Historically, revascularization of ischemic tissue was believed to occur through the migration and proliferation of endothelial cells in nearby tissues; however, evidence accumulated in recent years indicates that a subpopulation of adult, peripheral-blood cells, collectively referred to as endothelial progenitor cells (EPCs1), can differentiate into mature endothelial cells. After ischemic insult, EPCs are believed to home to sites of neovascularization, where they contribute to vascular regeneration by forming a structural component of capillaries and by secreting angiogenic factors; new evidence indicates that EPCs can also differentiate into cardiomyocytes and smooth-muscle cells. These insights into the molecular and cellular processes of tissue formation suggest that cardiac function may be preserved after myocardial infarction by transplanting EPCs into ischemic heart tissue, thereby enhancing vascular and myocardial recovery. This therapeutic strategy has been effective in animal models of ischemic disorders, and results from randomized clinical trials suggest that cellbased strategies may be safe and feasible for treatment of myocardial infarction in humans and have provided early evidence of efficacy. However, the scarcity of EPCs in the peripheral blood and evidence that several disease states reduce EPC number and/or function have prompted the development of several strategies to overcome these limitations, such as the administration of genetically modified EPCs that overexpress angiogenic growth factors. To optimize therapeutic outcomes, researchers must continue to refine methods of EPC purification, expansion, and administration, and to develop techniques that overcome the intrinsic scarcity and phenotypic deficiencies of EPCs.

We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC-mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.angiogenesis | stem cell | vasculogenesis

Aims To describe the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in hospitalized elderly patients with heart failure. Methods and results The FRAGILE‐HF study was a prospective multicentre cohort study enrolling consecutive hospitalized patients with heart failure aged ≥65 years. The study objectives were to examine the prevalence, overlap, and prognostic implications of the coexistence of multiple frailty domains. Physical frailty, social frailty, and cognitive dysfunction were evaluated by the Fried phenotype model, Makizako's 5 items, and Mini‐Cog, respectively. The primary study outcome was the combined endpoint of heart failure rehospitalization and all‐cause death within 1 year. Among 1180 enrolled hospitalized patients (median age, 81 years; 57.4% male), physical frailty, social frailty, and cognitive dysfunction were identified in 56.1%, 66.4%, and 37.1% of the patients, respectively. The number of identified frailty domains was 0, 1, 2, and 3 in 13.5%, 31.4%, 36.9%, and 18.2% of the patients, respectively. During follow‐up, the combined endpoint occurred in 383 patients. Adjusted hazard ratios for 1, 2, and 3 domains, with 0 domains as the reference, were 1.38 [95% confidence interval (CI) 0.89–2.13; P = 0.15], 1.60 (95% CI 1.04–2.46; P = 0.034), and 2.04 (95% CI 1.28–3.24; P = 0.003), respectively. Incorporating the number of frailty domains into the pre‐existing risk model yielded a 22.0% (95% CI 0.087–0.352; P = 0.001) net reclassification improvement for the primary outcome. Conclusions The coexistence of multiple frailty domains is prevalent in hospitalized elderly patients with heart failure. Holistic assessment of multi‐domain frailty provides additive value to known prognostic factors.

AimsLoop diuretics are first‐line medications for congestive heart failure (CHF); however, they are associated with serious adverse effects, including decreased renal function, and sympathetic nervous and renin–angiotensin system activation. We tested whether tolvaptan, a vasopressin V2‐receptor antagonist, could reduce unfavourable furosemide‐induced effects during CHF treatment.Methods and resultsSixty patients emergently hospitalized owing to CHF‐induced dyspnea were randomly assigned to receive either 40 mg intravenous furosemide daily or 7.5 mg oral tolvaptan for 5 days after admission. Both groups also received intravenous carperitide and canrenoate potassium. As results, baseline patient characteristics were similar between the furosemide (n = 30) and the tolvaptan (n = 30) groups, with no significant difference in 5 day urine volume or fluid balance. Brain natriuretic peptide and body weight improvements were similar between groups. However, serum creatinine (Cr) level did not increase, and the incidence of worsening renal function was significantly lower in the tolvaptan group. Consequently, the Cr increase to gain 1000 mL urine was 2.5‐fold lower in the tolvaptan group. Furthermore, the blood urea nitrogen (BUN)/Cr ratio significantly decreased in the tolvaptan group, suggesting that renal perfusion was preserved, and urea reuptake and passive water reabsorption were suppressed following tolvaptan treatment. Although catecholamine improvements after treatment were not significantly different, plasma renin activity was enhanced in the furosemide group.ConclusionsAs compared with furosemide, tolvaptan in patients with acute heart failure is associated with comparable decongestion, better preservation of renal function and less activation of renin–angiotensin system. (UMIN 000014134).

Aims Sarcopenia, one of the extracardiac factors for reduced functional capacity and poor outcome in heart failure (HF), may act differently between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). We sought to investigate the impact of sarcopenia on mortality in HFpEF and HFrEF. Methods and results We performed a post hoc analysis of a multicentre prospective cohort study, including 942 consecutive older (age ≥65 years) hospitalized patients: 475 with HFpEF (ejection fraction ≥45%, age 81 ± 7 years, 48.8% men) and 467 with HFrEF (ejection fraction <45%, age 78 ± 8 years, 68.1% men). Sarcopenia was diagnosed according to the international criteria incorporating muscle strength (handgrip strength), physical performance (gait speed), and skeletal muscle mass (appendicular skeletal mass). The HFpEF group consisted of fewer patients with low appendicular skeletal muscle mass index measured using bioelectrical impedance analysis [<7.0 kg/m2 (men) and <5.7 (women); 22.1% vs. 31.0%, P = 0.003], and more patients with low handgrip strength [<26 kg (men) and <18 (women); 67.8% vs. 55.5%, P < 0.001], and slow gait speed [<0.8 m/s (both sexes); 54.5% vs. 41.1%, P < 0.001] than the HFrEF group, resulting in a similar sarcopenia prevalence in the two groups (18.1% vs. 21.6%, P = 0.191). Sarcopenia was an independent predictor of 1-year mortality in both HFpEF and HFrEF [hazard ratio (95% confidence interval) 2.42 (1.36–4.32), P = 0.003 in HFpEF and 2.02 (1.08–3.75), P = 0.027 in HFrEF; P for interaction = 0.666] after adjustment for other predictors. Conclusions In older patients with HF, sarcopenia contributes to mortality similarly in HFpEF and HFrEF.