Inflammatory cardiomyopathy is defined as myocarditis in association with cardiac dysfunction and ventricular remodelling 1,2. Despite extensive research and improved diagnosis and understanding of the pathogenesis of inflammatory cardiomyopathy, this disorder is still associated with a poor prognosis when complicated by left ventricular (LV) dysfunction, heart failure (HF) or arrhythmia 3. Furthermore, fulminant myocarditis, a rare, sudden and severe cardiac inflammation, is one of the main causes of cardiogenic shock in young adults 4,5. Prompt diagnosis and specific treatment strategies are needed to reduce mortality and the need for heart transplantation in these patients 4,5. Many questions remain unanswered regarding the pathogenesis of inflammatory cardiomyopathy and the role of the viral infection, the immune system, the host genetic background and the environment in disease progression and prognosis. These gaps in knowledge highlight the need for advanced experimental systems that can better model the human immune system and the need to improve the characterization and classification of the patients, for example, with the use of phenomapping and phenomics, which involve detailed evaluation of immune status, viral presence and/or other biomarkers. In this Review, we discuss the available evidence and identify the gaps in our understanding of the pathogenesis, diagnosis, treatment and prognosis of myocarditis and inflammatory cardiomyopathy, appraise the available animal and cell models of these conditions and propose future directions for the field. We discuss the role

Background-Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. Methods and Results-Patients with HFNEF (nϭ70) and patients without heart failure symptoms (nϭ20) were enrolled.Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with decreased stroke volume and a leftward shift of pressure-volume loops during atrial pacing. Conclusions-Increased left ventricular stiffness contributed to increased end-diastolic pressure during handgrip exercise and decreased stroke volume during atrial pacing in patients with HFNEF. These data suggest that left ventricular stiffness modulates cardiac function in HFNEF patients and suggests that diastolic dysfunction with increased stiffness is a target for treating HFNEF.

Rationale: Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated. Objective: To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI). Key Words: myocardial infarction Ⅲ angiogenesis Ⅲ gene therapy Ⅲ apoptosis M yocardial infarction (MI) remains a major cause of morbidity and mortality and it is responsible for about one third of heart failure cases worldwide. 1 Sudden occlusion of a major coronary artery and acute myocardial ischemia causes rapid death of cardiomyocytes and vascular cells in the area of interest. 2 Loss of cardiomyocytes and vasculature leads to progressive fibrous replacement of myocardium, hypertrophic growth of the spared myocardium, and left ventricular (LV) dilatation. Maladaptive ventricular remodeling contributes to post-MI heart failure, 3 and prognosis of heart failure patients is still poor. 4 Myocardial ischemia triggers a spontaneous angiogenic response aimed at reestablishing myocardial blood flow. Nonetheless, this protective response is usually not sufficient. 5 Nerve growth factor (NGF) is a secreted glycoprotein of the neurotrophin family. NGF elicits its biological effects mainly by binding the high-affinity TrkA receptor (tropomyosin-related receptor A, which is a tyrosine kinase). We and others previously demonstrated that NGF, via TrkA, promotes angiogenesis and endothelial cells (ECs) survival through a mechanism involving the serine/threonine kinase Akt (also known as protein kinase B). 6,7 Akt regulates a variety of cellular functions and it is strongly implicated in angiogenesis and cell survival. 8 We also demonstrated that cultured cardiomyocytes express TrkA and release NGF. 9 Moreover, NGF is an autocrine prosurvival factor for the cardiomyocyte through the Akt/Forkhead box-O transcription factors (Foxo) pathway. 9 Foxo factors stimulate cell death and are downstream targets of Akt. 10 Akt-mediated phosphorylation regulates Foxo-3a subcellular localization and activity: unphosphorylated Foxo-3a resides in the nucleus, whereas Foxo-3a phosphorylation leads to its nuclear exclusion and inactivation. 11 Moreover, Foxo-1 and -3a represses angiogenesis by downregulating endothelial nitric oxide synthase. 12 Experimental evidences suggest that myocardial repair is, at least in part, dependent on c-kit receptor-expressing (c-kit pos ) progenitor cell populations. [13][14][15] Lineage negative Original received October 5, 2009; revision received February 19, 2010; accepted February 23, 2010. 13 Activation of the c-kit receptor is mediated by its ligand stem cell factor (SCF), a cytokine that exists in soluble or membraneassociated form. 16 The membrane-bound SCF isoform, which is predominant in vivo...

