Cold-stored platelets for acute bleeding in cardiac surgical patients: a narrative review.

PURPOSE: Cold-stored platelets (CSP) are an increasingly active topic of international research. They are maintained at 1-6 °C, in contrast to standard room-temperature platelets (RTP) kept at 20-24 °C. Recent evidence suggests that CSP have superior hemostatic properties compared with RTP. This narrative review explores the application of CSP in adult cardiac surgery, summarizes the preclinical and clinical evidence for their use, and highlights recent research. SOURCE: A targeted search of MEDLINE and other databases up to 24 February 2022 was conducted. Search terms combined concepts such as cardiac surgery, blood, platelet, and cold-stored. Searches of trial registries ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were included. Articles were included if they described adult surgical patients as their population of interest and an association between CSP and clinical outcomes. References of included articles were hand searched. PRINCIPAL FINDINGS: When platelets are stored at 1-6 °C, their metabolic rate is slowed, preserving hemostatic function for increased storage duration. Cold-stored platelets have superior adhesion characteristics under physiologic shear conditions, and similar or superior aggregation responses to physiologic agonists. Cold-stored platelets undergo structural, metabolic, and molecular changes which appear to "prime" them for hemostatic activity. While preliminary, clinical evidence supports the conduct of trials comparing CSP with RTP for patients with platelet-related bleeding, such as those undergoing cardiac surgery. CONCLUSION: Cold-stored platelets may have several advantages over RTP, including increased hemostatic capacity, extended shelf-life, and reduced risk of bacterial contamination. Large clinical trials are needed to establish their potential role in the treatment of acutely bleeding patients.

RéSUMé: OBJECTIF: Les plaquettes conservées au froid (PCF) sont un sujet de recherche internationale de plus en plus populaire. Ces plaquettes sont maintenues à une température de 1-6 °C, contrairement aux plaquettes standard conservées à température ambiante (PTA), maintenues à 20­24 °C. Des données probantes récentes suggèrent que les PCF ont des propriétés hémostatiques supérieures aux PTA. Ce compte rendu narratif explore l'application de PCF en chirurgie cardiaque chez l'adulte, résume les données probantes précliniques et cliniques de leur utilisation, et met en évidence les recherches récentes. SOURCES: Une recherche ciblée dans MEDLINE et d'autres bases de données jusqu'au 24 février 2022 a été effectuée. Les termes de recherche combinaient des concepts en anglais tels que cardiac surgery, blood, platelet et cold-stored (soit chirurgie cardiaque, plaquette, et entreposage frigorifique). Des recherches dans les registres d'études ClinicalTrials.gov et le système d'enregistrement international des essais cliniques (ICTRP) de l'OMS ont été incluses. Les articles ont été inclus s'ils décrivaient des patient·es adultes de chirurgie en tant que population d'intérêt et une association entre les PCF et les issues cliniques. Les références des articles inclus ont fait l'objet d'une recherche manuelle. CONSTATATIONS PRINCIPALES: Lorsque les plaquettes sont conservées entre 1 et 6 °C, leur taux métabolique est ralenti, préservant la fonction hémostatique pour une durée d'entreposage accrue. Les plaquettes conservées au froid ont des caractéristiques d'adhésion supérieures dans des conditions de cisaillement physiologique et des réponses d'agrégation similaires ou supérieures aux agonistes physiologiques. Les plaquettes conservées au froid subissent des changements structurels, métaboliques et moléculaires qui semblent les « amorcer ¼ pour une activité hémostatique. Bien que préliminaires, les données probantes cliniques appuient la réalisation d'études comparant les PCF aux PTA chez la patientèle présentant des saignements liés aux plaquettes, tels que les personnes bénéficiant d'une chirurgie cardiaque. CONCLUSION: Les plaquettes conservées au froid peuvent présenter plusieurs avantages par rapport aux PTA, notamment une capacité hémostatique accrue, une durée de conservation prolongée et un risque réduit de contamination bactérienne. De grands essais cliniques sont nécessaires pour établir leur rôle potentiel dans le traitement de la patientèle en hémorragie aiguë.

