Background— The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated. Methods and Results— Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of ≈130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (≈50%) and heart tissue (≈3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion. Conclusions— Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.

Introduction Mechanisms underlying inotropic failure in septic shock are incompletely understood. We previously identified the presence of exosomes in the plasma of septic shock patients. These exosomes are released mainly by platelets, produce superoxide, and induce apoptosis in vascular cells by a redoxdependent pathway. We hypothesized that circulating plateletderived exosomes could contribute to inotropic dysfunction of sepsis.

BackgroundCell therapy approaches for biologic cardiac repair hold great promises, although basic fundamental issues remain poorly understood. In the present study we examined the effects of timing and routes of administration of bone marrow cells (BMC) post-myocardial infarction (MI) and the efficacy of an injectable biopolymer scaffold to improve cardiac cell retention and function.Methodology/Principal Findings 99mTc-labeled BMC (6×106 cells) were injected by 4 different routes in adult rats: intravenous (IV), left ventricular cavity (LV), left ventricular cavity with temporal aorta occlusion (LV+) to mimic coronary injection, and intramyocardial (IM). The injections were performed 1, 2, 3, or 7 days post-MI and cell retention was estimated by γ-emission counting of the organs excised 24 hs after cell injection. IM injection improved cell retention and attenuated cardiac dysfunction, whereas IV, LV or LV* routes were somewhat inefficient (<1%). Cardiac BMC retention was not influenced by timing except for the IM injection that showed greater cell retention at 7 (16%) vs. 1, 2 or 3 (average of 7%) days post-MI. Cardiac cell retention was further improved by an injectable fibrin scaffold at day 3 post-MI (17 vs. 7%), even though morphometric and function parameters evaluated 4 weeks later displayed similar improvements.Conclusions/SignificanceThese results show that cells injected post-MI display comparable tissue distribution profile regardless of the route of injection and that there is no time effect for cardiac cell accumulation for injections performed 1 to 3 days post-MI. As expected the IM injection is the most efficient for cardiac cell retention, it can be further improved by co-injection with a fibrin scaffold and it significantly attenuates cardiac dysfunction evaluated 4 weeks post myocardial infarction. These pharmacokinetic data obtained under similar experimental conditions are essential for further development of these novel approaches.

BackgroundCardiac cell transplantation is compromised by low cell retention and poor graft viability. Here, the effects of co-injecting adipose tissue-derived stem cells (ASCs) with biopolymers on cell cardiac retention, ventricular morphometry and performance were evaluated in a rat model of myocardial infarction (MI).Methodology/Principal Findings 99mTc-labeled ASCs (1×106 cells) isolated from isogenic Lewis rats were injected 24 hours post-MI using fibrin a, collagen (ASC/C), or culture medium (ASC/M) as vehicle, and cell body distribution was assessed 24 hours later by γ-emission counting of harvested organs. ASC/F and ASC/C groups retained significantly more cells in the myocardium than ASC/M (13.8±2.0 and 26.8±2.4% vs. 4.8±0.7%, respectively). Then, morphometric and direct cardiac functional parameters were evaluated 4 weeks post-MI cell injection. Left ventricle (LV) perimeter and percentage of interstitial collagen in the spare myocardium were significantly attenuated in all ASC-treated groups compared to the non-treated (NT) and control groups (culture medium, fibrin, or collagen alone). Direct hemodynamic assessment under pharmacological stress showed that stroke volume (SV) and left ventricle end-diastolic pressure were preserved in ASC-treated groups regardless of the vehicle used to deliver ASCs. Stroke work (SW), a global index of cardiac function, improved in ASC/M while it normalized when biopolymers were co-injected with ASCs. A positive correlation was observed between cardiac ASCs retention and preservation of SV and improvement in SW post-MI under hemodynamic stress.ConclusionsWe provided direct evidence that intramyocardial injection of ASCs mitigates the negative cardiac remodeling and preserves ventricular function post-MI in rats and these beneficial effects can be further enhanced by administrating co-injection of ASCs with biopolymers.

Background: Myocardial infarction (MI) is accompanied by cardiac growth, increased collagen deposition, cell death and new vascularization of the cardiac tissue, which results in reduced ventricular compliance. The MiRNA-29 family (29a, 29b, and 29c) targets mRNAs that encode collagens and other proteins involved in fibrosis. In this study we assessed the effects of swimming training (ST) on expression of the cardiac miRNA-29 family and on genes encoding collagen after MI in rats. Methods: ST consisted of 60 min/day/10 weeks and began four weeks after MI. MiRNA and collagen expression analysis were performed in the infarcted region (IR), border region (BR) of the infarcted region and in the remote myocardium (RM) of the left ventricle. Results: MiRNA-29a expression increased 32% in BR and 52% in RM in the TR-INF compared with SED-INF. MiRNA-29c increased by 63% in BR and 55% in RM in TR-INF compared with SED-INF group. COL IAI and COL IIIAI decreased by 63% and 62% in TR-INF, respectively, compared with SED-INF. COLIIIAI expression decreased by 16% in TR-INF compared with SED-INF. Conclusion: Altogether, our results showed that ST restores cardiac miRNA-29 (a and c) levels and prevents COL IAI and COL IIIAI expression in BR and RM, which may contribute to the improvement in ventricular function induced by swimming training, after MI.

