Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of relaxin.

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation.

Anterior-wall and non-anterior-wall STEMIs do not differ in long-term mortality: results from the augsburg myocardial infarction registry.

Background: Different ST-segment elevation myocardial infarction (STEMI) localizations go along with dissimilarities in the size of the affected myocardium, the causing coronary vessel occlusion, and the right ventricular participation. Therefore, this study aims to clarify if there is any difference in long-term survival between anterior- and non-anterior-wall STEMI. Methods: This study included 2,195 incident STEMI cases that occurred between 2009 and 2017, recorded by the population-based Augsburg Myocardial Infarction Registry, Germany. The study population comprised 1.570 men and 625 women aged 25-84 years at acute myocardial infarction. The patients were observed from the day of their first acute event with an average follow-up period of 4.3 years, (standard deviation: 3.0). Survival analyses and multivariable Cox regression analyses were performed to examine the association between infarction localizations and long-term all-cause mortality. Results: Of the 2,195 patients, 1,118 had an anterior (AWS)- and 1,077 a non-anterior-wall-STEMI (NAWS). No significant associations of the STEMI localization with long-term mortality were found. When comparing AWS with NAWS, a hazard ratio of 0.91 [95% confidence interval: 0.75-1.10] could be calculated after multivariable adjustment. In contrast to NAWS, AWS was associated with a greater <28 day mortality, less current or former smoking and higher creatine kinase-myocardial band levels (CK-MB) and went along with a higher frequency of impaired left ventricular ejection fraction (<30%). Conclusions: Despite pathophysiological differences between AWS and NAWS, and identified differences in multiple clinical characteristics, no significant differences in long-term mortality between both groups were observed.

[Atrioventricular block and left ventricular wall mobility disorder in a 44-year-old female patient : A case report of a rarity with pitfalls]. / Atrioventrikuläre Blockierung und linksventrikuläre Wandbewegungsstörung bei einer 44-jährigen Patientin : Fallbericht über eine Rarität mit Tücken.

Eosinophilic myocarditis is a rare condition with good treatment options, which can be difficult to diagnose. The clinical presentation can vary from asymptomatic to life-threatening forms. This article describes the case of a 44-year-old woman who suffered from vertigo, chest pain and dyspnea. The woman presented with an intermittent atrioventricular (AV) block II Mobitz type II° and mild impairment of left ventricular ejection fraction. Hypereosinophilia in the peripheral blood, cardiac magnetic resonance imaging (MRI) and endomyocardial biopsy led to the diagnosis of eosinophilic myocarditis, most likely as a result of an allergic reaction to Aspergillus fumigatus. A general treatment recommendation cannot be made due to the lack of evidence-based guidelines; however, recent scientific studies confirmed timely, high-dose steroid administration over several months to be the mainstay of treatment of eosinophilic myocarditis. The following article may be helpful in the early diagnosis and treatment of this underdiagnosed and insidious disease.

[Cardiomyopathy in a 22-year-old man with a long history of methamphetamine abuse]. / Kardiomyopathie bei einem 22-Jährigen mit langjährigem Methamphetaminkonsum.

This article presents the case of a 22-year-old male patient with cardiomyopathy associated with a long history of methamphetamine abuse. Echocardiography revealed a dilated cardiomyopathy with highly reduced systolic pump function and severe mitral valve regurgitation. Inotropic treatment and MitraClip® (Abbott Vascular, Santa Clara, CA, USA) implantation resulted in enhancement of hemodynamics. The rising prevalence of methamphetamine abuse should give reason to raise awareness for the diagnostic work-up and patient history particularly in cases of unexplained cardiomyopathy in young patients.

Transient elevation of high-sensitive troponin T after Cardioband implantation.

