Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 ...expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1+ cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.
► STAT3 depletion or DOX used in tumor therapy impair endothelial differentiation of CPC ► Cardiac STAT3 depletion or DOX reduce cardiac EPO levels and CCR2 activation in CPC ► EPO preserves endothelial differentiation by maintaining CCR2 activity on CPC ► STAT3-depleted or DOX-treated hearts can be protected by treatment with synthetic EPO
A task force has been established by the European Society of Cardiology to investigate the role of progenitor/stem cell therapy in the treatment of cardiovascular disease. This article is the ...consensus of this group, of what clinical studies are needed in this field, and the challenges to be addressed in the translation of progenitor/stem cell biology to repair of the heart.
...beneficial effects of bromocriptine on the sympathetic nervous system and on hemodynamics may combine to assist recovery of PPCM patients. ...a controlled randomized study is needed in order to ...determine the true value of bromocriptine as a specific novel therapy for PPCM.
The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses, such as ...proliferation and apoptosis. The constitutive activation of STAT3 promotes tumor growth and angiogenesis and is associated with drug resistance in cancer therapy. In contrast, in the heart, the down-regulation of STAT3 has been associated with end-stage heart failure in patients. Moreover, multiple studies showed that the activation of STAT3 promotes cardiomyocyte survival and hypertrophy, as well as cardiac angiogenesis, in response to various pathophysiologic stimuli, strongly suggesting that STAT3 is beneficial for the heart. Conditional knockout (STAT3-KO) mice harboring a cardiomyocyte-restricted deletion of STAT3 showed enhanced susceptibility to cardiac injury caused by myocardial ischemia, systemic inflammation, or drug toxicity. STAT3-KO mice were also more prone to the pathogenesis of age-related heart failure. Thus, STAT3 is involved in multiple mechanisms required for the protection of the heart from injury and heart failure. These observations should be taken into account in designing novel therapeutic strategies for the prevention of cardiac failure.
Radiofrequency ablation of pulmonary veins (PVs) has emerged as an effective treatment for patients with paroxysmal atrial fibrillation (AF). However, serious complications raise concern about an ...even wider application. In terms of safety, cryoenergy has advantages compared with radiofrequency. A new cryoenergy balloon catheter has been recently developed to make AF ablation shorter and safer.
The purpose of this study was to test the 6-month efficacy of this new device for ablation of paroxysmal AF.
Twenty-one patients with highly symptomatic paroxysmal AF, normal left atrial size, and frequent episodes of AF were included. All PVs were targeted during cryoballoon ablation. Patients received 24-hour Holter electrocardiograms (ECGs) and event recorder during follow-up after 1, 3, and 6 months.
A total of 81 (95%) of 85 PVs could be completely isolated with a single-balloon technique. Procedure time was 165 +/- 35 minutes, and fluoroscopy time was 39 +/- 9 minutes. After 6 months, 86% of the patients were free of symptomatic AF. In two of three patients with recurrence of AF, complete PV isolation has not been achieved initially. After a second procedure (1.04 procedures per patient), 90% of the patients were free of symptomatic AF. Three phrenic nerve palsies occurred during ablation of the right superior PV; two completely resolved after 6 and 9 months, and one is still persisting after 2 months.
This is the first study that reports the results of the new cryoballoon AF ablation approach showing 86% freedom from AF recurrence after 6 months. Cryoballoon PV ablation promises to be effective for patients with paroxysmal AF and normally sized left atria.
Growth of functional arteries is essential for the restoration of blood flow to ischemic organs. Notch signaling regulates arterial differentiation upstream of ephrin-B2 during embryonic development, ...but its role during postnatal arteriogenesis is unknown. Here, we identify the Notch ligand Delta-like 1 (Dll1) as an essential regulator of postnatal arteriogenesis. Dll1 expression was specifically detected in arterial endothelial cells, but not in venous endothelial cells or capillaries. During ischemia-induced arteriogenesis endothelial Dll1 expression was strongly induced, Notch signaling activated and ephrin-B2 upregulated, whereas perivascular cells expressed proangiogenic vascular endothelial growth factor, and the ephrin-B2 activator EphB4. In heterozygous Dll1 mutant mice endothelial Notch activation and ephrin-B2 induction after hindlimb ischemia were absent, arterial collateral growth was abrogated and recovery of blood flow was severely impaired, but perivascular vascular endothelial growth factor and EphB4 expression was unaltered. In vitro, angiogenic growth factors synergistically activated Notch signaling by induction of Dll1, which was necessary and sufficient to regulate ephrin-B2 expression and to induce ephrin-B2 and EphB4-dependent branching morphogenesis in human arterial EC. Thus, Dll1-mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis.