Heart Failure Trial Update-Analysis of Recent Data.

The prevalence of heart failure (HF) continues to increase, and its economic effect is significant in the United States and globally. During the past 2 years, a number of high-quality clinical trials were published with the aim of addressing different stages of the disease process and improving outcomes for patients with preserved and depressed ejection fraction (EF). In this review, data from these trials are summarized and critically appraised. There are several important findings from these studies, including, but not limited to, the benefit of dapagliflozin in HF with reduced EF, sacubitril-valsartan in acute decompensated HF, thoracotomy in left ventricular assist device implantation, and the overall risk-benefit ratios of centrifugal pumps as opposed to continuous flow pumps. Effective therapies for HF with preserved EF continue to evolve for this varied group of high morbidity and mortality conditions.

Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury.

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.

Chronic Thromboembolic Pulmonary Hypertension-Management Strategies and Outcomes.

Chronic thromboembolic pulmonary hypertension (CTEPH) is rare but complex pathophysiological disease with hallmark features of chronic thrombotic mechanical obstruction, right ventricular dysfunction, and secondary pulmonary arteriopathy. It increasingly is being understood that chronic infection/inflammation, abnormal fibrinolysis, and cytokines play an important role in pathogenesis such that only a subset of patients with pulmonary embolism develop CTEPH. Diagnosis remains challenging given the lack of early clinical signs and overlap with other cardiopulmonary conditions. Pulmonary endarterectomy is the surgical procedure of choice with good postoperative survival and functional outcomes, especially when done at high-volume centers with a multidisciplinary approach. There has been a resurgence of balloon pulmonary angioplasty (BPA) as salvage therapy for inoperable CTEPH or in its newfound hybrid role for persistent postoperative pulmonary hypertension with excellent 1-year and 3-year survival. Use of riociguat has shown promising improvements in functional outcomes up to 2 years after initiation. Endothelin receptor antagonists serve a supplemental role postoperatively or in inoperable CTEPH. The role of drug therapy preoperatively or in tandem with BPA is currently under investigation.

Using Acellular Bioactive Extracellular Matrix Scaffolds to Enhance Endogenous Cardiac Repair.

An inability to recover lost cardiac muscle following acute ischemic injury remains the biggest shortcoming of current therapies to prevent heart failure. As compared to standard medical and surgical treatments, tissue engineering strategies offer the promise of improved heart function by inducing regeneration of functional heart muscle. Tissue engineering approaches that use stem cells and genetic manipulation have shown promise in preclinical studies but have also been challenged by numerous critical barriers preventing effective clinical translational. We believe that surgical intervention using acellular bioactive ECM scaffolds may yield similar therapeutic benefits with minimal translational hurdles. In this review, we outline the limitations of cellular-based tissue engineering strategies and the advantages of using acellular biomaterials with bioinductive properties. We highlight key anatomic targets enriched with cellular niches that can be uniquely activated using bioactive scaffold therapy. Finally, we review the evolving cardiovascular tissue engineering landscape and provide critical insights into the potential therapeutic benefits of acellular scaffold therapy.

Heparin Augmentation Enhances Bioactive Properties of Acellular Extracellular Matrix Scaffold.

