure is heterogeneous, warranting a better understanding of outcome predictors. This study assessed left ventricular volume, a surrogate of disease severity, on cell therapy benefit. Small to large infarctions were induced in murine hearts to model moderate, advanced, and end-stage ischemic cardiomyopathy. At 1 month postinfarction, cardiomyopathic cohorts with comparable left ventricular enlargement and dysfunction were randomized 1:1 to those that either received sham treatment or epicardial delivery of cardiopoietic stem cells (CP). Progressive dilation and pump failure consistently developed in sham. In comparison, CP treatment produced significant benefit at 1 month post-therapy, albeit with an efficacy impacted by cardiomyopathic stage. Advanced ischemic cardiomyopathy was the most responsive to CP-mediated salvage, exhibiting both structural and functional restitution, with proteome deconvolution substantiating that cell therapy reversed infarction-induced remodeling of functional pathways. Moderate cardiomyopathy was less responsive to CP therapy, improving contractility but without reversing preexistent heart enlargement. In end-stage disease, CP therapy showed the least benefit. This proof-of-concept study thus demonstrates an optimal window, or "Goldilocks principle," of left ventricular enlargement for maximized stem cell-based cardiac repair. Disease severity grading, prior to cell therapy, should be considered to inform regenerative medicine interventions.

To investigate the impact of established cardiovascular disease (CVD) on 10-year all-cause death following coronary revascularization in patients with complex coronary artery disease (CAD).

Background Substantial differences exist between different guideline-recommended pretest probability (PTP) models for the detection of obstructive coronary artery disease (CAD). This study was performed to study the performance of the 2021 American Heart Association/American College of Cardiology (AHA/ACC) guideline-recommended PTP (AHA/ACC-PTP) model in assessing the likelihood of obstructive CAD compared with previously proposed models. Methods and Results Symptomatic patients (N=50 561) referred for coronary computed tomography angiography were included. The reference standard was invasive coronary angiography with optional fractional flow reserve measurements. The AHA/ACC-PTP values based on sex and age were calculated and compared with the 2019 European Society of Cardiology guideline PTP values based on sex, age, and symptoms as well as the risk factor-weighted clinical likelihood values based on sex, age, symptoms, and risk factors. The AHA/ACC-PTP maximum values overestimated by a factor of 2.6 the actual prevalence of CAD. Compared with the AHA/ACC-PTP model (area under the receiver-operating curve, 71.5 [95% CI, 70.7-72.2]), inclusion of typicality of symptoms in the European Society of Cardiology guideline PTP improved discrimination of CAD (area under the receiver-operating curve, 75.5 [95% CI, 74.7-76.3]). Inclusion of both symptoms and risk factors in the risk factor-weighted clinical likelihood model further improved discrimination (area under the receiver-operating curve, 77.7 [95% CI, 77.0-78.5]). The proportion of patients classified as very low PTP was lower using the AHA/ACC-PTP (5%) compared with the European Society of Cardiology guideline PTP (19%) and the risk factor-weighted clinical likelihood (49%) models. Conclusions The new AHA/ACC-PTP model overestimates the prevalence of obstructive CAD substantially if type of symptoms and risk factors are not taken into account. Inclusion of both symptoms and risk factors improves model performance and identifies more patients with very low likelihood of CAD in whom further testing can be deferred.

Stem cell paracrine activity is implicated in cardiac repair. Linkage between secretome functionality and therapeutic outcome was here interrogated by systems analytics of biobanked human cardiopoietic cells, a regenerative biologic in advanced clinical trials. Protein chip array identified 155 proteins differentially secreted by cardiopoietic cells with clinical benefit, expanded into a 520 node network, collectively revealing inherent vasculogenic properties along with cardiac and smooth muscle differentiation and development. Next generation RNA sequencing, refined by pathway analysis, pinpointed miR-146 dependent regulation upstream of the decoded secretome. Intracellular and extracellular integration unmasked commonality across cardio-vasculogenic processes. Mirroring the secretome pattern, infarcted hearts benefiting from cardiopoietic cell therapy restored the disease proteome engaging cardiovascular system functions. The cardiopoietic cell secretome thus confers a therapeutic molecular imprint on recipient hearts, with response informed by predictive systems profiling.

