Panagiota Christia

The pathogenesis of cardiac fibrosis

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

Targeting inflammatory pathways in myocardial infarction

Acute cardiomyocyte necrosis in the infarcted heart generates damage‐associated molecular patterns (DAMPs), activating complement and Toll‐Like Receptor (TLR)/Interleukin (IL)‐1 signalling and triggering an intense inflammatory reaction. Infiltrating leucocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels, the geometric, functional and molecular alterations associated with postinfarction remodelling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the postinfarction inflammatory reaction may be crucial to protect the myocardium from dilative remodelling and progressive dysfunction. Inhibition and resolution of postinfarction inflammation involve mobilization of inhibitory mononuclear cell subsets and require activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the postinfarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti‐integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischaemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodelling. Given the pathophysiologic complexity of postinfarction remodelling, personalized biomarker‐based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro‐inflammatory signals (such as IL‐1 and monocyte chemoattractant protein‐1) may be effective in patients with defective resolution of postinfarction inflammation who exhibit progressive dilative remodelling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti‐TGF strategies.

Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis

Understanding the role of fibroblasts in pathologic conditions is hampered by the absence of specific markers. Fibroblast-specific protein (FSP)1 has been suggested as a fibroblast-specific marker in normal and fibrotic tissues; FSP1 reporter mice and FSP1-Cre-driven gene deletion are considered reliable strategies to investigate fibroblast biology. Because fibroblasts are abundant in normal and injured mammalian hearts, we studied the identity of FSP1(+) cells in the infarcted and remodeling myocardium using mice with green fluorescent protein (GFP) expression driven by the FSP1 promoter. Neonatal and adult mouse hearts had low numbers of FSP1(+) cells. Myocardial infarction induced marked infiltration with FSP1-expressing cells that peaked after 72 h of reperfusion. Using flow cytometry, we identified 50% of FSP1(+) cells as hematopoietic cells; many endothelial cells were also FSP1(+). Increased infiltration with FSP1(+) cells was also noted in the pressure-overloaded myocardium. Although some FSP1(+) cells had fibroblast morphology, >30% were identified as hematopoietic cells, endothelial cells, or vascular smooth muscle cells. In contrast, periostin did not stain leukocytes or vascular cells but labeled spindle-shaped interstitial cells and, as a typical matricellular protein, was deposited in the matrix. CD11b(+) myeloid cells sorted from the infarcted heart had higher FSP1 expression than corresponding CD11b-negative cells, highlighting the predominant expression by hematopoietic cells. FSP1 is not a specific marker for fibroblasts in cardiac remodeling and fibrosis.

Systematic characterization of myocardial inflammation, repair, and remodeling in a mouse model of reperfused myocardial infarction.

Mouse models of myocardial infarction are essential tools for the study of cardiac injury, repair, and remodeling. Our current investigation establishes a systematic approach for quantitative evaluation of the inflammatory and reparative response, cardiac function, and geometry in a mouse model of reperfused myocardial infarction. Reperfused mouse infarcts exhibited marked induction of inflammatory cytokines that peaked after 6 hr of reperfusion. In the infarcted heart, scar contraction and chamber dilation continued for at least 28 days after reperfusion; infarct maturation was associated with marked thinning of the scar, accompanied by volume loss and rapid clearance of cellular elements. Echocardiographic measurements of end-diastolic dimensions correlated well with morphometric assessment of dilative remodeling in perfusion-fixed hearts. Hemodynamic monitoring was used to quantitatively assess systolic and diastolic function; the severity of diastolic dysfunction following myocardial infarction correlated with cardiomyocyte hypertrophy and infarct collagen content. Expression of molecular mediators of inflammation and cellular infiltration needs to be investigated during the first 72 hr, whereas assessment of dilative remodeling requires measurement of geometric parameters for at least four weeks after the acute event. Rapid initiation and resolution of the inflammatory response, accelerated scar maturation, and extensive infarct volume loss are important characteristics of infarct healing in mice.

Patent foramen ovale: Unanswered questions.

The foramen ovale is a remnant of the fetal circulation that remains patent in 20-25% of the adult population. Although long overlooked as a potential pathway that could produce pathologic conditions, the presence of a patent foramen ovale (PFO) has been associated with a higher than expected frequency in a variety of clinical syndromes including cryptogenic stroke, migraines, sleep apnea, platypnea-orthodeoxia, deep sea diving associated decompression illness, and high altitude pulmonary edema. A unifying hypothesis is that a chemical or particulate matter from the venous circulation crosses the PFO conduit between the right and left atria to produce a variety of clinical syndromes. Although observational studies suggest a therapeutic benefit of PFO closure compared to medical therapy alone in patients with cryptogenic stroke, 3 randomized controlled trials (RCTs) did not confirm the superiority of PFO closure for the secondary prevention of stroke. However, meta-analyses of these RCTs demonstrate a significant benefit of PFO closure over medical therapy alone. Similarly, observational studies provide support for PFO closure for symptomatic relief of migraines. But one controversial randomized study failed to replicate the results of the observational studies while another two demonstrated a partial benefit. The goal of this review is to discuss the clinical conditions associated with PFO and provide internists and primary care physicians with current data on PFO trials, and clinical insight to help guide their patients who are found to have a PFO on echocardiographic testing.