Extracellular matrix (ECM) maintains a reservoir of bioactive growth factors and matricellular proteins that provide bioinductive effects on local cells that influence phenotype and behaviors. Bioactive acellular ECM scaffolds can be used therapeutically to stimulate adaptive tissue repair. Fibroblast growth factor-2 (FGF-2) attenuates transforming growth factor-ß1 (TGF-ß1)-mediated cardiac fibrosis. Heparin glycosaminoglycan can influence FGF-2 bioactivity and could be leveraged to enhance tissue engineering strategies. We explored the effects of heparin on FGF-2 enhancement of bioactive ECM scaffold biomaterials for its antifibrotic effect on attenuating human cardiac myofibroblast activation. Increasing heparin concentration at a fixed concentration of FGF-2 markedly increased the amount of FGF-2 retained and eluted by ECM scaffolds. To explore synergistic bioinductive effects of heparin and FGF-2, collagen gel contraction assay using human cardiac myofibroblasts was performed in vitro. Myofibroblast activation was induced by profibrotic cytokine, TGF-ß1. FGF-2 and heparin in combination reduced human cardiac myofibroblast-mediated collagen gel contraction to a greater extent than FGF-2 alone. These observations were confirmed for both human atrial and human ventricular cardiac fibroblasts. Cell death was not different between groups. In summary, heparin is an effective adjuvant to enhance FGF-2 loading and elution of acellular ECM scaffold biomaterials. Heparin increases the bioactive effects of FGF-2 in attenuating human cardiac myofibroblast activation in response to profibrotic TGF-ß1. These data may inform tissue engineering strategies for myocardial repair to prevent fibrosis.

Adhesive-Enhanced Sternal Closure: Feasibility and Safety of Late Sternal Reentry.

This clinical case report describes sternal reentry performed years after adhesive-enhanced sternal closure using Kryptonite bone cement. This report provides novel data on the late effects of this innovation. We observed that sternal reentry is feasible and safe. The adhesive did not weaken from biodegradation over a period of several years. There was no evidence of adherence to adjacent soft tissues or other nonbony deep mediastinal structures. Surgeons who receive patients who require redoing cardiac surgery after adhesive-enhanced closure with Kryptonite can be reassured that sternal reentry is safe and feasible.

Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair.

Structural cardiac remodeling after ischemic injury can induce a transition to heart failure from progressive loss of cardiac function. Cellular regenerative therapies are promising but face significant translational hurdles. Tissue extracellular matrix (ECM) holds the necessary environmental cues to stimulate cell-based endogenous myocardial repair pathways and promote adaptive remodeling toward functional recovery. Heart epicardium has emerged as an important anatomic niche for endogenous repair pathways including vasculogenesis and cardiogenesis. We show that acellular ECM scaffolds surgically implanted on the epicardium following myocardial infarction (MI) can attenuate structural cardiac remodeling and improve functional recovery. We assessed the efficacy of this strategy on post-MI functional recovery by comparing intact bioactive scaffolds with biologically inactivated ECM scaffolds. We confirm that bioactive properties within the acellular ECM biomaterial are essential for the observed functional benefits. We show that interaction of human cardiac fibroblasts with bioactive ECM can induce a robust cell-mediated vasculogenic paracrine response capable of functional blood vessel assembly. Fibroblast growth factor-2 is uncovered as a critical regulator of this novel bioinductive effect. Acellular bioactive ECM scaffolds surgically implanted on the epicardium post-MI can reprogram resident fibroblasts and stimulate adaptive pro-reparative pathways enhancing functional recovery. We introduce a novel surgical strategy for tissue repair that can be performed as an adjunct to conventional surgical revascularization with minimal translational challenges.

Trainee Perceptions of the Canadian Cardiac Surgery Workforce: A Survey of Canadian Cardiac Surgery Trainees.

Management of cardiac surgery health human resources (HHR) has been challenging, with recent graduates struggling to secure employment and a shortage of cardiac surgeons predicted as early as 2020. The length of cardiac surgery training prevents HHR supply from adapting in a timely fashion to changes in demand, resulting in a critical need for active workforce management. This study details the results of the 2015 Canadian Society of Cardiac Surgeons (CSCS) workforce survey undertaken as part of the CSCS strategy for active workforce management. The 38-question survey was administered electronically to all 96 trainees identified as being registered in a Canadian cardiac surgery residency program for the 2015-2016 academic year. Eighty-four of 96 (88%) trainees responded. The majority of participants were satisfied with their training experience. However, 29% stated that their clinical and operative exposure needed improvement, and 57% of graduating trainees did not believe that they would be competent to practice independently at the conclusion of their training. Although 51% of participants believe the job market is improving, 94% of senior trainees found it competitive or extremely difficult to secure an attending staff position. Participants highlighted a need for improved career counselling and formal mentorship. Although the job market is perceived to be improving, a mismatch in the cardiac surgery workforce supply and demand remains because current trainees continue to experience difficulty securing employment after the completion of residency training. Trainees have identified improved career counselling and mentorship as potential strategies to aid graduates in securing employment.