Multi-detector computed tomography angiography (MDCTA) has been increasingly used in the evaluation of the coronary arteries. The purpose of this study was to review the literature on the diagnostic performance of MDCTA in the acute setting, for the detection of non-ST-elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP).

Background The Purkinje network appears to play a pivotal role in the triggering as well as maintenance of ventricular fibrillation. Irreversible electroporation ( IRE ) using direct current has shown promise as a nonthermal ablation modality in the heart, but its ability to target and ablate the Purkinje tissue is undefined. Our aim was to investigate the potential for selective ablation of Purkinje/fascicular fibers using IRE . Methods and Results In an ex vivo Langendorff model of canine heart (n=8), direct current was delivered in a unipolar manner at various dosages from 750 to 2500 V, in 10 pulses with a 90-μs duration at a frequency of 1 Hz. The window of ventricular fibrillation vulnerability was assessed before and after delivery of electroporation energy using a shock on T-wave method. IRE consistently eradicated all Purkinje potentials at voltages between 750 and 2500 V (minimum field strength of 250-833 V/cm). The ventricular electrogram amplitude was only minimally reduced by ablation: 0.6±2.3 mV ( P=0.03). In 4 hearts after IRE delivery, ventricular fibrillation could not be reinduced. At baseline, the lower limit of vulnerability to ventricular fibrillation was 1.8±0.4 J, and the upper limit of vulnerability was 19.5±3.0 J. The window of vulnerability was 17.8±2.9 J. Delivery of electroporation energy significantly reduced the window of vulnerability to 5.7±2.9 J ( P=0.0003), with a postablation lower limit of vulnerability=7.3±2.63 J, and the upper limit of vulnerability=18.8±5.2 J. Conclusions Our study highlights that Purkinje tissue can be ablated with IRE without any evidence of underlying myocardial damage.

Incorporation of remote monitoring of pulmonary artery pressure and vital signs has been demonstrated to reduce heart failure (HF) hospitalization and all-cause mortality in selected symptomatic HF patients. The aim of this study is to investigate the safety and accuracy of the new CordellaTM Pulmonary Artery Pressure Sensor (Endotronix, Inc., Chicago, IL, USA) and the usability of the comprehensive CordellaTM Heart Failure System (CHFS).

Introduction: Transcatheter aortic valve implantation (TAVI) is the standard of care for the majority of patients with severe symptomatic aortic stenosis (AS) at excessive-, high- and intermediate-surgical risk. A proportion of patients referred for TAVI do not undergo the procedure and proceed with an alternate treatment strategy. There is scarce data describing the final treatment allocation of such patients. Hence, we sought to evaluate the final treatment allocation of patients referred for TAVI in contemporary practice. Methods: We performed a single center prospective observational study, including all patients referred to our institution for treatment of severe aortic stenosis between February 2014 and August 2017. Baseline demographic and clinical data were recorded. Patients were categorized according to treatment allocation: TAVI, surgical aortic valve replacement (SAVR) or optimal medical therapy (OMT). Clinical outcomes were adjudicated according to VARC-2 definitions. All patients were discussed at a dedicated Heart Team meeting. Results: Total of 245 patients were referred for assessment to a dedicated TAVI clinic during the study period. Patients with moderate (N = 32; 13.1%) and asymptomatic (N = 31; 13.1%) AS were excluded. Subsequently, 53.9% (N = 132) received TAVI, 12.7% (N =31) were managed with OMT, and 7.3% (N =18) had SAVR. Reasons for OMT included primarily: patient's preference (N = 12; 38.7%); excessive surgical risk (N = 4; 12.9%) and severe frailty (N = 5; 16.1%). Reasons for surgical referral included low surgical risk (N = 11; 61.1%), excessive annulus size (N = 5; 27.8%), and aortic root dilatation (N = 2; 11.1%). Patients proceeding to SAVR had lower surgical risk than those in either the OMT or TAVI cohorts (P < 0.001). Mean STS score in SAVR group was 2.2 ± 1.3 vs. 4.5 ± 2.4 in OMT cohort and 6.1 ± 4.9 in TAVI cohort. Six-month all-cause mortality was 16.7, 19.4, and 9.3% among those receiving SAVR, OMT, and TAVI, respectively. Conclusions: Almost half of all patients with severe AS referred to a dedicated TAVI clinic did not receive a TAVI. A considerable proportion of patients were reclassified as moderate AS (13%), were asymptomatic (13%), or intervention was determined to be futile (13%) due to advanced frailty. Early detection and increased awareness of valvular heart disease are required to increase the number of patients that can benefit from TAVI.

