Circulating microRNAs and cardiomyocyte proliferation in heart failure patients related to 10 years survival.

AIMS: Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking cardiovascular therapy and clinical outcome has been the dream of scientists for decades. Concepts involving embryonic pathways to regenerate adult failing hearts became popular in the early millennium. Since then, abundant data on stem cell research have been published, never reaching widespread application in heart failure therapy. Another conceptual access, using mechanotransduction in cardiac veins to limit myocardial decay, is pressure-controlled intermittent coronary sinus occlusion (PICSO). Recently, we reported acute molecular signs and signals of PICSO activating regulatory miRNA and inducing cell proliferation mimicking cardiac development in adult failing hearts. According to a previously formulated hypothesis, 'embryonic recall', this study aimed to define molecular signals involved in endogenous heart repair during PICSO and study their relation to patient survival. METHODS AND RESULTS: We previously reported a study on the acute molecular effects of PICSO in an observational non-randomized study. Eight out of the thirty-two patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) were treated with PICSO. Survival was monitored over 10 years, and coronary sinus blood samples were collected during intervention before and after 20 min and tested for miRNA signalling and proliferation when co-cultured with cardiomyocytes. A numerically lower death rate post-CRT and PICSO as compared with control CRT only, and a non-significant reduction in all-cause mortality risk of 42% was observed (37.5% vs. 54.0%, relative risk = 0.58, 95% confidence interval: 0.17-2.05; P = 0.402). Four miRNAs involved in cell cycle, proliferation, morphogenesis, embryonic development, and apoptosis significantly increased concomitantly in survivors and PICSO compared with a decrease in non-survivors (hsa-miR Let7b, P < 0.01; hsa-miR- 421, P < 0.006; hsa-miR 363-3p, P < 0.03 and hsa-miR 19b-3p P < 0.01). In contrast, three miRNAs involved in proliferation and survival, determining cell fate, and recycling endosomes decreased in survivors and PICSO (hsa miR 101-3p, P < 0.03; hsa-miR 25-3p, P < 002; hsa-miR 30d-5p P < 0.04). In vitro cellular proliferation increased in survivors and lowered in non-survivors showing a pattern distinction, discriminating longevity according to up to 10-year survival in heart failure patients. CONCLUSIONS: This study proposes that generating regenerative signals observed during PICSO intervention relate to patient outcomes. Morphogenetic pathways induced by periods of flow reversal in cardiac veins in a domino-like pattern transform embryonic into regenerative signals. Studies supporting the conversion of mechanochemical signals into regenerative molecules during PICSO are warranted to substantiate predictive power on patient longevity, opening new therapeutic avenues in otherwise untreatable heart failure.

Signs and signals limiting myocardial damage using PICSO: a scoping review decoding paradigm shifts toward a new encounter.

Background: Inducing recovery in myocardial ischemia is limited to a timely reopening of infarct vessels and clearing the cardiac microcirculation, but additional molecular factors may impact recovery. Objective: In this scoping review, we identify the paradigm shifts decoding the branching points of experimental and clinical evidence of pressure-controlled intermittent coronary sinus occlusion (PICSO), focusing on myocardial salvage and molecular implications on infarct healing and repair. Design: The reporting of evidence was structured chronologically, describing the evolution of the concept from mainstream research to core findings dictating a paradigm change. All data reported in this scoping review are based on published data, but new evaluations are also included. Results: Previous findings relate hemodynamic PICSO effects clearing reperfused microcirculation to myocardial salvage. The activation of venous endothelium opened a new avenue for understanding PICSO. A flow-sensitive signaling molecule, miR-145-5p, showed a five-fold increase in porcine myocardium subjected to PICSO.Verifying our theory of "embryonic recall," an upregulation of miR-19b and miR-101 significantly correlates to the time of pressure increase in cardiac veins during PICSO (r2 = 0.90, p < 0.05; r2 = 0.98, p < 0.03), suggesting a flow- and pressure-dependent secretion of signaling molecules into the coronary circulation. Furthermore, cardiomyocyte proliferation by miR-19b and the protective role of miR-101 against remodeling show another potential interaction of PICSO in myocardial healing. Conclusion: Molecular signaling during PICSO may contribute to retroperfusion toward deprived myocardium and clearing the reperfused cardiac microcirculation. A burst of specific miRNA reiterating embryonic molecular pathways may play a role in targeting myocardial jeopardy and will be an essential therapeutic contribution in limiting infarcts in recovering patients.

Mitral Butterfly: Preclinical Experience of a Novel Chordal Repair Device Using an Artificial Papillary Muscle.

