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Aims Coronary microvascular dysfunction (CMD) is related to the pathophysiology, mortality, and morbidity of heart failure with preserved ejection fraction (HFpEF). A novel single-photon emission computed tomography (SPECT) camera with cadmium zinc telluride (CZT) detectors allows for the quantification of absolute myocardial blood flow and myocardial flow reserve (MFR) in patients with coronary artery disease. However, the potential of CZT-SPECT assessing for CMD has never been evaluated in patients with HFpEF. Methods and results The clinical records of 127 consecutive patients who underwent dynamic CZT-SPECT were retrospectively reviewed. Rest and stress scanning were started simultaneously with 3 and 9 MBq/kg of 99mTc-sestamibi administration, respectively. Dynamic CZT-SPECT imaging data were analysed using a net-retention model with commercially available software. Transthoracic echocardiography was performed in all patients. The MFR value was significantly lower in the HFpEF group (mean ± SEM = 2.00 ± 0.097) than that in the non-HFpEF group (mean ± SEM = 2.74 ± 0.14, P = 0.0004). A receiver operating characteristic analysis indicated that if a cut-off value of 2.525 was applied, MFR could efficiently distinguish HFpEF from non-HFpEF. Heart failure with preserved ejection fraction had a consistently low MFR, regardless of the diastolic dysfunction score. Heart failure with preserved ejection fraction patients with MFR values lower than 2.075 had a significantly higher incidence of heart failure exacerbation. Conclusion Myocardial flow reserve assessed by CZT-SPECT was significantly reduced in patients with HFpEF. A lower MFR was associated with a higher hospitalization rate in these patients. Myocardial flow reserve assessed by CZT-SPECT has the potential to predict future adverse events and stratify the severity of disease in patients with HFpEF.

Objective: Lymphatic vessels are distributed throughout the body and tightly collaborate with blood vessels to maintain tissue homeostasis. However, the functional roles of lymphangiogenesis in the process of reparative angiogenesis in ischemic tissues are largely unknown. Accordingly, we investigated potential roles of lymphangiogenesis using a mouse model of ischemia-induced angiogenesis. Approach and Results: Male C57BL/6J mice were subjected to unilateral hindlimb ischemia, in which not only angiogenesis but also lymphangiogenesis was induced. Next, the excessive and prolonged tissue edema model significantly deteriorated reparative angiogenesis and blood perfusion recovery in ischemic limbs. Finally, implantation of adipose-derived regenerative cells augmented ischemia-induced lymphangiogenesis, which was accompanied by reduced tissue edema and inflammation, resulting in improving reparative angiogenesis and blood perfusion recovery. In addition, inhibition of lymphangiogenesis by MAZ51, a specific VEGFR3 (vascular endothelial cell growth factor receptor 3) inhibitor, resulted in enhanced inflammatory cell infiltration, gene expression of TNF (tumor necrosis factor)-α, IL (interleukin)-1β, IL-6, TGF (transforming growth factor)-β, angiostatin, vasohibin, and endostatin, and tissue edema, resulting in reduced angiogenesis. Conclusions: The lymphatic system may have a clearance role of tissue edema and inflammation, which contribute to functional reparative angiogenesis in response to tissue ischemia. Modulation of lymphangiogenesis would become a novel therapeutic strategy for severe ischemic disease in addition to ordinary vascular intervention and therapeutic angiogenesis.

Delirium is a common adverse event observed in patients admitted to the intensive care unit (ICU). However, the prognostic value of delirium and its determinants have not been thoroughly investigated in patients with acute heart failure (AHF).We investigated 408 consecutive patients with AHF admitted to the ICU. Delirium was diagnosed by means of the Confusion Assessment Method for ICU tool and evaluated every 8 hours during the patients' ICU stays.Delirium occurred in 109 patients (26.7%), and the in-hospital mortality rate was significantly higher in patients with delirium (13.8% vs 2.3%; P0.001). Multivariate logistic regression analysis showed that delirium independently predicted in-hospital mortality (odds ratio [OR] 4.33, confidence interval [CI] 1.62-11.52; P = 0.003). Kaplan-Meier analysis showed that the 12-month mortality rate was significantly higher in patients with delirium compared with those without (log-rank test: P0.001), and Cox proportional hazards analysis showed that delirium remained an independent predictor of 12-month mortality (hazard ratio 2.19, 95% CI 1.49-3.25; P0.001). The incidence of delirium correlated with severity of heart failure as assessed by means of the Get With The Guidelines-Heart Failure risk score (chi-square test: P = 0.003). Age (OR 1.05, 95% CI 1.02-1.09; P = 0.003), nursing home residential status (OR 3.32, 95% CI 1.59-6.94; P = 0.001), and dementia (OR 5.32, 95% CI 2.83-10.00; P0.001) were independently associated with the development of delirium.Development of delirium during ICU stay is associated with short- and long-term mortality and is predicted by the severity of heart failure, nursing home residential, and dementia status.