[Figure: see text].

Introduction: Cyclic plaque structural stress has been hypothesized as a mechanism for plaque fatigue and eventually plaque rupture. A novel approach to derive cyclic plaque stress in vivo from optical coherence tomography (OCT) is hereby developed. Materials and Methods: All intermediate lesions from a previous OCT study were enrolled. OCT cross-sections at representative positions within each lesion were selected for plaque stress analysis. Detailed plaque morphology, including plaque composition, lumen and internal elastic lamina contours, were automatically delineated. OCT-derived vessel and plaque morphology were included in a 2-dimensional finite element analysis, loaded with patient-specific intracoronary pressure tracing data, to calculate the changes in plaque structural stress (ΔPSS) on vessel wall over the cardiac cycle. Results: A total of 50 lesions from 41 vessels were analyzed. A significant ΔPSS gradient was observed across the plaque, being maximal at the proximal shoulder (45.7 [32.3, 78.6] kPa), intermediate at minimal lumen area (MLA) (39.0 [30.8, 69.1] kPa) and minimal at the distal shoulder (35.1 [28.2, 72.3] kPa; p = 0.046). The presence of lipidic plaques were observed in 82% of the diseased segments. Larger relative lumen deformation and ΔPSS were observed in diseased segments, compared with normal segments (percent diameter change: 8.2 ± 4.2% vs. 6.3 ± 2.3%, p = 0.04; ΔPSS: 59.3 ± 48.2 kPa vs. 27.5 ± 8.2 kPa, p < 0.001). ΔPSS was positively correlated with plaque burden (r = 0.37, p < 0.001) and negatively correlated with fibrous cap thickness (r = -0.25, p = 0.004). Conclusions: ΔPSS provides a feasible method for assessing plaque biomechanics in vivo from OCT images, consistent with previous biomechanical and clinical studies based on different methodologies. Larger ΔPSS at proximal shoulder and MLA indicates the critical sites for future biomechanical assessment.

The aim of the present analysis is to compare the quantitative angiographic aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) among three balloon-expandable valves.

Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy.

The BubR1 gene encodes for a mitotic regulator that ensures accurate segregation of chromosomes through its role in the mitotic checkpoint and the establishment of proper microtubule-kinetochore attachments. Germline mutations that reduce BubR1 abundance cause aneuploidy, shorten lifespan and induce premature ageing phenotypes and cancer in both humans and mice. A reduced BubR1 expression level is also a feature of chronological ageing, but whether this age-related decline has biological consequences is unknown. Using a transgenic approach in mice, we show that sustained high-level expression of BubR1 preserves genomic integrity and reduces tumorigenesis, even in the presence of genetic alterations that strongly promote aneuplodization and cancer, such as oncogenic Ras. We find that BubR1 overabundance exerts its protective effect by correcting mitotic checkpoint impairment and microtubule-kinetochore attachment defects. Furthermore, sustained high-level expression of BubR1 extends lifespan and delays age-related deterioration and aneuploidy in several tissues. Collectively, these data uncover a generalized function for BubR1 in counteracting defects that cause whole-chromosome instability and suggest that modulating BubR1 provides a unique opportunity to extend healthy lifespan.

To optimize the regenerative proficiency of stem cells, a cardiopoietic protein-based cocktail consisting of multiple growth factors has been developed and advanced into clinical trials for treatment of ischemic heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-mRNA (M3 RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal transcription factor, Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In vitro, eCP demonstrated protective antioxidant capacity with enhanced superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In vivo, in a murine model of myocardial infarction, intramyocardial delivery of eCP (600 000 cells per heart) improved cardiac performance and protected against decompensated heart failure. Thus, heart repair competent stem cells, armed with antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a protein-independent single gene manipulation, expanding the available regenerative toolkit.