Safety and efficacy of prophylactic negative pressure wound therapy following open saphenous vein harvest in cardiac surgery: a feasibility study.

Objectives: Surgical site complications following great saphenous vein (GSV) harvest presents a significant risk of morbidity. Negative pressure wound therapy (NPWT) has shown promise in the treatment and prophylaxis of open wounds and surgical incisions but has not been studied following GSV harvest. We performed a feasibility study examining the use of NPWT following GSV harvest for coronary bypass surgery. Methods: Sixty-four patients were recruited in this single-centre, single-blind, randomized controlled trial. The primary endpoint assessed feasibility by examining rates of device complication and malfunction. Secondary endpoints included rates of surgical site infection, lower leg complications, discharge date, and quality of life at discharge and 6 weeks. NPWT was delivered using the Prevena NPWT device. Results: There were no complications associated with NPWT which required intervention aside from discontinuation. NPWT was tolerated in 91% (30/33) of patients for the duration of treatment with an average of 4.8 days (±1.45 days). Device malfunction which required discontinuation was 6% (2/33) and involved a malfunctioning pressure sensor and did not affect patient care or present safety concerns. One patient had allergic contact dermatitis to the adhesive and had the device removed. NPWT patients had an earlier date of discharge (6 vs 10 days, P = 0.008), increased ability for self-care ( P = 0.0234) and quality of life ( P = 0.039) at initial assessment, and increased mobility at initial and follow-up assessment ( P = 0.0117 and 0.0123). Conclusions: The use of NPWT following GSV harvest is safe, well tolerated and improves postoperative recovery with prolonged impact on mobility at 6 weeks. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01698372 ; registration number: NCT01698372.

Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery.

BACKGROUND: Infarcted myocardium can remodel after successful reperfusion, resulting in left ventricular dilation and heart failure. Epicardial infarct repair (EIR) using a bioinductive extracellular matrix (ECM) biomaterial is a novel surgical approach to promote endogenous myocardial repair and functional recovery after myocardial infarction. Using a pre-clinical porcine model of coronary ischemia-reperfusion, we assessed the effects of EIR on regional functional recovery, safety, and possible mechanisms of benefit. METHODS: An ECM biomaterial (CorMatrix ECM) was applied to the epicardium after 75 minutes of coronary ischemia in a porcine model. Following ischemia-reperfusion injury, animals were randomly assigned in 2:1 fashion to EIR (n = 8) or sham treatment (n = 4). Serial cardiac magnetic resonance imaging was performed on normal (n = 4) and study animals at baseline (1 week) and 6 weeks after treatment. Myocardial function and tissue characteristics were assessed. RESULTS: Functional myocardial recovery was significantly increased by EIR compared with sham treatment (change in regional myocardial contraction at 6 weeks, 28.6 ± 14.0% vs 4.2 ± 13.5% wall thickening, p < 0.05). Animals receiving EIR had reduced adhesions compared with animals receiving sham treatment (1.44 ± 0.51 vs 3.08 ± 0.89, p < 0.05). Myocardial fibrosis was not increased, and EIR did not cause myocardial constriction, as left ventricular compliance by passive pressure distention at matched volumes was similar between groups (13.9 ± 4.0 mm Hg in EIR group vs 16.0 ± 5.2 mm Hg in sham group, p = 0.61). Animals receiving EIR showed evidence of vasculogenesis in the region of functional recovery. CONCLUSIONS: In addition to the beneficial effects of successful reperfusion, EIR using a bioinductive ECM enhances myocardial repair and functional recovery. Clinical translation of EIR early after myocardial infarction as an adjunct to surgical revascularization may be warranted in the future.

Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-ß1.

Following myocardial infarction (MI), cardiac myofibroblasts remodel the extracellular matrix (ECM), preventing mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis, and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity; however, the mechanisms are unclear. We assessed the influence of peripheral blood monocytes on human cardiac myofibroblast activity in a three-dimensional (3D) ECM microenvironment. Human cardiac myofibroblasts isolated from surgical biopsies of the right atrium and left ventricle were seeded into 3D collagen matrices. Peripheral blood monocytes were isolated from healthy human donors and cocultured with myofibroblasts. Monocytes increased myofibroblast activity measured by collagen gel contraction (baseline: 57.6 ± 5.9% vs. coculture: 65.2 ± 7.1% contraction; P < 0.01) and increased local ECM remodeling quantified by confocal microscopy. Under coculture conditions that allow indirect cellular interaction via paracrine factors but prevent direct cell-cell contact, monocytes had minimal effects on myofibroblast activity (17.9 ± 11.1% vs. 6.4 ± 7.0% increase, respectively; P < 0.01). When cells were cultured under direct contact conditions, multiplex analysis of the coculture media revealed an increase in the paracrine factors TGF-ß1 and matrix metalloproteinase 9 compared with baseline (122.9 ± 10.1 pg/ml and 3,496.0 ± 190.4 pg/ml, respectively, vs. 21.5 ± 16.3 pg/ml and 183.3 ± 43.9 pg/ml; P < 0.001). TGF-ß blockade abolished the monocyte-induced increase in cardiac myofibroblast activity. These data suggest that direct cell-cell interaction between monocytes and cardiac myofibroblasts stimulates TGF-ß-mediated myofibroblast activity and increases remodeling of local matrix. Peripheral blood monocyte interaction with human cardiac myofibroblasts stimulates myofibroblast activity through release of TGF-ß1. These data implicate inflammation as a potential driver of cardiac fibrosis.

Dual antiplatelet therapy use by Canadian cardiac surgeons.

BACKGROUND: Dual antiplatelet therapy is the cornerstone treatment for patients with acute coronary syndrome. Recent Canadian Guidelines recommend the use of dual antiplatelet therapy for 1 year after coronary artery bypass grafting in patients with acute coronary syndrome, but considerable variability remains. METHODS: We performed a survey of 75 Canadian cardiac surgeons to assess the use of dual antiplatelet therapy. RESULTS: Whereas 58.6% of respondents indicated that the benefits of dual antiplatelet therapy were seen irrespective of how patients were managed after acute coronary syndrome, 36.2% believed that the benefits of dual antiplatelet therapy were limited to those treated medically or percutaneously. In regard to the timing of dual antiplatelet therapy administration, 57% of respondents indicated that dual antiplatelet therapy should be given upstream in the emergency department, whereas 36.2% responded that dual antiplatelet therapy should be given only once the coronary anatomy has been defined. The majority surveyed (81%) weighed bleeding risk as being more important than ischemic risk reduction. In stable patients after acute coronary syndrome, the majority of surgeons would wait approximately 4 days after the last dose of P2Y12 antagonist before coronary artery bypass grafting. Only 44.6% indicated that they routinely use dual antiplatelet therapy postrevascularization in the setting of acute coronary syndrome. Rather, most surgeons use dual antiplatelet therapy for select patients, such as those with a stented vessel without a bypass graft, endarterectomy, or off-pump coronary artery bypass grafting. CONCLUSIONS: Cardiac surgeons exhibit variation in their attitudes and practice patterns toward dual antiplatelet therapy after coronary artery bypass grafting, and in approximately half of cases, their practice does not adhere to current guideline recommendations. New trials focusing on coronary artery bypass grafting cases in their primary analysis and educational initiatives for surgeons that focus on guideline recommendations may be warranted.

Valve-Related Hemodynamics Mediate Human Bicuspid Aortopathy: Insights From Wall Shear Stress Mapping.