Transcatheter mitral repair is based on the principle of artificial monochordal repair. In this paper, the authors show an alternative, based on the realization of an artificial papillary muscle concept that avoids multiple chordal replacements and fixation in the myocardium. Unlike the interposition of artificial chordae between the free edge of the leaflet and the myocardium, the so-called Mitral Butterfly device collects a multitude of chordae in a matrix connected to a swing arm, stabilizing prolapsing forces with a broad atrial support. Device testing in chronic animal models and in silico substantiated the underlying device concept and performance after 90 days.

Acute molecular effects of pressure-controlled intermittent coronary sinus occlusion in patients with advanced heart failure.

AIMS: Cardiac repair has steered clinical attention and remains an unmet need, because available regenerative therapies lack robust mechanistic evidence. Pressure-controlled intermittent coronary sinus occlusion (PICSO), known to induce angiogenetic and vasoactive molecules as well as to reduce regional ischemia, may activate endogenous regenerative processes in failing myocardium. We aimed to investigate the effects of PICSO in patients with advanced heart failure undergoing cardiac resynchronization therapy. METHODS AND RESULTS: Eight out of 32 patients were treated with PICSO, and the remainder served as controls. After electrode testing including left ventricular leads, PICSO was performed for 20 min. To test immediate molecular responses, in both patient groups, coronary venous blood samples were taken at baseline and after 20 min, the time required for the intervention. Sera were tested for microRNAs and growth factors. To test the ability of up-regulated soluble factors on cell proliferation and expression of transcription factors [e.g. Krüppel-like factor 4 (KLF-4)], sera were co-cultured with human cardiomyocytes and fibroblasts. As compared with controls, significant differential expression (differences between pre-values and post-values in relation to both patient cohorts) of microRNA patterns associated with cardiac development was observed with PICSO. Importantly, miR-143 (P < 0.048) and miR-145 (P < 0,047) increased, both targeting a network of transcription factors (including KLF-4) that promote differentiation and repress proliferation of vascular smooth muscle cells. Additionally, an increase of miR-19b (P < 0.019) known to alleviate endothelial cell apoptosis was found, whereas disadvantageous miR-320b (P < 0.023) suspect to impair expression of c-myc, normally provoking cell cycle re-entry in post-mitotic myocytes and miR-25 (P < 0.023), decreased, a target of anti-miR application to improve contractility in the failing heart. Co-cultured post-PICSO sera significantly increased cellular proliferation both in fibroblasts (P < 0.001) and adult cardiomycytes (P < 0.004) sampled from a transplant recipient as compared with controls. Adult cardiomyocytes showed a seven-fold increase of the transcription factor KLF-4 protein when co-cultured with treated sera as compared with controls. CONCLUSIONS: Here, we show for the first time that PICSO, a trans-coronary sinus catheter intervention, is associated with an increase in morphogens secreted into cardiac veins, normally present during cardiac development, and a significant induction of cell proliferation. Present findings support the notion that epigenetic modifications, that is, haemodynamic stimuli on venous vascular cells, may reverse myocardial deterioration. Further investigations are needed to decipher the maze of complex interacting molecular pathways in failing myocardium and the potential role of PICSO to reinitiate developmental processes to prevent further myocardial decay eventually reaching clinical significance.

From state-of-the-art cell therapy to endogenous cardiac repair.

Clinical heart failure prevention and contemporary therapy often involve breaking the vicious cycle of global haemodynamic consequences of myocardial decay. The lack of effective regenerative therapies results in a primary focus on preventing further deterioration of cardiac performance. The cellular transplantation hypothesis has been evaluated in many different preclinical models and a handful of important clinical trials. The primary expectation that cellular transplants will be embedded into failing myocardium and fuse with existing functioning cells appears unlikely. A multitude of cellular formulas, access routes and clinical surrogate endpoints for evaluation add to the complexity of cellular therapies. Several recent large clinical trials have provided insights into both the regenerative potential and clinical improvement from non-regenerative mechanisms. Initiating endogenous repair seems to be another meaningful alternative to recover structural integrity in myocardial injury. This option may be achieved using a transcoronary sinus catheter intervention, implying the understanding of basic principles in biology. With intermittent reduction of outflow in cardiac veins (PICSO), vascular cells appear to be activated and restart a programme similar to pathways in the developing heart. Structural regeneration may be possible without requiring exogenous agents, or a combination of both approaches may become clinical reality in the next decade.

Closed-loop helium circulation system for actuation of a continuously operating heart catheter pump.