To investigate the effect of anti-cytokine-based therapy in the course of diabetic cardiomyopathy, we performed a study using an anti-TNF-alpha monoclonal antibody treatment (mab) in Sprague male Dawley (SD) rats with streptozotocin-induced diabetic cardiomyopathy. Five days after streptozotocin injection, rats were treated with the anti-TNF-alpha mAb C432A for 6 weeks.At the end of the study, left ventricular (LV) function was determined by a pressure-catheter. Intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, beta2-lymphocyte-integrins(+) (CD18(+), CD11a(+), CD11b(+)), ED1/CD68(+) and cytokine (TNF-alpha, interleukin (IL)-1beta)- expressing infiltrates, total collagen content and stainings of collagen I and III were quantified by digital image analysis. LV phosphorylated and total ERK protein levels were determined by Western Blot. TNFalpha-antagonism reduced ICAM-1- and VCAM-1 expression and leukocyte infiltration to levels of non-diabetics and decreased macrophage residence by 3.3-fold compared with untreated diabetics. In addition, anti-TNF-alpha mAb-treatment decreased diabetes-induced cardiac TNF-alpha and IL-1beta expression by 2.0-fold and 1.8- fold, respectively, and reduced the ratio of phosphorylated to total ERK by 2.7-fold. The reduction in intramyocardial inflammation was associated with a 5.4-fold and 3.6-fold reduction in cardiac collagen I and III content, respectively. This was reflected by a normalization of cardiac total collagen content to levels of non-diabetics and associated with an improved LV function. TNFalpha-antagonism attenuates the development of experimental diabetic cardiomyopathy associated with a reduction of intramyocardial inflammation and cardiac fibrosis.

The mechanisms contributing to diabetic cardiomyopathy, as well as the protective pathways of the kallikrein-kinin-system (KKS), are incompletely understood. In a kallikrein-overexpressing rat model of streptozotocin (STZ)-induced diabetic cardiomyopathy, we investigated the involvement of inflammatory pathways, endothelial dysfunction, and oxidative stress. Six weeks after STZ injection, impairment of left ventricular (LV) function parameters measured by a Millar-tip catheter (peak LV systolic pressure; dP/dtmax; dP/dtmin) was accompanied by a significant increment of ICAM-1 and VCAM-1 (CAMs) expression, as well as of beta2-leukocyte-integrins+ (CD18+, CD11a+, CD11b+) and cytokine (TNF-alpha and IL-1beta)-expressing infiltrates in male Sprague-Dawley (SD-STZ) rats compared with normoglycemic littermates. Furthermore, SD-STZ rats demonstrated a significant impairment of endothelium-dependent relaxation evoked by acetylcholine and significantly increased plasma TBARS (plasma thiobarbituric acid reactive substances) levels as a measure of oxidative stress. These diabetic cardiomyopathy-associated alterations were significantly attenuated (P<0.05) in diabetic transgenic rats expressing the human kallikrein 1 (hKLK1) gene with STZ-induced diabetes. CAMs expression, beta2-leukocyte-integrins+, and cytokine-expressing infiltrates correlated significantly with all evaluated LV function parameters. The multiple protective effects of the KKS in experimental diabetic cardiomyopathy comprise the inhibition of intramyocardial inflammation (CAMs expression, beta2-leukocyte-integrins+ infiltration and cytokine expression), an improvement of endothelium-dependent relaxation and the attenuation of oxidative stress. These insights might have therapeutic implications also for human diabetic cardiomyopathy.

