Acellular human amniotic fluid protects the ischemic-reperfused rat myocardium.

Amniotic products are potent immunomodulators used clinically to repair tissue injury. Little information exists regarding the potential of cell-free human amniotic fluid (hAF) to treat cardiovascular disease. Herein, we sought to determine the influence and efficacy of acellular hAF on myocardial ischemia-reperfusion injury. Processed hAF was obtained from volunteer donors at the time of elective caesarean section and manufactured using proprietary methods. Left anterior descending coronary artery ligation was performed on rats for 60 min. Thirty minutes after release and reperfusion, either saline or hAF was injected intramyocardially. Serial echocardiography revealed that compared with saline-injected rats, hAF animals maintained their ejection fraction and did not adversely remodel through the 4-wk period. This preserved ventricular function correlated with decreased infarct size, less fibrosis, and reduced expression of cytokines and infiltrating inflammatory cells. Comparative arrays of different donor hAF lots confirmed the presence of a wide array of immunomodulatory and host-defense proteins. The observed functional cardioprotection was furthermore evident when given intravenously and across multiple hAF donors. In conclusion, our data demonstrate, for the first time, the cardioprotective effect of acellular hAF on myocardial injury. These observations spanned across diverse donors and likely result from the mixture of a plethora of naturally produced cytokines, chemokines, and immune-modulating proteins rather than a single, defined mechanistic culprit. The ubiquitous availability of hAF as a cell-free solution further suggests its potential for widespread adoption as a therapy for myocardial ischemia-reperfusion injury.NEW & NOTEWORTHY Rather than targeting a single pathway implicated in myocardial reperfusion injury, cell-free human amniotic fluid-a naturally derived cocktail composed of thousands of proteins involved with innate immunity and anti-inflammation-markedly reduces injury and preserves cardiac function in a model of rodent myocardial ischemia-reperfusion. With its ubiquitous availability as well as its anti-inflammatory and nonimmunogenic properties, human cell-free amniotic fluid offers potential for use as a cardioprotective adjunct.

Interleukin-1 Receptor Antagonism Abrogates Acute Pressure Overload-Induced Murine Heart Failure.

BACKGROUND: Recent clinical trials have suggested that blockade of interleukin-1 (IL-1) can have a favorable impact on patients with myocardial infarction and heart failure. However, the mechanism of antagonism of this specific cytokine in mediating cardiac disease remains unclear. Hence, we sought to determine the influence of IL-1 blockade on acute hypertensive remodeling. METHODS: Transverse aortic constriction was performed in C57BL mice with or without intraperitoneal administration of interleukin 1 receptor antagonism (IL-1Ra). Function, structure, and molecular diagnostics were subsequently performed and analyzed. RESULTS: Six weeks after transverse aortic constriction, a progressive decline of ejection fraction and increases in left ventricle mass and dimensions were effectively mitigated with IL-1Ra. Transverse aortic constriction resulted in an expected profile of hypertrophic markers including myosin heavy chain, atrial natriuretic peptide, and skeletal muscle actin, which were all significantly lower in IL-1Ra treated mice. Although trichrome staining 2 weeks after transverse aortic constriction demonstrated similar levels of fibrosis, IL-1ra-reduced expression of collagen-1, tissue inhibitor of metallopeptidase 1, and periostin. Investigating the angiogenic response to pressure overload, similar levels of vascular endothelial growth factor were observed, but IL-1Ra was associated with more stromal cell-derived factor-1. Immune cell infiltration (macrophages and lymphocytes) was also decreased in IL-1Ra treated mice. Similarly, cytokine concentrations of IL-1, IL-18, and IL-6 were all reduced in IL-1Ra-treated animals. CONCLUSIONS: Interleukin-1Ra prevents the progression toward heart failure associated with acute pressure overload. This functional response was associated with reductions in mediators of fibrosis, cellular infiltration, and cytokine production. These results provide mechanistic insight into recent clinical trials and could springboard future investigations in patients with pressure-overload-based cardiomyopathies.

