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BACKGROUND: Percutaneous tricuspid valve leaflet repair is an emerging treatment option for severe tricuspid regurgitation (TR). Recent studies demonstrated the usefulness and feasibility of the lately introduced TriClip and PASCAL Transcatheter Valve Repair System. However, initial experiences regarding safety and efficacy of the novel transcatheter PASCAL Ace implant system have not yet been reported. METHODS: Sixteen patients with severe, massive, or torrential TR underwent tricuspid leaflet repair using the PASCAL Ace implant at our cardiology department. All patients suffered from symptomatic right-sided heart failure with New York Heart Association functional class III or IV. Clinical, laboratory, echocardiographic, and procedural data were assessed. The primary efficiency end point was postprocedural reduction in TR of at least 1 grade. Secondary end points were feasibility, safety, clinical outcome, and improvement of structural and functional right heart parameters obtained by echocardiography. RESULTS: Eleven procedures (69%) resulted in successful reduction of TR. In 4 patients, PASCAL Ace implantation was not successful and one patient did not achieve TR reduction despite PASCAL Ace implantation. One major bleeding related to the intervention occurred. Eight patients (73%) with successful TR reduction reported a significant improvement of New York Heart Association functional class 4 weeks after implantation (P=0.008). A significant reduction in right atrial volume from 84Â41 mL/m² to 69Â36 mL/m² (P=0.004) and right ventricular end-diastolic diameter from 50Â7 mm to 47Â8 mm (P=0.013) was observed; however, we did not see an improvement in right ventricular function directly after implantation. CONCLUSIONS: Tricuspid valve leaflet repair using the transcatheter PASCAL Ace implant system has the potential to improve clinical status and right heart reverse remodeling in patients with severe TR. [ABSTRACT FROM AUTHOR]

The article discusses research that examined the role of G protein-coupled receptors (GPCRs) kinases (GRK2) and its activity during acute myocardial ischemic injury. Activation of prosurvival kinases and subsequent nitric oxide (NO) production by GPCRs protect myocardium in ischemia/reperfusion injury. A cardiac-specific GRK2 was used in a ischemia/reperfusion injury (I/R) model with B-adrenergic receptor (BAR). Results showed that the GPCRs have reduced the effect of acute ischemic myocardial injury.

The article presents the findings of the study on the role of myocardial G protein-coupled receptor kinase (GRK)2, which is a critical regulator of cardiac ß-adrenergic receptor (ßAR) signaling and cardiac function. It reveals that its upregulation in heart defect may continue to depress cardiac function and contribute to mortality in such syndrome. Moreover, the results establish a specific causal role for GRK2 in post-infarction cardiac remodeling.

The article reports on the findings of a study concerning the molecular target systems that have been subjected to intense investigation in an attempt to make gene therapy for human heart failure (HF) a reality. It mentions that gene therapy in HF was in its clinically with the predominant number of experience being from animal models. The study clearly identified the detrimental molecular targets and the means to manipulate these targets and safe gene transfer to human myocardium.

Background: Accumulation of CXCR4 (C-X-C motif chemokine receptor 4)-positive immune cells after acute myocardial infarction (AMI) can be visualized by positron emission tomography. For a broader clinical application, there is a need for CXCR4-directed radiotracers labeled with isotopes that can be used with single-photon emission computed tomography (SPECT). We report on the detection of CXCR4 expression after AMI in humans using the novel tracer [ 99m Tc]-PentixaTec., Methods: In this retrospective analysis, 9 patients with AMI after mechanical revascularization underwent myocardial inflammation imaging with [ 99m Tc]-PentixaTec SPECT/computed tomography and rest perfusion SPECT imaging. Tracer uptake in the infarcted area, spleen, bone marrow, and blood pool were used for semiquantitative analysis and calculation of signal-to-background ratios. The extent and intensity of SPECT-derived inflammatory changes were compared with serological markers and perfusion defects., Results: CXCR4-directed SPECT was positive in all patients. Increased CXCR4 expression was only detected in areas with diminished perfusion corresponding to the affected vessel in coronary angiography, with a signal-to-background ratio (infarcted area-to-blood pool) of 2.36±0.74. Uptake in bone marrow and spleen showed a significant correlation with CXCR4 expression in the infarcted areas (r=0.73 and P =0.03 for spleen and r=0.81 and P =0.008 for bone marrow, respectively). The extent and intensity of SPECT-derived inflammatory changes showed no significant association with serum troponin, CK (creatine kinase), leukocyte, or CRP (C-reactive protein) levels., Conclusions: This is the first report of in vivo CXCR4 imaging after AMI using a 99m Tc-labeled tracer. Increased CXCR4 expression was observed locally in the infarcted region and was related to a systemic inflammatory response in the reticuloendothelial system. This proof-of-concept investigation demonstrates the general feasibility of evaluating the inflammation-related CXCR4 expression in the myocardium after AMI using conventional scintigraphy or SPECT and might, thus, broaden its worldwide application in clinical practice., Competing Interests: All the authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this article.