Background High-risk percutaneous coronary intervention (PCI) in patients with left ventricular (LV) systolic dysfunction has been proven to induce reverse LV remodeling. However, the impact of high-risk PCI focusing on rotational atherectomy (RA) in patients with severe LV systolic dysfunction has not been completely addressed. Methods Among 4339 consecutive patients who underwent PCI, 178 patients with 192 lesions were treated with RA. The reduced ejection fraction (EF) group (LVEF ≤35%) included 25 patients, the mid-range EF group (LVEF 36–50%) included 44 patients, and the preserved EF group (LVEF >50%) included 109 patients. The primary outcome was a composite of cardiac death, non-fatal myocardial infarction, target-vessel revascularization, and ischemic stroke. Results The cumulative 1-year incidence of the primary outcome was similar among the three groups (reduced EF, 29%; mid-range EF, 25%; preserved EF, 26%; p = 0.95). After adjusting for confounding factors, the incidence of the primary outcome in the reduced EF group (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.43–2.37; p = 0.87) and the mid-range EF group (HR, 0.99; 95% CI, 0.47–1.94; p = 0.97) was similar to that in the preserved EF group. LVEF was significantly improved in the reduced EF and mid-range EF groups compared with the preserved EF group (absolute change in LVEF: 13.6 ± 11.3%, 9.0 ± 10.1%, and −0.7 ± 7.8%, respectively; p Conclusions Reduced EF was not associated with increase in the primary outcome in patients undergoing RA. This seemed to result from the improved LV function after PCI. Summary for annotated table of contents This single center analysis study investigated 1-year composite outcome of cardiac death, non-fatal myocardial infarction, target-vessel revascularization, and ischemic stroke in patients with severe LV systolic dysfunction undergoing RA compared with that in patients with preserved LV function. The cumulative 1-year incidence of the composite outcome was similar among the three groups (reduced EF, 29%; mid-range EF, 25%; preserved EF, 26%; p = 0.95). LVEF was significantly improved in the reduced EF and mid-range EF groups compared with the preserved EF group (absolute change in LVEF: 13.6 ± 11.3%, 9.0 ± 10.1%, and −0.7 ± 7.8%, respectively; p

Adipose-derived regenerative cell (ADRC) is a promising alternative source of autologous somatic stem cells for the repair of damaged tissue. This study aimed to assess the safety and feasibility of autologous ADRC implantation for therapeutic angiogenesis in patients with critical limb ischaemia (CLI). A clinical pilot study—Therapeutic Angiogenesis by Cell Transplantation using ADRCs (TACT-ADRC) study—was initiated in Japan. Adipose tissue was obtained by ordinary liposuction method. Isolated ADRCs were injected into the ischaemic limb. We performed TACT-ADRC procedure in five patients with CLI. At 6 months, no adverse events related to the TACT-ADRC were observed. No patients required major limb amputation, and ischaemic ulcers were partly or completely healed during the 6-month follow-up. In all cases, significant clinical improvements were seen in terms of rest pain and 6-min walking distance. Numbers of circulating CD34+ and CD133+ cells markers of progenitor cell persistently increased after ADRC implantation. The ratio of VEGF-A165b (an anti-angiogenic isoform of VEGF) to total VEGF-A in plasma significantly decreased after ADRC implantation. In vitro experiments, cultured with ADRC-conditioned media (CM) resulted in increased total VEGF-A and decreased VEGF-A165b in C2C12 cells, but not in macrophages. ADRC-CM also increased CD206+ cells expression and decreased TNF-α in macrophages. Autologous ADRC implantation was safe and effective in patients with CLI and could repair damaged tissue via its ability to promote angiogenesis and suppress tissue inflammation.

Background: Adipose-derived regenerative cells (ADRCs) are promising stem cells for regenerative medicine that are easy to harvest from adipose tissues and can expand in vitro . While ADRCs can differentiate into mesodermal lineage cells including adipocytes, osteocytes, and chondrocytes, little is known about differentiating adult ADRCs into mature cardiomyocytes. Objective: The aim of this study was to explore how to differentiate adult mouse ADRCs into cardiomyocytes efficiently and test their effect on the myocardial infarction mouse model in vivo . Method and Results: We performed differential expression analysis to identify transcriptional factors which were upregulated in developing mice heart (E11.5) compared with ADRCs. We systemically screened the combinations of the required transcription factors in ADRCs derived from αMHC-EGFP reporter mice. Here, we identified the following six genes; Baf60c , Gata4 , Gata6 , Klf15 , Mef2a , Myocd , not more or less, as the best combination to efficiently induce αMHC in ADRCs. Fluorescence-activated cell sorting analysis showed that 3.0±0.61% (n=3) ADRCs were positive for αMHC after introducing these six factors. In addition, quantitative PCR demonstrated that several other marker genes of mature cardiomyocytes, including Actc1 , Tnnt2 , Ttn , Fhod3 , were confirmed to be upregulated by six factors. Immunocytochemical staining showed that most of the induced ADRCs had fibrous conformation of sarcomeric α-actin. Moreover, the gene expression pattern of the cells showed upregulation of genes associated with cardiac muscle cell differentiation. Finally, injection of the induced ADRCs into acute myocardial infarction lesions in vivo resulted in the improvement of survival rate (p=0.028, n=32), fractional shortening (p=0.012, n=7, 15), and the reduction of infarction scar area compared to the injection of ADRCs without induction (p=0.029, n=7). The induced ADRCs could survive in situ and continued to express the cardiac troponin T protein for four weeks after injection. Conclusions: The combination of six transcriptional factors could induce cardiomyocyte-like gene expression patterns on adult ADRCs. The induced ADRCs could have a therapeutic effect on an experimental ischemic heart model in vivo .

Background and purpose Fluorine-18-flurodeoxyglucose positron emission tomography (18FDG-PET) is a useful examination assessing active inflammatory myocardium noninvasively in patients with cardiac sarcoidosis (CS). Though immunosuppression like prednisolone (PSL) and Methotrexate (MTX) as alternative therapy is used to suppress the inflammation, little is known about the rate of response and efficacy of MTX for intolerance to PSL therapy. Methods From Aug 2016, we prospectively enrolled CS with positively accumulated of FDG in the heart. The initial dose of PSL was 30mg/day, wherefrom the dose was tapered down 5mg/month until 6 months. After 6 months, follow-up 18FDG-PET was performed. Using 18FDG-PET images, we calculated total lesion glycolysis (TLG; SUVmeam x metabolic volume) and calculated the reduction rate of TLG. In order to estimate the response rate to PSL therapy, responder group (R-group) was defined as TLG reduction rate ≥70% and poor-responder group (PR-group) was defined as TLG reduction rate Results In 64 CS patients, 55 patients had serial 18FDG-PET before and 6 months after PSL therapy. 18FDG-PET images were acquired following 7 day's carbohydrate limitation and after at least 18-h fasting (mean free fatty acid level right before 18FDG-PET acquisition was 1.05 mEq/L). The mean age was 63.4 years old and 42 (76.4%) patients were female. Because of 6 months PSL therapy, even though there were no significant difference in BNP (from 59.9 (26.2–137.6) to 60.4 (18.5–122.0) (P=0.593), LV-Dd (from 50.9 (44.5–59.5) to 49.7 (45.5–61.3) (P=0.666) and LV-EF (from 49.5 (34.4–62.5) to 49.9 (38.0–62.0) (P=0.792) at pre and post therapy, respectively, TLG were detected significant reduction from 216.4 (74.2–411.6) to 0.8 (0.0–8.2), (p Conclusions 1) By immunosuppression therapy using PSL for CS, about 86% patients showed significant reduction of myocardial FDG accumulation. 2) When detected intolerance for PSL therapy, MTX might be effective for reduction of inflammation of sarcoidosis in the heart, which might be effective as an alternate therapy in CS. The TLG level after randomization Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Grant-in-aid for scientific research

Prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Tsuda et al. show that Crhr2 activation causes cardiac dysfunction and suggest Crhr2 blockade is a promising therapeutic strategy for chronic heart failure., Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein–coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3′-5′-cyclic adenosine monophosphate (cAMP)–dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.

This study aimed to investigate whether indices of left ventricular (LV) dyssynchrony by gated myocardial perfusion SPECT (GMPS) could be useful to predict prognosis in chronic kidney disease (CKD) patients with normal perfusion defect scores. One hundred and sixty-seven CKD patients with normal perfusion defect scores on adenosine-stress 201Tl GMPS and no previous history of overt heart diseases were enrolled. Phase standard deviation (PSD) and bandwidth (BW) were automatically calculated from GMPS. The major adverse cardiac events (MACEs) for a mean of 560 days were defined as sudden cardiac death, fatal arrhythmias, and acute coronary syndrome requiring urgent coronary revascularization. Patients were divided into two groups according to the presence or absence of MACEs. The MACEs occurred in 12 patients (7.1%). Patients who experienced MACEs showed significantly higher PSD and wider BW than those who did not. In the Kaplan-Meier event-free survival analysis, cardiac event rate was significantly higher in the high-PSD and wide-BW group (n = 81) than in the low-PSD and narrow-BW group (n = 71) (P = .002). The multivariate regression analysis revealed that the PSD was associated with MACEs (odds ratio 1.33, 95% confidence interval 1.05-1.69, P = .01). The LV dyssynchrony indices from GMPS may be novel prognostic predictors in CKD patients with normal perfusion defect scores.

Background: Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear. Methods: To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1 flox/flox and Pkn2 flox/flox mice and applied a mouse model of transverse aortic constriction– and angiotensin II–induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA. Results: We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload– and angiotensin II–induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload– and angiotensin II–induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction– and angiotensin II–induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor–mediated expression of cardiac hypertrophy– and fibrosis-associated genes. Conclusions: Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.

Background and purpose Fluorine-18-flurodeoxyglucose positron emission computed tomography (18FDG-PET CT) is the sole but time-consuming and expensive examination assessing active inflammatory myocardium noninvasively in patients with cardiac sarcoidosis (CS). Though immunosuppression is used to treat CS, little is known about the cardiac biomarkers for determining therapeutic effect to immunosuppression therapy other than 18FDG-PET. Methods From Aug 2016, we prospectively enrolled 50 sarcoidosis patients with positively accumulated of FDG in the heart. The initial dose of prednisolone was 30mg/day, wherefrom the dose was tapered down 5mg/month until 6 months. After 6 months, follow-up 18FDG-PET was performed. Using 18FDG-PET images, we calculated total lesion glycolysis (TLG; SUVmeam x metabolic volume) and compared it to various cardiac markers. Non-responder was defined as TLG reduction rate Results In 50 CS patients, 41 patients had serial 18FDG-PET before and 6 months after immunosuppression therapy. 18FDG-PET images were acquired following 7 day's carbohydrate limitation and after at least 18-h fasting (mean free fatty acid level right before 18FDG-PET acquisition was 1.03 mEq/L). The mean age and plasma brain natriuretic peptide (BNP) level were 61.9 years old, 184 pg/mL at baseline, respectively. Because of immunosuppression therapy, TLG was significantly reduced from 195.3 (38.6–339.6) to 1.1 (0.01–7.37), p Figure 1 Conclusions 1) By immunosuppression therapy using prednisolone for CS, about 85% patients showed significant reduction of increased myocardial FDG accumulation. 2) The sustained high level of serum TnT at post 6 months therapy indicates persistent inflammation of sarcoidosis in the heart, which could be an expedient marker for determining therapeutic effect.

Background Exposure to chronic psychosocial stress is a risk factor for atherosclerosis‐based cardiovascular disease. We previously demonstrated the increased expressions of cathepsin S (CatS) in atherosclerotic lesions. Whether CatS participates directly in stress‐related neointimal hyperplasia has been unknown. Methods and Results Male wild‐type and CatS‐deficient mice that underwent carotid ligation injury were subjected to chronic immobilization stress for morphological and biochemical studies at specific times. On day 14 after stress/surgery, stress enhanced the neointima formation. At the early time points, the stressed mice had increased plaque elastin disruption, cell proliferation, macrophage accumulation, mRNA and/or protein levels of vascular cell adhesion molecule‐1, angiotensin II type 1 receptor, monocyte chemoattractant protein‐1, gp91 phox , stromal cell–derived factor‐1, C‐X‐C chemokine receptor‐4, toll‐like receptor‐2, toll‐like receptor‐4, SC 35, galectin‐3, and CatS as well as targeted intracellular proliferating‐related molecules (mammalian target of rapamycin, phosphorylated protein kinase B, and p‐glycogen synthase kinase‐3α/β). Stress also increased the plaque matrix metalloproteinase‐9 and matrix metalloproteinase‐2 mRNA expressions and activities and aorta‐derived smooth muscle cell migration and proliferation. The genetic or pharmacological inhibition of CatS by its specific inhibitor (Z‐ FL ‐COCHO) ameliorated the stressed arterial targeted molecular and morphological changes and stressed aorta‐derived smooth muscle cell migration. Both the genetic and pharmacological interventions had no effect on increased blood pressure in stressed mice. Conclusions These results demonstrate an essential role of CatS in chronic stress–related neointimal hyperplasia in response to injury, possibly via the reduction of toll‐like receptor‐2/toll‐like receptor‐4–mediated inflammation, immune action, and smooth muscle cell proliferation, suggesting that CatS will be a novel therapeutic target for stress‐related atherosclerosis‐based cardiovascular disease.