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

Background Recent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD-mediated cardiac improvement to guide patient selection, treatment, and monitoring. Methods and Results Ninety-three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)-4, IL-5, IL-6, IL-7, IL-13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription-3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01-0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00-0.43), independently predict cardiac improvement, creating a 2-cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001). Conclusions Baseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2-cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD-mediated cardiac improvement and device weaning.

Longitudinal assessment of the platelet transcriptome in advanced heart failure patients following mechanical unloading.

Patients with heart failure (HF) and left ventricular assist devices (LVAD) have dysregulated thrombo-inflammatory responses, mediated in part by platelets. While studies of platelet activation have been undertaken in HF, changes in the platelet transcriptome in HF patients following mechanical unloading with an LVAD have not been investigated. We prospectively enrolled and longitudinally followed advanced HF patients (n = 32) for a mean of 57 months post-LVAD implantation. For comparison, healthy donors were also enrolled (n = 20). Platelets were hyperactive in HF, as evidenced by significantly increased formation of circulating platelet-monocyte aggregate formation. Platelet transcriptome interrogation by next-generation RNA-sequencing identified that the expression of numerous genes (n = 588) was significantly (FDR < 0.05) altered in HF patients prior to LVAD implantation. Differentially expressed genes were predicted to have roles in angiogenesis, immune and inflammatory responses, apoptosis, and cardiac muscle contraction. 90 days following LVAD implantation, the majority (80%) of differentially expressed genes in HF patients normalized, as compared to the platelet transcriptomes of healthy donors. In conclusion, advanced HF is associated with marked alterations in the platelet transcriptome. While LVAD implantation to off load the failing heart results in resolution in the majority of differentially expressed genes, a subset of the platelet transcriptome remains persistently altered.

Surgical explantation of atrial septal closure devices for refractory nickel allergy symptoms.

OBJECTIVES: Systemic allergic reactions to nickel alloys in percutaneous atrial septal defect occlusion devices have a poorly defined natural history. We describe our experience of surgical removal of the offending device in a series of patients with nickel allergy and refractory symptoms. METHODS: Patients with atrial septal defect device explants for nickel allergy were reviewed. Administered questionnaires focused on symptoms, quality of life, and satisfaction along with the 36-Item Short Form Health Survey to measure physical and mental health postsurgery. RESULTS: Atrial septal defect devices were removed for nickel allergy in 58 patients during the past 10 years. The median age was 42 years (range, 24-71 years) and 95% were women. Explantation occurred at a median of 8 years (range, 6 months-18 years) after insertion. Symptoms included fatigue (82%), chest pain (78%), headache (73%), and palpitation (58%). Surveys were available for 45 patients: 58% rated their quality of life as poor and 69% were not at all satisfied with their device. Postexplant, all patients reported improvement in their symptoms, with 18 patients (42%) noting complete resolution. In 12 patients prospectively studied, the preoperative scores in physical and mental health domains were lower than the validation group, indicating significant disability. Similarly, there was marked improvement in each domain postremoval. CONCLUSIONS: Patients with nickel allergy and severe refractory symptoms after atrial septal defect device implantation experience profound resolution of symptoms and improved quality of life after removal. Nickel allergy should be considered before device insertion, and a low threshold should exist for surgical removal for refractory symptoms.

Cardiomyocyte p65 nuclear factor-κB is necessary for compensatory adaptation to pressure overload.