Background: Acute cellular rejection (ACR) in heart transplant (HTx) recipients may be accompanied by cardiac cell damage with subsequent exposure to cardiac autoantigens and the production of cardiac autoantibodies (aABs). This study aimed to evaluate a peptide array screening approach for cardiac aABs in HTx recipients during ACR (ACR-HTx)., Methods: In this retrospective single-center observational study, sera from 37 HTx recipients, as well as age and sex-matched healthy subjects were screened for a total of 130 cardiac aABs of partially overlapping peptide sequences directed against structural proteins using a peptide array approach., Results: In ACR-HTx, troponin I (TnI) serum levels were found to be elevated. Here, we could identify aABs against beta-2-adrenergic receptor (β-2AR: EAINCYANETCCDFFTNQAY) to be upregulated in ACR-HTx (intensities: 0.80 versus 1.31, P = 0.0413). Likewise, patients positive for β-2AR aABs showed higher TnI serum levels during ACR compared with aAB negative patients (10.0 versus 30.0 ng/L, P = 0.0375). Surprisingly, aABs against a sequence of troponin I (TnI: QKIFDLRGKFKRPTLRRV) were found to be downregulated in ACR-HTx (intensities: 3.49 versus 1.13, P = 0.0025). A comparison in healthy subjects showed the same TnI sequence to be upregulated in non-ACR-HTx (intensities: 2.19 versus 3.49, P = 0.0205), whereas the majority of aABs were suppressed in non-ACR-HTx., Conclusions: Our study served as a feasibility analysis for a peptide array screening approach in HTx recipients during ACR and identified 2 different regulated aABs in ACR-HTx. Hence, further multicenter studies are needed to evaluate the prognostic implications of aAB testing and diagnostic or therapeutic consequences., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Partial circulatory support is a promising concept for the treatment of heart failure patients. A better understanding of induced hemodynamic changes is essential for optimizing treatment efficacy. Computational fluid dynamics (CFD) is an alternative method to gain insight into flow phenomena difficult to obtain in vivo. In 10 patients implanted with a Circulite Synergy Micro-pump (HeartWare, Framingham, Massachusetts) (a continuous flow partial circulatory assist device connecting the left atrium to the right subclavian artery), transient CFD simulations were performed. Patients were divided into two groups depending on their cardiac output (CO; high CO group: 5.5 ± 1.1 L/min, low CO group: 1.7 ± 0.7 L/min). The partial assist device provided a supporting flow of 1.5 ± 0.8 L/min. Support was highest at diastole and decreased during systole because of a collision of the blood flows from the partial assist device and the CO. Reversed flow counteracting the flow of the device was significantly higher for the high CO group (mean flow in peak systole: -2.18 ± 1.08 vs. 0.23 ± 0.59 L/min; p = 0.002) showing an inverse correlation between CO and amount of reversed flow during peak systole (R = -0.7; p < 0.02). The flow collision lead to higher total pressures at the point of collision and consequently in the Circulite outflow graft. The CFD simulations allow quantifying hemodynamic alterations in patients with partial support consisting of a flow collision, thereby reducing effectiveness of the circulatory support. Partial support in heart failure patients alternates their hemodynamics not only in providing support for the circulation but also inducing unfavorable changes in flow patterns.

Background: Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required., Methods and Results: Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II-IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (P<0.001), quality of life (Minnesota Living with Heart Failure score, P<0.001), and 6-minute walk distance (P<0.01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index (P<0.001), with a concomitant small stable increase in the right ventricular end-diastolic volume index (P<0.001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure (P<0.01). Survival at 1 year was 95%, and there was no evidence of device-related complications., Conclusions: These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913613., (© 2016 The Authors.)

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

Objectives: The interaction of the heat shock protein 90 (Hsp90) with the endothelial NO synthase (eNOS) has been shown to account for a sustained production of NO in vitro. Here, we examined whether overexpression of Hsp90 in a pig model of cardiac infarct could preserve the myocardium from the deleterious effects of ischemia-reperfusion., Methods and Results: Percutaneous liposome-based gene transfer was performed by retroinfusion of the anterior interventricular vein before left anterior descending occlusion and reperfusion. We found that recombinant Hsp90 expression in the ischemic region of the heart led to a 33% reduction in infarct size and prevented the increase in postischemic left ventricular end diastolic pressure observed in mock-transfected animals. Regional myocardial function, assessed by subendocardial segment shortening in the infarct region, was increased in Hsp90-transfected animals at baseline and after pacing. All these effects were completely abrogated by administration of the NOS inhibitor N(G)-nitro-L-arginine methyl ester. We further documented in vivo and in cultured endothelial cells that the cardioprotective effects of Hsp90 were associated to its capacity to act as an adaptor for both the kinase Akt and the phosphatase calcineurin, thereby promoting eNOS serine 1177 phosphorylation and threonine 495 dephosphorylation, respectively., Conclusions: Hsp90 is a promising target to enhance NO formation in vivo, which may efficiently reduce myocardial reperfusion injury.

Background: Ventricle-to-coronary artery bypass (VCAB) is an experimental revascularization procedure that provides predominantly systolic instead of diastolic blood flow to a coronary artery., Methods and Results: In a pig model, a stent-based procedure (VSTENT) was developed to create a VCAB. After thoracotomy, a covered VSTENT was implanted between the left ventricle and the left anterior descending coronary artery (LAD). Distal LAD flow, regional myocardial function, and intracoronary pressures were determined at different degrees of LAD stenosis and during complete LAD occlusion. During 3 hours of LAD occlusion, VSTENT preserved net forward flow at 70+/-6% and regional myocardial function at 71+/-8% of baseline. Preservation of net flow was influenced by the positioning of the VSTENT, with higher preservation also under conditions of increased oxygen demand if a "valve-like mechanism" was present during diastole. At a hemodynamically relevant level of LAD stenosis (>70%), systolic inflow was predominant after VSTENT implantation. Changes in mean diastolic intracoronary pressure that resulted from different degrees of LAD stenosis were linearly correlated to net flow after VSTENT implantation (r=0.88; P<0.001)., Conclusions: VSTENT for ventricle-to-coronary artery bypass was feasible and preserved 70+/-6% of baseline flow during complete LAD occlusion. The degree of preservation was dependent on the position of the VSTENT creating a valve-like mechanism during diastole. Residual diastolic blood flow through a high-grade LAD stenosis influenced net flow favorably, because diastolic backflow decreased with increasing mean diastolic intracoronary pressure.