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.

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.

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.

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.

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.

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.

The salvage potential of coronary sinus interventions: meta-analysis and pathophysiologic consequences.

OBJECTIVES: Intermittent coronary sinus occlusion has been described to be effective in salvaging ischemic myocardium. This meta-analysis aims to review the efficacy of intermittent coronary sinus occlusion and intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood as methods of myocardial salvage. METHODS: A Medline search was performed to review the published literature on intermittent coronary sinus occlusion. The study inclusion criterion was a randomized, placebo-controlled trial with area of infarction (expressed as a percentage of the area at risk) as the primary end point. RESULTS: Seven experimental trials comprising 125 test animals were found that analyzed the effects of intermittent coronary sinus occlusion on ischemic damage during coronary occlusion. A further 5 studies comprising 88 animals were designed to evaluate the effect of intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood on the infarct size. A meta-analysis of the 7 studies analyzing the effect of intermittent coronary sinus occlusion revealed a significant reduction in infarct size of 29.3% in the treatment group compared with that in the placebo group (P <.001; 95% confidence interval, -40.9 to -17.7). A meta-analysis of the 5 trials analyzing the effect of intermittent coronary sinus occlusion in combination with retroperfusion revealed a reduction in infarct size of 39.4% in the treatment group compared with that in the placebo group (P <.001; 95% confidence interval, -48.9 to -29.9). Comparison between intermittent coronary sinus occlusion and intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood showed no statistical difference (P =.19). An inverse relationship between achieved coronary sinus pressure increase per minute and infarct size could be found in the intermittent coronary sinus occlusion group (r = -0.92; P <.007), whereas in combination with retroperfusion, there was a negative correlation both between achieved coronary sinus pressure and the amount of the retroperfusate and myocardial salvage (r = -0.97; P <.004). CONCLUSIONS: The use of intermittent coronary sinus occlusion and intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood significantly decreases ischemic damage during coronary occlusions. Intermittent coronary sinus occlusion in combination with retroperfusion exhibits no significant profit in salvaging the ischemic myocardium in comparison with that provided by intermittent coronary sinus occlusion alone.

A double patch sandwich technique for surgical repair of acute aortic dissection type A.

BACKGROUND: This study compares two groups of patients with acute aortic dissection type A in whom two different techniques of anastomotic reinforcement were used, and evaluates the impact of these two techniques on perioperative blood loss and surgical outcome. METHODS: One hundred eighty-five consecutive patients with acute aortic dissection type A between 1998 and 2002 were grouped according to the technique utilized for reinforcing the aortic anastomotic site. Group A consisted of 21 patients in whom a novel double patch sandwich technique was used, whereas in group B (164 patients) conventional Teflon felt strips served as reinforcement. RESULTS: Preoperative profiles were comparable for both groups. Deep hypothermia and circulatory arrest were used in 180 patients (97%). Retrograde cerebral perfusion and retrograde cardioplegia were used in 70 patients (38%). Hospital mortality for the two groups was 4.7% (1 of 21) and 18% (29 out of 164), p < 0.30, respectively. On average 2 versus 6 U of PRBC (p < 0.21), and 3 versus 5 U of FFP (p < 0.004) were given during operation in groups A and B, respectively, and indicates reduced suture line bleeding in group A. CONCLUSIONS: Modifications in the surgical technique for repair of acute aortic dissection type A, and in anastomotic reinforcement in particular, may lead to substantial reduction of suture line bleeding and diminished blood loss and transfusion requirements, and favorably affects patient outcome. Nevertheless, continued effort is mandatory to further enhance surgical outcome in this patient population.