BACKGROUND: Nuclear factor κB (NF-κB) is often implicated in contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. We have previously demonstrated that pharmacological inhibition of NF-κB at the time of acute pressure overload accelerates the progression of left ventricular hypertrophy to heart failure in mice. NF-κB regulates angiogenesis and other factors responsible for compensatory reaction to intracellular hypoxia. We hypothesized that impaired angiogenesis may be the trigger, not the result, of pathological left ventricular hypertrophy through NF-κB-related pathways. METHODS AND RESULTS: Transgenic mice were generated with cardiomyocyte-specific deletion of the p65 subunit of NF-κB. Mice underwent transverse aortic constriction and serially followed up with echocardiography for 6 weeks. Cardiomyocyte p65 NF-κB deletion promoted maladaptive left ventricular hypertrophy and accelerated progression toward heart failure as measured by ejection fraction, left ventricular mass, and lung congestion. Transgenic mice had higher levels of fibrosis and periostin expression. Whole-field digital microscopy revealed increased capillary domain areas in knockout mice while concurrently demonstrating decreased microvessel density. This observation was associated with decreased expression of hypoxia-inducible factor 1α. CONCLUSIONS: Rather than developing compensatory left ventricular hypertrophy, pressure overload in cardiomyocyte NF-κB-deficient mice resulted in functional deterioration that was associated with increased fibrosis, decreased hypoxia-inducible factor expression, and decreased microvessel density. These observations mechanistically implicate NF-κB, and its regulation of hypoxic stress, as an important factor determining the path between adaptive hypertrophy and maladaptive heart failure.

Animal model of reversible, right ventricular failure.

BACKGROUND: Heart failure is a leading cause of death but very little is known about right ventricular (RV) failure (RVF) and right ventricular recovery (RVR). A robust animal model of reversible, RVF does not exist, which currently limits research opportunities and clinical progress. We sought to develop an animal model of reversible, pressure-overload RVF to study RVF and RVR. MATERIALS AND METHODS: Fifteen New Zealand rabbits underwent implantation of a fully implantable, adjustable, pulmonary artery band. Animals were assigned to the control, RVF, and RVR groups (n = 5 for each). For the RVF and RVR groups, the pulmonary artery bands were serially tightened to create RVF and released for RVR. Echocardiographic, cardiac magnetic resonance imaging, and histologic analysis were performed. RESULTS: RV chamber size and wall thickness increased during RVF and regressed during RVR. RV volumes were 1023 µL ± 123 for control, 2381 µL ± 637 for RVF, and 635 µL ± 549 for RVR, and RV wall thicknesses were 0.98 mm ± 0.12 for controls (P = 0.05), 1.72 mm ± 0.60 for RVF, and 1.16 mm ± 0.03 for RVR animals (P = 0.04), respectively. Similarly, heart weight, liver weight, cardiomyocyte size, and the degree of cardiac and hepatic fibrosis increased with RVF and decreased during RVR. CONCLUSIONS: We report an animal model of chronic, reversible, pressure-overload RVF to study RVF and RVR. This model will be used for preclinical studies that improve our understanding of the mechanisms of RVF and that develop and test RV protective and RVR strategies to be studied later in humans.

A modified murine model for the study of reverse cardiac remodelling.

BACKGROUND: The authors previously reported a murine model of left ventricular hypertrophy (LVH) and regression using a suture technique of transverse aortic arch constriction and subsequent removal. A number of issues have limited the widespread adoption of this method. The present study assessed a modification of this model using a titanium clip. METHODS: Male C57BL/6 mice (n=95) underwent minimally invasive aortic banding for three, four or six weeks with or without subsequent band removal for one week. Hearts were evaluated both structurally and functionally using heart weight/body weight ratios, transthoracic echocardiography and direct left ventricular pressure measured using catheterization. RESULTS: Clip banding resulted in a threefold gradient across the transverse aortic arch. Pressure overload induced concentric LVH by three weeks that progressively decompensated. By six weeks, hearts were significantly dilated, with poor left ventricular function. Clips were removed in a minimally invasive procedure after each time point. When overloaded for either three or four weeks, removal of the clip with subsequent pressure relief enabled regression of LVH and restoration of function. When removed after six weeks of banding, mouse hearts were unable to reverse remodel and maintained elevated left ventricular end-diastolic pressures and lung congestion. CONCLUSIONS: The application and removal of a titanium clip successfully induced pressure overload and relief associated with the serial development and reversal of LVH. Compared with similar models using suture ligation and release, this method was found to be a simple, effective (no slipped bands) and reproducible method to study murine LVH, heart failure and its regression.