BACKGROUND: Currently available, pneumatic-based medical devices are operated using closed-loop pulsatile or open continuous systems. Medical devices utilizing gases with a low atomic number in a continuous closed loop stream have not been documented to date. This work presents the construction of a portable helium circulation addressing the need for actuating a novel, pneumatically operated catheter pump. The design of its control system puts emphasis on the performance, safety and low running cost of the catheter pump. METHODS AND RESULTS: Static and dynamic characteristics of individual elements in the circulation are analyzed to ensure a proper operation of the system. The pneumatic circulation maximizes the working range of the drive unit inside the catheter pump while reducing the total size and noise production.Separate flow and pressure controllers position the turbine's working point into the stable region of the pressure creation element. A subsystem for rapid gas evacuation significantly decreases the duration of helium removal after a leak, reaching subatmospheric pressure in the intracorporeal catheter within several milliseconds. CONCLUSIONS: The system presented in the study offers an easy control of helium mass flow while ensuring stable behavior of its internal components.

Contemporary perspective on endogenous myocardial regeneration.

Considering the complex nature of the adult heart, it is no wonder that innate regenerative processes, while maintaining adequate cardiac function, fall short in myocardial jeopardy. In spite of these enchaining limitations, cardiac rejuvenation occurs as well as restricted regeneration. In this review, the background as well as potential mechanisms of endogenous myocardial regeneration are summarized. We present and analyze the available evidence in three subsequent steps. First, we examine the experimental research data that provide insights into the mechanisms and origins of the replicating cardiac myocytes, including cell populations referred to as cardiac progenitor cells (i.e., c-kit+ cells). Second, we describe the role of clinical settings such as acute or chronic myocardial ischemia, as initiators of pathways of endogenous myocardial regeneration. Third, the hitherto conducted clinical studies that examined different approaches of initiating endogenous myocardial regeneration in failing human hearts are analyzed. In conclusion, we present the evidence in support of the notion that regaining cardiac function beyond cellular replacement of dysfunctional myocardium via initiation of innate regenerative pathways could create a new perspective and a paradigm change in heart failure therapeutics. Reinitiating cardiac morphogenesis by reintroducing developmental pathways in the adult failing heart might provide a feasible way of tissue regeneration. Based on our hypothesis "embryonic recall", we present first supporting evidence on regenerative impulses in the myocardium, as induced by developmental processes.

PICSO: from myocardial salvage to tissue regeneration.

Despite advances in primary percutaneous interventions (PPCI), management of microvascular obstructions in reperfused myocardial tissue remains challenging and is a high-risk procedure. This has led to renewed interest in the coronary venous system as an alternative route of access to the myocardium. This article reviews historical data describing therapeutic options via cardiac veins as well as discussing the clinical potential and limitations of a catheter intervention: pressure controlled intermittent coronary sinus occlusion (PICSO). Collected experimental and clinical information suggest that PICSO also offers the potential for tissue regeneration beyond myocardial salvage. A meta-analysis of observer controlled pICSO application in animal studies showed a dose dependent reduction in infarct size of 29.3% (p < 0.001). Additionally, a 4-fold increase of hemeoxygenase-1 gene expression (p < 0.001) in the center of infarction and a 2.5 fold increase of vascular endothelial growth factor (VEGF) (p < 0.002) in border zones suggest that molecular pathways are initiating structural maintenance. Early clinical evidence confirmed significant salvage and event free survival in patients with acute myocardial infarction and risk reduction for event free survival 5 years after the acute event (p < 0.0001). This experimental and clinical evidence was recently corroborated using modern PICSO technology in PPCI showing a significant reduction of infarct size, when compared to matched controls (p < 0.04). PICSO enhances redistribution of flow towards deprived zones, clearing microvascular obstruction and leading to myocardial protection. Beyond salvage, augmentation of molecular regenerative networks suggests a second mechanism of PICSO involving the activation of vascular cells in cardiac veins, thus enhancing structural integrity and recovery.

Left ventricular pseudoaneurysm following mitral valve repair.

We present a rare case of a left ventricular pseudoaneurysm following mitral valve repair probably due to testing the valve's competence. The pseudoaneurysm was treated successfully with a sutureless technique in which layers of a biodegradable collagen system with fibrinogen-based coating were used. We reviewed the literature regarding left ventricular rupture following mitral valve surgery published from 1990 until 2006. Overall, the incidence of this complication was 0.56% for 10978 operations, and the mortality rate was 57.4%. We also describe a possible mechanism common to all forms of left ventricular rupture.

Myocardial protection via the coronary sinus.