BACKGROUND: Suspected genetic causes for extracellular matrix (ECM) dysregulation in the ascending aorta in patients with bicuspid aortic valves (BAV) have influenced strategies and thresholds for surgical resection of BAV aortopathy. Using 4-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we have documented increased regional wall shear stress (WSS) in the ascending aorta of BAV patients. OBJECTIVES: This study assessed the relationship between WSS and regional aortic tissue remodeling in BAV patients to determine the influence of regional WSS on the expression of ECM dysregulation. METHODS: BAV patients (n = 20) undergoing ascending aortic resection underwent pre-operative 4D flow CMR to regionally map WSS. Paired aortic wall samples (i.e., within-patient samples obtained from regions of elevated and normal WSS) were collected and compared for medial elastin degeneration by histology and ECM regulation by protein expression. RESULTS: Regions of increased WSS showed greater medial elastin degradation compared to adjacent areas with normal WSS: decreased total elastin (p = 0.01) with thinner fibers (p = 0.00007) that were farther apart (p = 0.001). Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor ß-1 (p = 0.04), matrix metalloproteinase (MMP)-1 (p = 0.03), MMP-2 (p = 0.06), MMP-3 (p = 0.02), and tissue inhibitor of metalloproteinase-1 (p = 0.04) in elevated WSS regions, indicating ECM dysregulation in regions of high WSS. CONCLUSIONS: Regions of increased WSS correspond with ECM dysregulation and elastic fiber degeneration in the ascending aorta of BAV patients, implicating valve-related hemodynamics as a contributing factor in the development of aortopathy. Further study to validate the use of 4D flow CMR as a noninvasive biomarker of disease progression and its ability to individualize resection strategies is warranted.

Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling.

BACKGROUND: Tissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFß1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling. OBJECTIVES: We examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling. METHODS: Human cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFß1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis. RESULTS: TGFß1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFß1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations. CONCLUSIONS: LMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.

Tetrandrine reverses human cardiac myofibroblast activation and myocardial fibrosis.

Tetrandrine (TTD) is a calcium channel blocker with documented antifibrotic actions. In this study, for the first time, we identified that TTD can directly prevent in vitro human cardiac myofibroblast activation and limit in vivo myocardial fibrosis. In vitro, cardiac myofibroblasts from human atrial biopsies (N = 10) were seeded in three-dimensional collagen matrices. Cell-collagen constructs were exposed to transforming growth factor-ß1 (10 ng/ml), with or without TTD (1 and 5 µM) for 48 h. Collagen gel contraction, myofibroblast activation (α-smooth muscle actin expression), expression of profibrotic mRNAs, and rate of collagen protein synthesis were compared. TTD decreased collagen gel contraction (79.7 ± 1.3 vs 60.1 ± 8.9%, P < 0.01), α-smooth muscle actin expression (flow cytometry), collagen synthesis ([(3)H]proline incorporation), and collagen mRNA expression. Cell viability was similar between groups (annexin positive cells: 1.7 vs. 1.4%). TTD inhibited collagen gel contraction in the presence of T-type and L-type calcium channel blockers, and the intracellular calcium chelator BAPTA-AM (15 µM), suggesting that the observed effects are not mediated by calcium homeostasis. In vivo, Dahl salt-sensitive hypertensive rats were treated with variable doses of TTD (by intraperitoneal injection over 4 wk) and compared with untreated controls (N = 12). Systemic blood pressure was monitored by tail cuff. Myocardial fibrosis and left ventricular compliance were assessed by histology and passive pressure-volume analysis. Myocardial fibrosis was attenuated compared with untreated controls (%collagen area: 9.4 ± 7.3 vs 2.1 ± 1.0%, P < 0.01). Left ventricular compliance was preserved. In conclusion, TTD reverses human cardiac myofibroblast activation and myocardial fibrosis, independent of calcium channel blockade.

Human cardiac fibroblast extracellular matrix remodeling: dual effects of tissue inhibitor of metalloproteinase-2.