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling.

NF-κB is a well-known transcription factor that is intimately involved with inflammation and immunity. We have previously shown that NF-κB promotes inflammatory events and mediates adverse cardiac remodeling following ischemia reperfusion (I/R). Conversely, others have pointed to the beneficial influence of NF-κB in I/R injury related to its anti-apoptotic effects. Understanding the seemingly disparate influence of manipulating NF-κB is hindered, in part, by current approaches that only indirectly interfere with the function of its most transcriptionally active unit, p65 NF-κB. Mice were generated with cardiomyocyte-specific deletion of p65 NF-κB. Phenotypically, these mice and their hearts appeared normal. Basal and stimulated p65 expression were significantly reduced in whole hearts and completely ablated in isolated cardiomyocytes. When compared with wild-type mice, transgenic animals were protected from both global I/R by Langendorff as well as regional I/R by coronary ligation and release. The protected, transgenic hearts had less cytokine activity and decreased apoptosis. Furthermore, p65 ablation was associated with enhanced calcium reuptake by the sarcoplasmic reticulum. This influence on calcium handling was related to increased expression of phosphorylated phospholamban in conditional p65 null mice. In conclusion, cardiomyocyte-specific deletion of the most active, canonical NF-κB subunit affords cardioprotection to both global and regional I/R injury. The beneficial effects of NF-κB inhibition are related, in part, to modulation of intracellular calcium homeostasis.

Inhibitory kappa-B kinase-ß inhibition prevents adaptive left ventricular hypertrophy.

BACKGROUND: Most cardiovascular studies have implicated the central transcription factor nuclear factor kappa-B (NF-κB) as contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. Pressure overload, left ventricular hypertrophy (LVH), and heart failure represent a spectrum of disease that has both adaptive and maladaptive components. In contrast to its known effects related to myocardial ischemia-reperfusion, we hypothesized that NF-κB is necessary for the compensatory phase of cardiac remodeling. METHODS: C57BL6 mice underwent minimally invasive transverse aortic constriction with or without inhibition of the proximal NF-κB kinase, inhibitory kappa-B kinase-ß. Isolated cardiomyocytes were cultured. Transthoracic echocardiography was performed on all mice. RESULTS: Inhibitory kappa-B kinase-ß inhibition successfully decreased cardiomyocyte expression of phosphorylated p65 NF-κB and decreased expression of hypertrophic markers with stimulation in vitro. Three weeks after transverse aortic constriction, the mice treated with inhibitory kappa-B kinase-ß inhibition more aggressively developed LVH, as measured by heart weight/body weight ratio, left ventricular mass, and wall thickness. These mice also demonstrated a functional decline, as measured by decreased fractional shortening and ejection fraction. These findings were associated with decreased protein expression of p65 NF-κB. CONCLUSIONS: Although short-term pressure-overload results in compensatory LVH with normal cardiac function, NF-κB inhibition resulted in increased LVH that was associated with functional deterioration. These observations suggest that NF-κB is an important part of the adaptive phase of LVH, and its inhibition detrimentally affects cardiac remodeling.

Lipomatosis of interventricular septum and both ventricles: an extremely rare pattern.

Fatty masses of the heart are relatively uncommon. This report is about an extremely rare case of cardiac lipomatosis that implicates both ventricles and inter-atrial septum. The patient was a 27-year-old female who was accidentally diagnosed during a routine physical examination. Trans-thoracic echocardiography (TTE) discovered a large homogenous bi-lobed, non-encapsulated echogenic mass. Magnetic resonance imaging (MRI) showed soft tissue abnormal enhancement in the anterior left base of the heart and sub-aortic outflow tract. A trans-jugular echomyocardial biopsy was done because of a lack of a definite diagnosis by non-invasive techniques. Pathological study showed benign fatty infiltration suggestive for benign lipomatous hypertrophy.