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Myocardial hypertrophy and dysfunction occur in response to excessive catecholaminergic drive. Adverse cardiac remodelling is associated with activation of proinflammatory cytokines in the myocardium. To test the hypothesis that exercise training can prevent myocardial dysfunction and production of proinflammatory cytokines induced by β-adrenergic hyperactivity, male Wistar rats were assigned to one of the following four groups: sedentary non-treated (Con); sedentary isoprenaline treated (Iso); exercised non-treated (Ex); and exercised plus isoprenaline (Iso+Ex). Echocardiography, haemodynamic measurements and isolated papillary muscle were used for functional evaluations. Real-time RT-PCR and Western blot were used to quantify tumour necrosis factor α, interleukin-6, interleukin-10 and transforming growth factor β 1 (TGF-β 1 ) in the tissue. NF-κB expression in the nucleus was evaluated by immunohistochemical staining. The Iso rats showed a concentric hypertrophy of the left ventricle (LV). These animals exhibited marked increases in LV end-diastolic pressure and impaired myocardial performance in vitro, with a reduction in the developed tension and maximal rate of tension increase and decrease, as well as worsened recruitment of the Frank-Starling mechanism. Both gene and protein levels of tumour necrosis factor α and interleukin-6, as well as TGF-β 1 mRNA, were increased. In addition, the NF-κB expression in the Iso group was significantly raised. In the Iso+Ex group, the exercise training had the following effects: (1) it prevented LV hypertrophy; (ii) it improved myocardial contractility; (3) it avoided the increase of proinflammatory cytokines and improved interleukin-10 levels; and (4) it attenuated the increase of TGF-β 1 mRNA. Thus, exercise training in a model of β-adrenergic hyperactivity can avoid the adverse remodelling of the LV and inhibit inflammatory cytokines. Moreover, the cardioprotection is related to beneficial effects on myocardial performance. Abbreviations CSA, cross-sectional area; +dP/dt, maximal positive time derivate of the developed pressure; −dP/dt, maximal negative time derivate of the developed pressure; DT, developed tension; +dT/dt, maximal rate of tension increase; −dT/dt, maximal rate of tension decrease; FS, left vetricular fractional shortening; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HR, heart rate; IL-6, interleukin-6; IL-10, interleukin-10; L max , maximal length; LV, left ventricle; LVEDD, left vetricular end-diastolic diameter; LVEDP, left vetricular end-diastolic pressure; LVESD, left vetricular end-systolic diameter; LVPWd, diastolic left vetricular posterior wall thickness; LVPWs, systolic left vetricular posterior wall thickness; LVSP, left vetricular systolic pressure; MAP, mean arterial pressure; NF-κB, nuclear factor-κB; RT, resting tension; TGF-β 1 , transforming growth factor β 1 ; TNF-α, tumour necrosis factor α.

SUMMARY. In studies utilizing the isolated isovolumic blood-perfused canine heart, left ventricular pressure was measured following a sudden expansion of ventricular volume. An increase in performance occurred in two phases: first, there was an instantaneous rise of developed pressure simultaneous with ventricular distension; in the second phase, developed pressure continued to increase for several minutes until a final steady state was reached. The immediate increase in developed pressure occurred with a prolongation of the time-to-peak pressure, and there was no further change of time-to-peak pressure during the time-dependent increase of developed pressure. In another series of experiments, systolic pressure was elevated without changing resting volume, and mechanical performance changed in a different manner: after an increase in systolic load, there was a modest and transient decrease of developed pressure; thereafter, ventricular pressure recovered only to original values. The influence of different degrees of ventricular expansion, calcium, and verapamil were studied. Under higher ventricular dilations the immediate as well as the slow increase of contraction were heightened and the time to reach half of the slow increase was shortened. When ventricular dilation was induced during an infusion of calcium chloride, higher values for the immediate pressure increase were observed, whereas the timedependent increase and the time to reach half of the slow increase did not change in comparison with control studies. Verapamil decreased the immediate and the time-dependent enhancement of contraction. The time-dependent increase in developed pressure occurs more slowly with verapamil. These findings in the intact heart are in accord with the hypothesis that myocardial stretch is followed by an increase in intracellular calcium stores, and with the concept that the Frank-Starling mechanism involves an activation of the contractile state. (Circ Res 55: 59-66, 1984)