The mammalian heart undergoes complex structural and functional remodeling to compensate for stresses such as pressure overload. While studies suggest that, at best, the adult mammalian heart is capable of very limited regeneration arising from the proliferation of existing cardiomyocytes, how myocardial stress affects endogenous cardiac regeneration or repair is unknown. To define the relationship between left ventricular afterload and cardiac repair, we induced left ventricle pressure overload in adult mice by constriction of the ascending aorta (AAC). One week following AAC, we normalized ventricular afterload in a subset of animals through removal of the aortic constriction (de-AAC). Subsequent monitoring of cardiomyocyte cell cycle activity via thymidine analog labeling revealed that an acute increase in ventricular afterload induced cardiomyocyte proliferation. Intriguingly, a release in ventricular overload (de-AAC) further increases cardiomyocyte proliferation. Following both AAC and de-AAC, thymidine analog-positive cardiomyocytes exhibited characteristics of newly generated cardiomyocytes, including single diploid nuclei and reduced cell size as compared to age-matched, sham-operated adult mouse myocytes. Notably, those smaller cardiomyocytes frequently resided alongside one another, consistent with local stimulation of cellular proliferation. Collectively, our data demonstrate that adult cardiomyocyte proliferation can be locally stimulated by an acute increase or decrease of ventricular pressure, and this mode of stimulation can be harnessed to promote cardiac repair.

Rationale: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. Objective: We investigated the role of myonectin in myocardial ischemic injury. Methods and Results: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. Conclusions: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.

Background Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular disease. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. This study investigated whether DATS modulates endothelial cell function, as well as revascularization processes in a mouse model of hind-limb ischemia.Methods and Results:Wild-type (WT), endothelial nitric oxide synthase-deficient (eNOS-KO) and Akt1-heterogenic deficient (Akt-Het) mice were subjected to unilateral hindlimb ischemia (HLI). DATS or a vehicle control was injected into the abdomen of mice for up to 10 days following HLI induction. Treatment with DATS enhanced blood flow recovery and capillary density in the ischemic limbs of WT mice. This was accompanied by a reduction in apoptotic activity and oxidative stress in the ischemic muscles. DATS also increased the phosphorylation of Akt and eNOS in ischemic muscles. In contrast to WT mice, DATS did not improve blood flow of eNOS-KO and Akt-Het mice. In cultured human umbilical vein endothelium cells, DATS decreased apoptotic activity and oxidative stress under hypoxic conditions, and stimulated the phosphorylation of Akt and eNOS. Inhibition of Akt or NOS signaling reversed DATS-stimulated eNOS phosphorylation and blocked the effects of DATS on apoptosis and oxidative stress. Conclusions These observations suggest that DATS promotes revascularization in response to HLI through its ability to stimulate the Akt-eNOS signaling pathway.

Rationale: Multiple progenitors derived from the heart and bone marrow (BM) have been used for cardiac repair. Despite this, not much is known about the molecular identity and relationship among these progenitors. To develop a robust stem cell therapy for the heart, it is critical to understand the molecular identity of the multiple cardiogenic progenitor cells. Objective: This study is the first report of high-throughput transcriptional profiling of cardiogenic progenitor cells carried out on an identical platform. Method and Results: Microarray-based transcriptional profiling was carried out for 3 cardiac (ckit + , Sca1 + , and side population) and 2 BM (ckit + and mesenchymal stem cell) progenitors, obtained from age- and sex-matched wild-type C57BL/6 mice. Analysis indicated that cardiac-derived ckit + population was very distinct from Sca1 + and side population cells in the downregulation of genes encoding for cell–cell and cell–matrix adhesion proteins, and in the upregulation of developmental genes. Significant enrichment of transcripts involved in DNA replication and repair was observed in BM-derived progenitors. The BM ckit + cells seemed to have the least correlation with the other progenitors, with enrichment of immature neutrophil–specific molecules. Conclusions: Our study indicates that cardiac ckit + cells represent the most primitive population in the rodent heart. Primitive cells of cardiac versus BM origin differ significantly with respect to stemness and cardiac lineage–specific genes, and molecules involved in DNA replication and repair. The detailed molecular profile of progenitors reported here will serve as a useful reference to determine the molecular identity of progenitors used in future preclinical and clinical studies.

Rationale: After cardiac injury, cardiac progenitor cells are acutely reduced and are replenished in part by regulated self-renewal and proliferation, which occurs through symmetric and asymmetric cellular division. Understanding the molecular cues controlling progenitor cell self-renewal and lineage commitment is critical for harnessing these cells for therapeutic regeneration. We previously have found that the cell surface ATP-binding cassette G-subfamily transporter 2 (Abcg2) influences the proliferation of cardiac side population (CSP) progenitor cells, but through unclear mechanisms. Objective: To determine the role of Abcg2 on cell cycle progression and mode of division in mouse CSP cells. Methods and Results: Herein, using CSP cells isolated from wild-type and Abcg2 knockout mice, we found that Abcg2 regulates G1-S cell cycle transition by fluorescence ubiquitination cell cycle indicators, cell cycle–focused gene expression arrays, and confocal live-cell fluorescent microscopy. Moreover, we found that modulation of cell cycle results in transition from symmetric to asymmetric cellular division in CSP cells lacking Abcg2. Conclusions: Abcg2 modulates CSP cell cycle progression and asymmetric cell division, establishing a mechanistic link between this surface transporter and cardiac progenitor cell function. Greater understanding of progenitor cell biology and, in particular, the regulation of resident progenitor cell homeostasis is vital for guiding the future development of cell-based therapies for cardiac regeneration.