Can intracoronary stem cell injection permanently improve cardiac function after myocardial infarction?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Can intracoronary stem cell injection permanently improve cardiac function after myocardial infarction?'. Altogether 314 papers were found using the reported search, of which five represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that stem cells may have controversial effects on cardiac function in long-term follow-up of more than two years as they improved the left ventricular ejection fraction and end systolic volume index just in two studies in which none of them utilized cardiac magnetic resonance imaging (MRI), as the most reliable method, to quantify cardiac function. However, all remaining three trials which reported negative results used cardiac MRI for assessment of cardiac indexes which may be more precise and accurate than echocardiographic assessments. So the reliability of the positive trials is lower than negative resulted trials in terms of cardiac function assessment method. Stem cell therapy almost always offered short-term benefits over the best medical treatment, but the long-term benefits are still a matter of debate.

Combined medical and surgical treatment of intracardiac hydatid cysts in 11 patients.

OBJECTIVES: Echinococcosis is a human parasitic disease common in sheep-rearing regions, which is caused by the larval stage of Echinococcus granolosus and can involve any heart region. We report 11 cases of cardiac hydatidosis who were treated medically and surgically. PATIENTS AND METHODS: Eleven patients diagnosed with cardiac echinococcosis were referred to the Cardiac Surgery Department of Shahid Madani Hospital from 1992 to 2004. Symptoms included dyspnea, palpitation, limb ischemia, fever, weight loss, hemiplegia, and loss of consciousness. Patients underwent surgical removal of the cyst followed by medical treatment until the titer of echinococcus hemaglutination test came to normal. RESULTS: Hospital stay and recovery time were uneventful in nine patients. One patient died due to acute renal failure before hospital discharge (9%) and another patient experienced cerebral hydatidosis 12 months after surgery (probably due to cyst embolism). The other nine patients had no complications during five years of follow-up. CONCLUSION: Surgical excision using cardiopulmonary bypass combined with medical therapy provides the most optimal treatment for cardiac echinococcosis.

Repair of aorto-left ventricular tunnel arising from the left sinus of valsalva.

Aortico-left ventricular tunnel (ALVT) is a rare congenital cardiac defect that bypasses the aortic valve via a para-valvular connection from the left ventricle to the aorta. In most cases, the tunnel arises from the right aortic sinus. In this case report, we are presenting a case of ALVT, of which the aortic orifice arose from the left aortic sinus, requiring special attention to avoid the left coronary artery injury at the time of surgical repair.

A large saphenous vein graft aneurysm one year after coronary artery bypass graft surgery presenting as a left lung mass.

Aneurysm of a saphenous vein graft (SVG) is a rare but fatal complication of coronary artery bypass graft (CABG) surgery. The development of SVG aneurysms appears usually about 10-20 years after the operation at an estimated rate of <1%. A 68-year-old male was referred to the emergency department after frequent episodes of dyspnea, chest pain and hemoptysis. He previously had CABG surgery one year before. The physical examination was normal. Chest radiogram showed a left pulmonary midzone mass. CT-angiogram demonstrated a large aortic pseudoaneurysm (6.36 x 6.06 cm) in the middle part of the ascending aorta. After sternotomy, the ascending aorta above sinotubular junction near the origin of brachiocephalic artery was resected and replaced with a tube graft. The patient was transferred to ICU with stable hemodynamic status. SVG aneurysm should be considered while encountering mediastinal mass or undiagnosed cardiopulmonary symptoms in patients with a previous history of CABG because of its rarity and overlap of symptoms with other thoracic, pulmonary, and cardiac diseases. Surgery seems to be the treatment of choice to reduce the risk of rupture and embolism.