OBJECTIVE: Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinases (MMPs) that attenuates maladaptive cardiac remodeling in ischemic heart failure. We examined the effects of TIMP-2 on human cardiac fibroblast activation and extracellular matrix (ECM) remodeling. METHODS: Human cardiac fibroblasts within a three-dimensional collagen matrix were assessed for phenotype conversion, ECM architecture and key molecular regulators of ECM remodeling after differential exposure to TIMP-2 and Ala+TIMP-2 (a modified TIMP-2 analogue devoid of MMP inhibitory activity). RESULTS: TIMP-2 induced opposite effects on human cardiac fibroblast activation and ECM remodeling depending on concentration. TIMP-2 activated fibroblasts into contractile myofibroblasts that remodeled ECM. At higher concentrations (>10 nM), TIMP-2 inhibited fibroblast activation and prevented ECM remodeling. As compared to profibrotic cytokine transforming growth factor (TGF)-beta1, TIMP-2 activated fibroblasts and remodeled ECM without a net accumulation of matrix elements. TIMP-2 increased total protease activity as compared to TGF-beta1. Ala+TIMP-2 exposure revealed that the actions of TIMP-2 on cardiac fibroblast activation are independent of its effects on MMP inhibition. In the presence of GM6001, a broad-spectrum MMP inhibitor, TIMP-2-mediated ECM contraction was completely abolished, indicating that TIMP-2-mediated fibroblast activation is MMP dependent. CONCLUSION: TIMP-2 functions in a contextual fashion such that the effect on cardiac fibroblasts depends on the tissue microenvironment. These observations highlight potential clinical challenges in using TIMP-2 as a therapeutic strategy to attenuate postinjury cardiac remodeling.

Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling.

OBJECTIVES: Dysregulation of extracellular matrix (ECM) following myocardial infarction is a key contributor to myocardial fibrosis, chamber dilation, and progression to heart failure. Basic fibroblast growth factor is a potent inhibitor of fibrosis. We propose a novel surgical procedure leveraging a commercially available ECM biomaterial for the treatment of ischemic heart failure. METHODS: Epicardial infarct repair using CorMatrix-ECM biomaterial patch (CorMatrix Cardiovascular Inc, Roswell, Ga) was compared with sham in a rat myocardial infarction model. Key indices of ischemic remodeling, including inflammation, fibrosis, and myocardial performance were evaluated 16 weeks post-treatment. RESULTS: Histology and immunohistochemistry demonstrated comprehensive integration of CorMatrix-ECM biomaterial patch without evidence of immune reaction and an increase in basic fibroblast growth factor expression in treated animals. Functional analysis by serial echocardiography of normal (n = 13), sham (n = 15), nonenhanced CorMatrix-ECM patch (n = 18), and basic fibroblast growth factor-enhanced CorMatrix-ECM patch (n = 10) animals revealed an improvement in ejection fraction in basic fibroblast growth factor-enhanced CorMatrix-ECM patch animals compared with shams (55.3% ± 8.0% vs 35.1% ± 7.6%; P < .001). Prevention of left ventricle remodeling was also confirmed by pressure volume loop analysis, which demonstrated reduced left ventricular end diastolic volumes in basic fibroblast growth factor-enhanced CorMatrix-ECM patch animals (n = 5) compared with shams (n = 6) (208.0 ± 59.3 µL vs 363. 1 ± 108.7 µL; P < .01) and improved left ventricle contractility in nonenhanced CorMatrix-ECM patch (n = 7) and basic fibroblast growth factor-enhanced CorMatrix-ECM patch animals compared with shams (0.709 ± 0.306 and 0.609 ± 0.160 vs 0.437 ± 0.218; P < .05). CONCLUSIONS: Epicardial infarct repair with basic growth factor-enhanced CorMatrix-ECM biomaterial patch attenuates myocardial remodeling and improves cardiac performance after subacute myocardial infarction in a rat coronary ligation model. These observations establish proof-of-concept for this novel surgical approach.