Over the past decade, extensive work in animal models and humans has identified the presence of progenitor cells within the adult heart, capable of cardiomyogenic differentiation and likely contributors to cardiomyocyte turnover during normal development and disease. Among the identified cardiac progenitor cells, there is a distinct subpopulation, termed “side population” (SP) progenitor cells, which are isolated by their unique ability to efflux DNA binding dyes through ATP-binding cassette transporter. This review highlights the literature on the isolation, characterization and functional relevance of CSP cells. We review the initial discovery of cardiac SP (CSP) cells in adult myocardium, as well as their capacity for functional cardiomyogenic differentiation and role in cardiac regeneration following myocardial injury. Finally, we discuss recent advances in understanding the molecular regulators of cardiac SP cell proliferation and differentiation, as well as likely future areas of investigation required to realize the goal of effective cardiac regeneration.

We sought to determine the relationship between (99m)Tc-sestamibi washout and myocardial properties in hypertrophic cardiomyopathy (HCM) patients.Twenty-four HCM patients underwent biventricular cardiac catheterization, with a micromanometer-tipped catheter, both at rest and during atrial pacing, echocardiography and myocardial (99m)Tc-sestamibi scintigraphy at rest. The (99m)Tc-sestamibi washout rate (WR) was calculated using initial and delayed planar images. The HCM patients were divided into two groups as follows: Group A consisted of 13 patients showing (99m)Tc-sestamibi WR22.5%; group B of 11 patients showing (99m)Tc-sestamibi WR ≥ 22.5%. Significant correlations were observed between (99m)Tc-sestamibi WR and percentage changes in pressure half-time (T (1/2)), as well as those in the maximum first derivative LV pressure (LV dP/dt (max)) (r = .43, P = .033; r = -.63, P = .001). The percentage changes in LV dP/dt (max) and those in T (1/2) were significantly more reduced in group B than in group A (P.05). The biphasic force-frequency relation was more frequently observed in group B than in group A (82% vs. 18%).Increased (99m)Tc-sestamibi washout is associated with an impaired contractile reserve and prolonged relaxation, suggesting that myocardial (99m)Tc-sestamibi scintigraphy may be useful in noninvasively detecting the early impairment of myocardial function in HCM patients.

1. To date, few prognostic indicators for ambulatory patients with idiopathic dilated cardiomyopathy (IDCM) have been identified. The purpose of the present study was to investigate the relationship between the occurrence of dobutamine-induced mechanical alternans (MA) and prognosis in ambulatory patients with IDCM. 2. Left ventricular pressure was measured during right atrial pacing and after intravenous infusion of dobutamine at incremental doses in 90 ambulatory patients with IDCM in sinus rhythm. Endomyocardial biopsy specimens were also obtained for quantitative analysis of gene expression. The patients were followed up for a mean of 2.5 years. 3. Patients were classified into three groups: (i) 60 patients who exhibited neither pacing- nor dobutamine-induced MA (Group N); (ii) 20 patients who manifested only pacing-induced MA (Group P); and (iii) 10 patients who developed both pacing- and dobutamine-induced MA (Group D). The sarcoplasmic/endoplasmic reticulum calcium ATPase 2a:phospholamban mRNA ratio was significantly higher in Group D patients than in patients in Groups N or P. Multivariate analysis revealed that dobutamine-induced MA (odds ratio 4.05; 95% confidence interval 1.35-12.2) was a significant independent predictor of cardiac events. Cardiac event-free survival in Group D was significantly lower than in Groups N or P, as determined by Kaplan-Meier analysis (P=0.002). 4. The occurrence of dobutamine-induced MA is a potentially useful clinical predictor of poor prognosis in ambulatory patients with IDCM in sinus rhythm.

The favorable effects of the peroxisome proliferator-activated receptor-γ ligand pioglitazone on glucose metabolism are associated with an increase in the fat-derived hormone adiponectin in the bloodstream. A recent clinical trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events, demonstrated that pioglitazone improved cardiovascular outcomes in patients with type 2 diabetes mellitus. However, the functional role of adiponectin in cardioprotection by pioglitazone has not been examined experimentally. Here we investigated the effect of pioglitazone on angiotensin II (Ang II)–induced cardiac hypertrophy and assessed the potential contribution of adiponectin to the action of pioglitazone on the heart. Wild-type or adiponectin-deficient mice were treated with pioglitazone as food admixture at a concentration of 0.01% for 1 week followed by 2 weeks of infusion with Ang II at 3.2 mg/kg per day. Ang II infusion in wild-type mice resulted in exacerbated myocyte hypertrophy and increased interstitial fibrosis, which were accompanied by elevated phosphorylation of extracellular signal-regulated kinase and expression of transforming growth factor-β1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-β1 expression in response to Ang II. Pioglitazone also increased the plasma adiponectin level and phosphorylation of cardiac AMP-activated protein kinase in wild-type mice in the presence of Ang II. The suppressive effects of pioglitazone on Ang II–induced cardiac hypertrophy and fibrosis were diminished in adiponectin-deficient mice. Furthermore, pioglitazone had no effects on the phosphorylation of extracellular signal-regulated kinase and AMP-activated protein kinase in the Ang II–infused heart of adiponectin-deficient mice. These data provide direct evidence that pioglitazone protects against Ang II–induced pathological cardiac remodeling via an adiponectin-dependent mechanism.