OBJECTIVE-We investigated the effect of pharmacological inhibition of the interleukin converting enzyme (ICE) on cardiac inflammation, apoptosis, fibrosis, and left ventricular function in an animal model of diabetes.RESEARCH DESIGN AND METHODS-Diabetes was induced in 24 Sprague-Dawley rats by injection of streptozotozin (STZ) (70 mg/kg). Diabetic animals were treated with the interleukin converting enzyme (ICE) inhibitor (ICEI) (n ϭ 12) or with a placebo (n ϭ 12). Nondiabetic rats served as controls (n ϭ 12). Left ventricular function was documented 6 weeks after induction of diabetes. Cardiac tissue was analyzed for the expression of cytokines, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, leukocyte and macrophage integrins, and collagen. Phosphorylation of Akt was analyzed by Western blot and apoptosis by Blc-2 and Bax measurements.RESULTS-Left ventricular function was significantly impaired in diabetic animals. This was accompanied by a significant increase of cytokines, cell adhesion molecules, leukocytes and macrophages, and collagen content. In addition, the phosphorylation state of Akt was reduced. These changes were significantly attenuated in the diabetic group treated with ICEI.CONCLUSIONS-Cardiac dysfunction is associated with cardiac inflammation in experimental diabetic cardiomyopathy. Both of these-cardiac dysfunction and inflammation-are attenuated after treatment with ICEI. These data suggest that anticytokine-based therapies might be beneficial in diabetic cardiomyopathy.

Mechanical circulatory support (MCS) is often required to stabilize patients with acute fulminant myocarditis with cardiogenic shock. This review gives an overview of the successful use of left-sided Impella in the setting of fulminant myocarditis and cardiogenic shock as the sole means of MCS as well as in combination with right ventricular (RV) support devices including extracorporeal life support (ECLS) (ECMELLA) or an Impella RP (BI-PELLA). It further provides evidence from endomyocardial biopsies that in addition to giving adequate support, LV unloading by Impella exhibits disease-modifying effects important for myocardial recovery (i.e., bridge-to-recovery) achieved by this newly termed "prolonged Impella" (PROPELLA) concept in which LV-IMPELLA 5.0, implanted via an axillary approach, provides support in awake, mobilized patients for several weeks. Finally, this review addresses the question of how to define the appropriate time point for weaning strategies and for changing or discontinuing unloading in fulminant myocarditis.

Background— The hallmarks of diabetic cardiomyopathy are cardiac oxidative stress, intramyocardial inflammation, cardiac fibrosis, and cardiac apoptosis. Given the antioxidative, antiinflammatory, and antiapoptotic potential of high-density lipoprotein (HDL), we evaluated the hypothesis that increased HDL via gene transfer (GT) with human apolipoprotein (apo) A-I, the principal apolipoprotein of HDL, may reduce the development of diabetic cardiomyopathy. Methods and Results— Intravenous GT with 3×10 12 particles/kg of the E1E3E4-deleted vector Ad.hapoA-I , expressing human apoA-I, or Ad.Null , containing no expression cassette, was performed 5 days after streptozotocin (STZ) injection. Six weeks after apoA-I GT, HDL cholesterol levels were increased by 1.6-fold ( P <0.001) compared with diabetic controls injected with the Ad.Null vector (STZ- Ad.Null ). ApoA-I GT and HDL improved LV contractility in vivo and cardiomyocyte contractility ex vivo, respectively. Moreover, apoA-I GT was associated with decreased cardiac oxidative stress and reduced intramyocardial inflammation. In addition, compared with STZ- Ad.Null rats, cardiac fibrosis and glycogen accumulation were reduced by 1.7-fold and 3.1-fold, respectively ( P <0.05). Caspase 3/7 activity was decreased 1.2-fold ( P <0.05), and the ratio of Bcl-2 to Bax was upregulated 1.9-fold ( P <0.005), translating to 2.1-fold ( P <0.05) reduced total number of cardiomyocytes with apoptotic characteristics and 3.0-fold ( P <0.005) reduced damaged endothelial cells compared with STZ- Ad.Null rats. HDL supplementation ex vivo reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold ( P <0.005). The apoA-I GT-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and glycogen synthase kinase ratio, respectively ( P <0.005). Conclusion— ApoA-I GT reduced the development of streptozotocin-induced diabetic cardiomyopathy.