Thrombocytopaenia as a Prognostic Indicator in Heart Failure with Reduced Ejection Fraction.

BACKGROUND Studies suggest that thrombocytopaenia is associated with a higher mortality in several diseases. Little is known about the effect of low platelet count on mortality in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to determine the prognostic value of thrombocytopaenia in these patients by assessing all-cause mortality. METHODS A total of 1,907 patients with HFrEF, defined by left ventricular ejection fraction <40% on echocardiography, were analysed in this multi-centre retrospective study. All patients were on medical therapy with a beta-blocker and an angiotensin-converting enzyme inhibitor. Patients were categorised into two groups based on platelet count measured within one month of the diagnosis of HFrEF: normal to mild thrombocytopaenia (platelet count 100,000-450,000 per uL); and moderate to severe thrombocytopaenia (platelet count <100,000 per uL). One-year all-cause mortality was compared between the two groups. RESULTS Mean age was 65±15 years and 62% of patients were male. Overall one-year mortality was 17.2% with higher mortality among patients with HFrEF and moderate/severe thrombocytopaenia compared to those with normal/mild thrombocytopaenia (33.0% vs. 15.4%, p <0.001). After adjusting for baseline characteristics, patients with HFrEF and moderate/severe thrombocytopaenia had a higher mortality compared to patients with normal/mild thrombocytopaenia (HR 1.84, 95% CI 1.33-2.56, p <0.001). CONCLUSION In patients with HFrEF, higher degree of thrombocytopaenia is associated with higher all-cause mortality. These findings may support the use of platelet counts as a prognostic marker in the assessment of the patient with HFrEF.

Atrial Fibrillation Identified During Echocardiography in a Patient with Recurrent Cardioembolic Events: A Case Report.

Patient: Female, 80 Final Diagnosis: Stroke Symptoms: Weakness • left sided Medication: — Clinical Procedure: Echocardiogram Specialty: Naurology Objective: Unusual clinical course Background: Stroke is the major cause of disability and the fifth leading cause of death in the United States. In 30–40% of strokes the etiology remains uncertain or unknown. Identifying the cause of a cerebrovascular event offers the opportunity for an intervention that may decrease the risk of future stroke and thus prevent the resultant impairment. Case Report: We report the case of an 80-year-old African American woman with a prior right middle cerebral artery stroke, who presented to the hospital with new left-sided weakness and was found to have a new right-sided frontal lobe infarct. Twenty-four hour Holter monitoring performed during this hospitalization and prior 24-h electrocardiogram (ECG) recording did not reveal an arrhythmia. However, the patient was found to have an isolated episode of atrial fibrillation (AF) during an echocardiogram as part of the evaluation for stroke etiology. Conclusions: AF is an important and treatable cause of recurrent stroke and needs to be ruled out by thorough evaluation before the diagnosis of cryptogenic stroke is assigned. Despite meticulous diagnostic work-up, many strokes caused by paroxysmal AF remain undetected and longer ECG monitoring (>24 h) may be required.

Assessment of Implantable Cardioverter-Defibrillator Used in Heart Failure with Reduced Ejection Fraction as Primary Prevention in an Underserved Population

Implantable cardioverter-defibrillator (ICD) implantation has been one of the milestones in the treatment of heart failure providing a significant survival benefit. Current guidelines recommend that patients who have a sustained low left ventricular ejection fraction (LVEF) of 35% or less should be evaluated for ICD for primary prophylaxis (P-ICD). Our study aimed to investigate the use of P-ICD and associated outcomes in Jacobi Medical Center, a municipal New York City public teaching hospital serving an inner-city patient population located in Bronx, NY.

Transient Giant R Wave as a Marker for Ischemia in Unstable Angina

Unstable angina is a clinical diagnosis that may present with or without electrocardiographic changes. The “giant R wave” on electrocardiogram has been reported as a manifestation of acute ischemia; however, it is a rare finding in current clinical practice. We describe a case of a patient with unstable angina and a transient “giant R wave” pattern with a culprit lesion in the right coronary artery.

Recurrent Stress Cardiomyopathy During COPD Exacerbation: Are Beta-adrenergic Agonists Only to Blame?

Takotsubo cardiomyopathy (TCM) is a variant of stress-induced cardiomyopathy, characterized by transient left ventricular dysfunction that may be associated with emotional or physical triggers. We present the case of a 51-year-old Caucasian female with severe chronic obstructive pulmonary disease (COPD) who presented with syncope and was found to have her second lifetime episode of stress-induced cardiomyopathy. Eight months prior, she had been admitted with a COPD exacerbation and was found to have left ventricular (LV) dysfunction with ejection fraction (EF) of 22% attributed to TCM with subsequent normalization of her left ventricular function. Recurrence of stress-induced cardiomyopathy associated with COPD is a rare phenomenon and its presentation raises the possibility of a common underlying mechanism.