Aims To examine the relation between mitochondrial dysfunction and myocardial contractile and relaxation reserves in hypertrophic cardiomyopathy (HCM). Methods and results Thirty HCM patients (LVEF ≥60%) underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial 99mTc-sestamibi scintigraphy at rest to calculate washout rate. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The HCM patients were divided into two groups—group A: normal force–frequency relation and a pressure half-time ( T 1/2) of

A 62 year-old female hemodialysis patient underwent parathyroidectomy to treat secondary hyperparathyroidism. On the preoperative assessment, the plasma levels of parathyroid hormone (PTH) and B-type natriuretic peptide (BNP) were elevated. Echocardiography showed reduced left ventricular (LV) contraction. Myocardial iodine-123-15-(p-iodophenyl)-3-(R,S) methylpentadecanoic acid (123I-BMIPP) scintigraphy showed moderately reduced tracer uptake in the postero-inferior area on single-photon emission computed tomography and decreased washout on the planar images. After parathyroidectomy, the plasma levels of PTH and BNP decreased, followed by improvement in LV contraction. Myocardial 123I-BMIPP scintigraphy revealed that the washout on planar images had increased, which suggests that myocardial 123I-BMIPP scintigraphy is useful for estimating the effect of parathyroidectomy on cardiac function. (Circ J 2009; 73: 1956-1960)

Objectives We performed dobutamine stress testing for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy (DCM). Background Catecholamine sensitivity is reduced in failing hearts as a result of myocardial abnormalities in the beta-adrenergic receptor signaling pathway. However, little is known about adrenergic myocardial contractile reserve in asymptomatic or mildly symptomatic patients with DCM. Methods The maximal first derivative of left ventricular pressure (LV dP/dtmax) was determined during infusion of dobutamine (10 μg kg−1 min−1) in 46 asymptomatic or mildly symptomatic (New York Heart Association functional class I or II) patients with DCM. The expression of messenger ribonucleic acid (mRNA) for contractile regulatory proteins in endomyocardial biopsy specimens was quantified by reverse transcription and real-time polymerase chain reaction analysis. Plasma norepinephrine levels were measured in all patients and [123I]metaiodobenzylguanidine (MIBG) scintigraphy performed. Results Patients were classified into 3 groups based on the percentage increase in LV dP/dtmax induced by dobutamine (ΔLV dP/dtmax) and on LV ejection fraction (LVEF) at baseline: group I (n = 18): ΔLV dP/dtmax >100% and LVEF >25%; group IIa (n = 17): ΔLV dP/dtmax ≤100% and LVEF > 25%; and group IIb (n = 11): ΔLV dP/dtmax ≤100% and LVEF ≤25%. The amounts of beta1-adrenergic receptor, sarcoplasmic reticulum Ca2+-adenosine triphosphatase, and phospholamban mRNA were significantly smaller in groups IIa and IIb than in group I. The plasma norepinephrine level was increased and the delayed heart/mediastinum count ratio in MIBG scintigraphy was decreased in both groups IIa and IIb. Conclusions Dobutamine stress testing is a useful diagnostic tool for identifying reduced adrenergic myocardial contractile reserve related to altered myocardial expression of beta1-adrenergic receptor, sarcoplasmic reticulum Ca2+-adenosine triphosphatase, and phospholamban genes even in asymptomatic or mildly symptomatic patients with DCM.

Rationale: In response to injury, the rodent heart is capable of virtually full regeneration via cardiomyocyte proliferation early in life. This regenerative capacity, however, is diminished as early as 1 week postnatal and remains lost in adulthood. The mechanisms that dictate postinjury cardiomyocyte proliferation early in life remain unclear. Objective: To delineate the role of miR-34a, a regulator of age-associated physiology, in regulating cardiac regeneration secondary to myocardial infarction (MI) in neonatal and adult mouse hearts. Methods and Results: Cardiac injury was induced in neonatal and adult hearts through experimental MI via coronary ligation. Adult hearts demonstrated overt cardiac structural and functional remodeling, whereas neonatal hearts maintained full regenerative capacity and cardiomyocyte proliferation and recovered to normal levels within 1-week time. As early as 1 week postnatal, miR-34a expression was found to have increased and was maintained at high levels throughout the lifespan. Intriguingly, 7 days after MI, miR-34a levels further increased in the adult but not neonatal hearts. Delivery of a miR-34a mimic to neonatal hearts prohibited both cardiomyocyte proliferation and subsequent cardiac recovery post MI. Conversely, locked nucleic acid–based anti–miR-34a treatment diminished post-MI miR-34a upregulation in adult hearts and significantly improved post-MI remodeling. In isolated cardiomyocytes, we found that miR-34a directly regulated cell cycle activity and death via modulation of its targets, including Bcl2, Cyclin D1, and Sirt1. Conclusions: miR-34a is a critical regulator of cardiac repair and regeneration post MI in neonatal hearts. Modulation of miR-34a may be harnessed for cardiac repair in adult myocardium.

Background The physiological mechanism of the increase in the electrocardiographic (ECG) R-wave voltage after revascularization in patients with acute myocardial infarction (MI) needs to be elucidated. Methods and Results One hundred and thirty-eight MI patients (83: anterior MI, 45: inferior MI, 10: lateral MI) underwent ECG and echocardiography in both the acute and subacute phases after emergency revascularization, as well as a resting thallium-201/iodine-123 15-p-iodophenyl-3-(R,S)-methyl pentadecanoic acid myocardial scintigraphy in the acute phase. The total sum of the R-wave voltage (ΣR) was calculated over multiple leads on ECG for each infarcted lesion. Scintigraphic defect on each tracer was expressed as the percentage (%) defect of the total left ventricular (LV) myocardium. The % defect-discordance on both images in the acute phase and the % increase in ΣR and the absolute increase in LV ejection fraction from the acute to the subacute phase (ΔEF) were also calculated. The ΣR in the subacute phase was significantly greater than that in the acute phase (p

Echocardiography is a widely accessible imaging modality that is commonly used to noninvasively characterize and quantify changes in cardiac structure and function. Ultrasonic assessments of cardiac tissue can include analyses of backscatter signal intensity within a given region of interest. Previously established techniques have relied predominantly on the integrated or mean value of backscatter signal intensities, which may be susceptible to variability from aliased data from low frame rates and time delays for algorithms based on cyclic variation. Herein, we describe an ultrasound-based imaging algorithm that extends from previous methods, can be applied to a single image frame and accounts for the full distribution of signal intensity values derived from a given myocardial sample. When applied to representative mouse and human imaging data, the algorithm distinguishes between subjects with and without exposure to chronic afterload resistance. The algorithm offers an enhanced surrogate measure of myocardial microstructure and can be performed using open-access image analysis software.