BACKGROUND: The Cardioband system enables percutaneous surgical-like direct mitral valve annuloplasty and, thereby, repair of severe functional mitral valve regurgitation (MR) in patients with advanced systolic heart failure (HF) and dilation of the left ventricular (LV) annulus. Since the device is anchored by screws in the LV annulus, limited myocardial injury is likely to occur. METHODS AND RESULTS: Five patients (Society of Thoracic Surgeons score: 2.7 ± 0.7%) with severe HF (LV ejection fraction [LVEF]: 17 ± 1%; LV end-diastolic diameter [LVEDD]: 71 ± 3 mm) were treated with the Cardioband (sizes C-F) receiving 14-17 screws in the LV annulus region. Myocardial injury was monitored by measuring high-sensitive cardiac troponin T (hsTnT) levels and by echocardiography. All patients showed significant periprocedural increase in hsTnT levels. Peak hsTnT concentration was reached between day 1 and day 6 (593 ± 141 pg/ml). None of the patients showed clinical signs of myocardial infarction, ST-segment elevation, new onset of deteriorated myocardial wall motion, or new ventricular tachycardia. hsTnT levels normalized in all patients after 14 days (hsTnT on day 0: 34 ± 6 pg/ml vs. hsTnT on day 14: 36 ± 6 pg/ml; p = 0.604). This nonischemic hsTnT kinetics was compared to a sixth patient who experienced proximal damage of the left circumflex artery (LCX) and ST-segment elevation during the Cardioband procedure, followed by immediate repair of the LCX, avoiding structural damage of the LV. CONCLUSION: Cardioband implantation is accompanied by significant elevation of hsTnT without causing structural myocardial damage or clinical symptoms such as worsening of LV function, new-onset LV regions exhibiting reduced wall motion, or ventricular tachycardia.

Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.

Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.

Targeting GRK2 by gene therapy for heart failure: benefits above ß-blockade.

Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of ß-adrenergic receptor antagonism.

Gene therapy targets in heart failure: the path to translation.

Heart failure (HF) is the common end point of cardiac diseases. Despite the optimization of therapeutic strategies and the consequent overall reduction in HF-related mortality, the key underlying intracellular signal transduction abnormalities have not been addressed directly. In this regard, the gaps in modern HF therapy include derangement of ß-adrenergic receptor (ß-AR) signaling, Ca(2+) disbalances, cardiac myocyte death, diastolic dysfunction, and monogenetic cardiomyopathies. In this review we discuss the potential of gene therapy to fill these gaps and rectify abnormalities in intracellular signaling. We also examine current vector technology and currently available vector-delivery strategies, and we delineate promising gene therapy structures. Finally, we analyze potential limitations related to the transfer of successful preclinical gene therapy approaches to HF treatment in the clinic, as well as impending strategies aimed at overcoming these limitations.

Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors.

Cornerstone for an efficient cardiac gene therapy is the need for a vector system, which enables selective and long-term expression of the gene of interest. In rodent animal models adeno-associated viral (AAV) vectors like AAV-6 have been shown to efficiently transduce cardiomyocytes. However, since significant species-dependent differences in transduction characteristics exist, large animal models are of imminent need for preclinical evaluations. We compared gene transfer efficiencies of AAV-6 and heparin binding site-deleted AAV-2 vectors in a porcine model. Application of the AAVs was performed by pressure-regulated retroinfusion of the anterior interventricular cardiac vein, which has been previously shown to efficiently deliver genes to the myocardium (3.5 x 10(10) viral genomes per animal; n=5 animals per group). All vectors harbored a luciferase reporter gene under control of a cytomegalovirus (CMV)-enhanced 1.5 kb rat myosin light chain promoter (CMV-MLC2v). Expression levels were evaluated 4 weeks after gene transfer by determining luciferase activities. To rule out a systemic spillover peripheral tissue was analyzed by PCR for the presence of vector genomes. Selective retroinfusion of AAV serotype 6 vectors into the anterior cardiac vein substantially increased reporter gene expression in the targeted distal left anterior descending (LAD) territory (65 943+/-31 122 vs control territory 294+/-69, P<0.05). Retroinfusion of AAV-2 vectors showed lower transgene expression, which could be increased with coadministration of recombinant human vascular endothelial growth factor (1365+/-707 no vascular endothelial growth factor (VEGF) vs 38 760+/-2448 with VEGF, P<0.05). Significant transgene expression was not detected in other organs than the heart, although vector genomes were detected also in the lung and liver. Thus, selective retroinfusion of AAV-6 into the coronary vein led to efficient long-term myocardial reporter gene expression in the targeted LAD area of the porcine heart. Coapplication of VEGF significantly increased transduction efficiency of AAV-2.