BACKGROUND: Recent reports on facilitated reperfusion therapy re-address interests in coronary sinus interventions (CSI). Patients in whom short time results have been reported earlier were re-evaluated, with the aim of gathering the long-term results of pressure-controlled intermittent coronary sinus occlusion (PICSO) generated in patients with acute myocardial infarction (MI) and revascularization. METHODS AND RESULTS: Thirty-four patients with ST elevated MI, in whom complete revascularization was achieved, underwent primary thrombolysis with or without PICSO. Follow-up data from these patients were collected for at least 48 months. Immediate perioperative differences were observed for time to peak creatine kinase (CK), as well as cumulative CK. In addition, the time until reperfusion was considerably less than for the control group (p=0.014). Long-term data showed significant differences in reinfarction (p=0.015), as well as in major adverse cardiovascular events, between the 2 groups (p<0.0001). CONCLUSION: These data, because of the wide interval between collection and current analysis, could have inherited historical bias. Nonetheless, they are also uniquely indicating the potential of CSI to induce not only immediate, but also clinically significant long-term, effects as an adjunct to reperfusion therapy. Therefore, CSI should be, once again, on the study agenda and be placed under contemporary and best-available scientific scrutiny.

Beck and back: a paradigm change in coronary sinus interventions--pulsatile stretch on intact coronary venous endothelium.

OBJECTIVES: Strategies to recover myocardium in therapeutically unresponsive patients are again under scrutiny, including techniques developed in the pioneering days of cardiothoracic surgery such as retroperfusion via the coronary sinus--the Beck procedure. An underestimated aspect of retroperfusion is the formation of new vessels. This early observation of neoangiogenesis may be an important mechanism in observed benefits. We hypothesized that periodic pressure elevation in coronary veins induces an analogy to shear stress angiogenic pulses by activating venous endothelium. Pulsatile stretch on venous endothelium can be achieved easily by a pressure-controlled intermittent balloon blockade of the coronary sinus outflow. METHODS: Three hours of myocardial ischemia was induced in 12 pigs. Pressure-controlled intermittent coronary sinus occlusion was applied in 6 animals 15 minutes after occlusion of the left anterior descending coronary artery. Postmortem myocardial specimens were taken, and heme oxygenase-1, vascular endothelial growth factor gene expression, and hypoxia-induced factor activity were measured. RESULTS: As compared with controls, treated animals released an angiogenic pulse by a 4-fold increase of heme oxygenase-1 gene expression in the infarct area (P < .001), together with a 2.5-fold enhanced transcription of vascular endothelial growth factor in the infarct (P < .006), border (P < .002), and remote (P < .02) areas, whereas hypoxia-induced factor activity was similar in both groups. A significant correlation (P < .01) of the achieved coronary sinus pressure elevation and gene expression was found. CONCLUSIONS: Mechanotransduction of pulsatile stretch on coronary venous endothelium by pressure-controlled intermittent coronary sinus occlusion induces heme oxygenase-1 and vascular endothelial growth factor gene expression, leaving the ischemic pathway of the hypoxia-induced factor activity unchanged. This cascade of molecular events closes the argument gap to historical reports of the Beck procedure on revascularization and myocardial salvage.

Cystic formation of the foramen ovale mimicking a right atrial myxoma.

A 65-year-old woman presented with shortness of breath, stenocardia, and tachycardia. She underwent several steps of examination. Echocardiography showed a suspicious formation in the right atrium extending into the inferior caval vein. The lesion was suspicious for a myxoma, a thrombus, or a malformation. Intraoperatively this formation presented as a cystic formation connected to the right atrial wall in the area of the foramen secundum and filled with blood and five calcified thrombi. We hypothesize that a slit-like opening in the foramen ovale produced a valve-like mechanism bulging parts of the septum secundum and produced this cystic formation.

Management of central coronary sinus ruptures using the pericardial patch repair technique.

BACKGROUND: Intraoperative coronary sinus rupture is a rare event; however, it carries potential mortality and its' management is technically challenging. A repair technique should provide adequate bleeding control while avoiding narrowing or stricture of the coronary sinus. METHODS: We retrospectively review our experience with a new pericardial patch repair technique. From January 1996 to May 2005 four cases of intraoperative coronary sinus injury were identified. Three female patients and one male patient with a mean age of 74 +/- 4 years underwent valve replacement and/or coronary artery bypass on cardiopulmonary bypass. A double pericardial patch technique sandwiched with human fibrin glue was used to cover the defect. RESULTS: In all patients treated with this method, the injury could be treated successfully. All patients were extubated on the first postoperative day and median intensive care unit stay was 3 days. Drains could be removed after 4 days median. Median hospital stay was 13 days. After a median follow-up of 33 months all patients are alive without any echocardiographic signs of impairments of the coronary sinus. CONCLUSIONS: We conclude that the pericardial patch technique is a safe and technically feasible technique for repair of central coronary sinus ruptures. Excellent bleeding control and, in our experience, no consecutive complications were observed.