Cysteine proteases play important roles in pathobiology. Here we reveal that cathepsin K (CatK) has a role in ischaemia-induced neovascularization. Femoral artery ligation-induced ischaemia in mice increases CatK expression and activity, and CatK-deficient mice show impaired functional recovery following hindlimb ischaemia. CatK deficiency reduces the levels of cleaved Notch1 (c-Notch1), Hes1 Hey1, Hey2, vascular endothelial growth factor, Flt-1 and phospho-Akt proteins of the ischaemic muscles. In endothelial cells, silencing of CatK mimicked, whereas CatK overexpression enhanced, the levels of c-Notch1 and the expression of Notch downstream signalling molecules, suggesting CatK contributes to Notch1 processing and activates downstream signalling. Moreover, CatK knockdown leads to defective endothelial cell invasion, proliferation and tube formation, and CatK deficiency is associated with decreased circulating endothelial progenitor cells-like CD31(+)/c-Kit(+) cells in mice following hindlimb ischaemia. Transplantation of bone marrow-derived mononuclear cells from CatK(+/+) mice restores the impairment of neovascularization in CatK(-/-) mice. We conclude that CatK may be a potential therapeutic target for ischaemic disease.

Investigation of cardiac progenitor cell proliferation and differentiation is essential for both the basic understanding of progenitor cell biology as well as the development of cellular therapeutics for tissue regeneration. Herein, we describe techniques used for the analysis of CSP cell proliferation, cell cycle status, and cardiomyogenic differentiation.

Investigation of cardiac progenitor cell proliferation and differentiation is essential for both the basic understanding of progenitor cell biology as well as the development of cellular therapeutics for tissue regeneration. Herein, we describe techniques used for the analysis of CSP cell proliferation, cell cycle status, and cardiomyogenic differentiation.

ObjectivesThis study investigated whether the technitium-99m sestamibi (MIBI) washout rate (WR) would predict mitochondrial damage and myocardial dysfunction in patients with dilated cardiomyopathy (DCM).BackgroundMyocardial mitochondrial damage reduces adenosine triphosphate production, resulting in myocardial dysfunction. Increased myocardial 99mTc-MIBI washout is reportedly caused by mitochondrial dysfunction.MethodsTwenty DCM patients (New York Heart Association functional class I–III) underwent myocardial 99mTc-MIBI scintigraphy and cardiac catheterization. Myocardial MIBI uptake was quantified as an early and delayed heart-to-mediastinum ratio, and WR was calculated. Maximum first derivative of left ventricular (LV) pressure (LV dP/dtmax) (an index of myocardial contractility) and LV pressure half-time (T1/2) (an index of myocardial relaxation) were calculated by the left ventricular pressure curve at baseline and during dobutamine infusion (15 μg/kg/min at maximum). Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The patients were divided into two groups as follows: 1) group A of 10 patients showing a WR ≤24.3% (median value) and 2) group B of 10 patients showing a WR >24.3%.ResultsWR was significantly correlated with the percentage changes in LV dP/dtmax (%LV dP/dtmax) (r: −0.59; p = 0.01) and T1/2 (r: −0.57; p = 0.03) from baseline to peak dobutamine stress. The %LV dP/dtmax was significantly greater in group B than in group A. The abundance of mRNAs for mitochondrial electron transport–related enzymes was more significantly reduced in group B than in group A. Electron microscopy revealed significant correlations between WR and the severity of mitochondrial damage (r: 0.88; p = 0.048) and glycogen accumulation (r: 0.90; p = 0.044).ConclusionsIncreased 99mTc-MIBI washout may predict mitochondrial dysfunction and the impairment of myocardial contractile and relaxation reserves during dobutamine stress in DCM patients.

Background: Increased hemodynamic stress induces left ventricular hypertrophy followed by heart failure. Accumulating evidence suggests that the adult mammalian heart possess regeneration ability through the action of resident stem/progenitor cell. However, the effects of hemodynamic fluctuation on cardiac progenitor cell proliferation and cardiac repair remain unknown. Results: Proliferation of Cardiac Side Population (CSP) cells and cardiomyocytes was evaluated in experimental models of Ascending Aortic Constriction (AAC)-induced left ventricular hypertrophy (LVH) in mice, over a period of seven weeks. Continuous AAC caused LVH while increasing the number of BrdU + CSP cells (one week post-AAC) and the amount of BrdU + cardiomyocytes (seven weeks post-AAC). To evaluate the effects of pressure fluctuation on CSP cell and cardiomyocyte proliferation we generated another group (de-AAC) in which the constriction was removed one week post-AAC. Interestingly, restoration of cardiac pressure further increased the proliferative capacity of CSP cells and cardiomyocytes. Conclusion: Our data show that restoration of hemodynamic stress confers favorable effects on cardiac repair through increase proliferation of CSP cells and cardiomyocytes. Thus, the hemodynamic state of the heart might be related to CSP cell proliferation and cardiomyogenesis.