Aims We have recently shown in the randomized-controlled BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial that intracoronary autologous bone marrow cell (BMC) transfer ...improves left ventricular (LV) ejection fraction recovery in patients after acute myocardial infarction (AMI). However, the impact of BMC therapy on LV diastolic function in patients after AMI has remained uncertain. Methods and results Using (tissue) Doppler echocardiography, we evaluated the effects of BMC transfer on LV diastolic function in patients enrolled in the BOOST trial. After successful primary percutaneous coronary intervention (PCI) for acute ST-elevation myocardial infarction (MI), patients were randomized to a control (n=29) or BMC transfer group (n=30). Diastolic function was determined 4.5±1.5 days after PCI, at 6 months, and at 18 months by measuring transmitral flow velocities (E/A ratio), diastolic myocardial velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). All analyses were performed in a blinded fashion. There was an overall effect of BMC transfer on E/A 0.33±0.12; 95% confidence interval (CI): 0.09–0.57; P=0.008 and Ea/Aa ratios (0.29±0.14; 95% CI: 0.01–0.57; P=0.04). In contrast, we found no effect of BMC transfer on DT (−5±14 ms; 95% CI: −33 to 22; P=0.70), IVRT (−7±7 ms; 95% CI: −20 to 6; P=0.29), and E/Ea ratio (0.35±0.14; 95% CI: −0.92 to 1.62; P=0.57). Conclusion Intracoronary autologous BMC transfer improves echocardiographic parameters of diastolic function in patients after AMI.
Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal ...transducers and activators of transcription (STAT). Superoxide (O(2)(-)) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O(2)(-) anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT(1)) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O(2)(-) anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O(2)(-) anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1alpha/ss, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47(phox), a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 micromol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O(2)(-) anions generated by the NAD(P)H oxidase system, and O(2)(-) anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O(2)(-) anions generated by the NAD(P)H oxidase system.
Recent investigation has focused on identifying signaling pathways that inhibit cardiac hypertrophy, a major risk factor for cardiovascular morbidity and mortality. In this context, nitric oxide ...(NO), signaling via cGMP and cGMP-dependent protein kinase type I(PKG I), has been recognized as a negative regulator of cardiac myocyte (CM) hypertrophy. However, the underlying mechanisms are poorly understood. Here, we show that PKG I inhibits CM hypertrophy by targeting the calcineurin-NFAT signaling pathway. Calcineurin, a Ca2+-dependent phosphatase, promotes hypertrophy in part by activating NFAT transcription factors which induce expression of hypertrophic genes, including brain natriuretic peptide (BNP). Activation of PKG I by NO/cGMP in CM suppressed NFAT transcriptional activity, BNP induction, and cell enlargement in response to α1-adrenoreceptor stimulation but not in response to adenoviral expression of a Ca2+-independent, constitutively active calcineurin mutant, thus demonstrating NO-cGMP-PKG I inhibition of calcineurin-NFAT signaling upstream of calcineurin. PKG I suppressed single L-type Ca2+-channel open probability, Ca2+itransient amplitude, and, most importantly, L-type Ca2+-channel current-induced NFAT activation, indicating that PKG I targets Ca2+-dependent steps upstream of calcineurin. Adenoviral expression of PKG I enhanced NO/cGMP inhibitory effects upstream of calcineurin, confirming that PKG I mediates NO/cGMP inhibition of calcineurin-NFAT signaling. In CM overexpressing PKG I, NO/cGMP also suppressed BNP induction and cell enlargement but not NFAT activation elicited by constitutively active calcineurin, which is consistent with additional, NFAT-independent inhibitory effect(s) of PKG I downstream of calcineurin. Inhibition of calcineurin-NFAT signaling by PKG I provides a framework for understanding how NO inhibits cardiac myocyte hypertrophy.
The angiotensin-converting enzyme (ACE) not only generates angiotensin II but is also the main enzyme that destroys bradykinin. It has been hypothesized, therefore, that bradykinin is involved in the ...vascular effects of ACE inhibitors. However, its contribution has never been demonstrated in humans because of the lack of specific bradykinin receptor antagonists.
High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in 10 healthy volunteers. The vascular effects of the ACE inhibitor quinaprilat, the selective bradykinin B2-receptor antagonist icatibant, and their combination were determined at rest, during reactive hyperemia (with increased flow causing endothelium-mediated, flow-dependent dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Neither icatibant nor quinaprilat affected arterial diameter or blood flow at rest. However, icatibant reduced flow-dependent dilation by 33%, and quinaprilat increased flow-dependent dilation over baseline by 46%. After coinfusion of quinaprilat and icatibant, flow-dependent dilation was reduced to a similar extent as after infusion of icatibant alone.
ACE inhibition enhances flow-dependent, endothelium-mediated dilation in humans by a bradykinin-dependent mechanism. This observation indicates that accumulation of endogenous bradykinin is involved in the vascular effects of ACE inhibitors in humans.
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