[Unusual infection with pulmonary round foci obtained through "hay packs"]. / Ungewöhnliche Infektion mit pulmonalen Rundherden nach Anwendung von "Heupackungen".

A 71-year-old female, who has been treated with steroids for 3 weeks, developed a severe pneumonia with septic shock and acute respiratory distress syndrome (ARDS). Despite broad antibiosis due to the detection of pseudomonas aeruginosa (blood culture) the inflammatory markers remained high and the respiratory situation went critical. No proof of a malignoma or autoimmune process was found, despite multiple round foci in x-ray and computer tomography. Finally the delayed diagnosis of pulmonary nocardiosis was adjusted, due to the long incubation period of the pathogen Nocardia farcinica. The infectious origin may be assumed in so called "hay packs" used during the patient's residence at a health resort. After adequate change of the antibiotic regimen stabilization was achieved and the patient meanwhile recovered from the disease.

Retroinfusion of NFkappaB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs.

Myocardial reperfusion injury is partially mediated by postischemic inflammation. Beyond acute PMN recruitment, postischemic inflammation comprises subacute PMN adhesion, eg via NFkappaB activation. In a pig model of 60-min LAD occlusion by PTCA ballon inflation and 1 to 7 days of reperfusion, we investigated the impact of targeted NFkappaB decoy oligonucleotide (ODN) transfection in the area at risk (AAR) on infarct size and regional myocardial function. After 55 min of LAD occlusion, liposomes containing NFkappaB ODN were selectively retroinfused into the anterior interventricular vein for 5 min. Then, retroinfusion was stopped and reperfusion was initiated. Where indicated, CD18 antibody IB4 was infused systemically at 30 min of ischemia. Methylen blue and tetrazolium-red staining were used for quantification of the infarct size. Subendocardial segment shortening (SES) by sonomicrometric crystals in infarct area and AAR was assessed under pacing (expressed as % of control region). NFkappaB decoy ODN retroinfusion reduced infarct size (36 +/- 4% versus 49 +/- 5% in control hearts at day 7), whereas functional reserve of the AAR (SES 73 +/- 17% versus 46 +/- 18% at 180/min) tended to improve. Similar effects were observed after IB4 infusion (38 +/- 5% infarct size, 85 +/- 7% SES at 180/min). A combination of NFkappaB decoy ODN retroinfusion and IB4 infusion further decreased infarct size (26 +/- 2%) and improved functional reserve (SES 94 +/- 6% at 180/min). We conclude that NFkappaB decoy ODN transfection by retroinfusion is feasible in pig hearts and provides postischemic cardioprotection in addition to CD18 blockade.

Endogenous release of tissue factor pathway inhibitor by topical application of an ointment containing mucopolysaccharide polysulfate to nonhuman primates.

Several studies have shown that tissue factor pathway inhibitor (TFPI) is released after the intravenous and subcutaneous administration of heparin and heparin-related drugs. Mucopolysaccharide polysulfate (MPS) is a preparation of glycosaminoglycans (GAGS) derived from mammalian cartilage, which has several structural and functional properties similar to heparin. Previous reports have shown that MPS is capable of releasing TFPI after intravenous administration. Therefore, this investigation was performed to determine the ability of topically administered MPS to release TFPI in a nonhuman primate model. A group of four monkeys were administered 3% MPS ointment in a dosage of 0.5 g/kg corresponding to 15 mg MPS/kg; another four monkeys were administered placebo ointment at a dosage of 0.5 g/kg once a day for 5 days in a period of 10 days. No effect of MPS was observed on the coagulation assays activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest or on the platelet count. However, both the total and free TFPI levels were significantly and progressively elevated over the 10-day period in comparison to the placebo control group (P<.05). It is proposed that the ability of the topically administered MPS to increase the free and total TFPI levels may be one of the modes of action that contributes to the anticoagulant and anti-inflammatory actions of this agent.