Background— Adiponectin plays a protective role in the development of obesity-linked disorders. We demonstrated that adiponectin exerts beneficial actions on acute ischemic injury in mice hearts. However, the effects of adiponectin treatment in large animals and its feasibility in clinical practice have not been investigated. This study investigated the effects of intracoronary administration of adiponectin on myocardial ischemia-reperfusion (I/R) injury in pigs. Methods and Results— The left anterior descending coronary artery was occluded in pigs for 45 minutes and then reperfused for 24 hours. Recombinant adiponectin protein was given as a bolus intracoronary injection during ischemia. Cardiac functional parameters were measured by a manometer-tipped catheter. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining. Tumor necrosis factor-α and interleukin-10 transcripts were analyzed by real-time polymerase chain reaction. Serum levels of derivatives of reactive oxygen metabolites and biological antioxidant potential were measured. Adiponectin protein was determined by immunohistochemical and Western blot analyses. Intracoronary administration of adiponectin protein led to a reduction in myocardial infarct size and improvement of left ventricular function in pigs after I/R. Injected adiponectin protein accumulated in the I/R-injured heart. Adiponectin treatment resulted in decreased tumor necrosis factor-α and increased interleukin-10 mRNA levels in the myocardium after I/R. Adiponectin-treated pigs had reduced apoptotic activity in the I/R-injured heart and showed increased biological antioxidant potential levels and decreased derivatives of reactive oxygen metabolite levels in the blood stream after I/R. Conclusions— These data suggest that adiponectin protects against I/R injury in a preclinical pig model through its ability to suppress inflammation, apoptosis, and oxidative stress. Administration of intracoronary adiponectin could be a useful adjunctive therapy for acute myocardial infarction.

Background Adiponectin is an adipose-derived plasma protein that exhibits beneficial actions on the heart. Recently, it was shown that adiponectin levels were elevated in patients with systolic heart failure. Objective To investigate the association between adiponectin levels and left ventricular (LV) diastolic function in patients with hypertrophic cardiomyopathy (HCM), characterised by diastolic dysfunction. Methods Twenty-six patients with HCM showing LV ejection fraction of >60% were enrolled. LV pressure half-time (T 1/2 ) was measured as an index of myocardial relaxation. Patients were divided into two groups on the basis of baseline T 1/2 (group A: T 1/2 1/2 ≥ 35 ms). Blood samples were simultaneously collected from the coronary sinus (CS) and aortic root (Ao) as well as the peripheral vein (PV) for measurement of plasma adiponectin levels. Results Plasma adiponectin levels were significantly higher in group B than in group A. Adiponectin levels in the PV were positively correlated with the baseline T 1/2 in patients with HCM. The transcardiac gradient of adiponectin as calculated by the Ao−CS difference was significantly higher in group A than in group B. The transcardiac gradient of adiponectin also inversely correlated with the baseline T 1/2 and adiponectin levels in PV in patients with HCM. The expression of AdipoR1 but not AdipoR2 in the heart decreased in group B. The baseline T 1/2 was negatively associated with AdipoR1 expression in patients with HCM. Conclusions These data document that adiponectin is an indicator of LV diastolic dysfunction in patients with HCM.

To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)].DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls.Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin.The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.

Impairment of myocardial relaxation reserve and subsequent impairment of contractile reserve constitute a primary manifestation of hypertrophic cardiomyopathy (HCM). Although these reserves reflect energy-consuming processes, the relation between their impairment and mitochondrial function in HCM has remained unclear. Thirty HCM patients underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial 99m Tc-sestamibi (MIBI) scintigraphy at rest. MIBI washout rate (WR) was calculated from initial and delayed left ventricular (LV) planar images. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopic observation. The HCM patients were divided into two groups: Group A consisted of 15 patients showing a normal force-frequency relation (FFR) and pressure half-time ( T 1/2 ) of T 1/2 of ≥30 ms. The MIBI WR was significantly correlated with T 1/2 at the peak pacing rate for all patients ( r = 0.74, P

he incidence of coronary artery disease (CAD) is increasing in Japan and consequently, the morbidity of CAD has become a major concern of public health, with an increase in the morbidity and mortality caused by ischemic heart failure. The effectiveness of coronary artery bypass surgery or percutaneous coronary intervention (PCI) has been established in terms of the improvement in survival and the reduction of hospitalizations for the management of ischemic heart failure in patients with severe CAD. 1,2 However, despite recent improvements in these therapeutic strategies, there are a number of patients who can not receive complete revascularization because of very severe atherosclerotic lesions or total arterial occlusion. These patients suffer from typical effort angina pectoris and left ventricular (LV) dysfunction. Several recent experimental and clinical studies have suggested that intramyocardial injection of autologous bone marrow-derived progenitor cells induces neovascularization in the ischemic myocardium and therefore improves myocardial perfusion, resulting in restored LV function3‐6 However, to develop this treatment strategy as a new therapeutic modality for CAD, its safety, feasibility, and effectiveness must be confirmed. Accordingly, the present study was designed to address the safety and feasibility of intramyocardial injections of autologous bone marrow mononuclear cells (ABMMCs), and to test the hypothesis that intramyocardial injection of ABMMCs in patients with CAD may promote neovascularization and contribute to the improvement of the LV global and/or regional function.

Small animal models of afterload stress have contributed much to our present understanding of the progression from hypertension to heart failure. High-sensitivity methods for phenotyping cardiac function in vivo, particular in the setting of compensated cardiac hypertrophy, may add new information regarding alterations in cardiac performance that can occur even during the earliest stages of exposure to pressure overload. We have developed an echocardiographic analytical method, based on speckle-tracking-based strain analyses, and used this tool to rapidly phenotype cardiac changes resulting from afterload stress in a small animal model. Adult mice were subjected to ascending aortic constriction, with and without subsequent reversal of the pressure gradient. In this model of compensated hypertrophic cardiac remodeling, conventional echocardiographic measurements did not detect changes in left ventricular (LV) function at the early time points examined. Strain analyses, however, revealed a decrement in basal longitudinal myofiber shortening that was induced by aortic constriction and improved following relief of the pressure gradient. Furthermore, we observed that pressure overload resulted in LV segmental dyssynchrony that was attenuated with return of the afterload to baseline levels. Herein, we describe the use of echocardiographic strain analyses for cardiac phenotyping in a mouse model of pressure overload. This method provides evidence of dyssynchrony and regional myocardial dysfunction that occurs early with compensatory hypertrophy, and improves following relief of aortic constriction. Importantly, these findings illustrate the utility of a rapid, non-invasive method for characterizing early cardiac dysfunction, not detectable by conventional echocardiography, following afterload stress.