Citations

Cell therapy is a potential therapeutic method for cerebral ischemia, which remains a serious problem. In the search for more effective therapeutic methods, many kinds of stem cells from various tissues have been developed and tested as candidate therapeutic agents. Among them, human umbilical cord blood (hUCB)‐derived mesenchymal stem cells (MSCs) are widely used for cell therapy because of their genetic flexibility. To confirm that they are effective and understand how they affect ischemic neural cells, hUCB‐MSCs were directly administered ipsilaterally into an ischemic zone induced by middle cerebral artery occlusion (MCAO). We found that the neurobehavioral performance of the hUCB‐MSC group was significantly improved compared with that of the vehicle‐injected control group. The infarct was also remarkably smaller in the hUCB‐MSC group. Additionally, hUCB‐MSC transplantation resulted in a greater number of newly generated cells and angiogenic and tissue repair factors and a lower number of inflammatory events in the penumbra zone. To determine why these events occurred, hUCB‐MSCs were assayed under hypoxic and normoxic conditions in vitro. The results showed that hUCB‐MSCs exhibit higher expression levels of thrombospondin1, pantraxin3, and vascular endothelial growth factor under hypoxic conditions than under normoxic conditions. These results were found to be correlated with our in vivo immunofluorescent staining results. On the basis of these findings, we suggest that hUCB‐MSCs may have a beneficial effect on cerebral ischemia, especially through angiogenesis, neurogenesis, and anti‐inflammatory effects, and thus could be used as a therapeutic agent to treat neurological disorders such as cerebral ischemia. © 2015 Wiley Periodicals, Inc.

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max /IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

Background— Left atrial (LA) structure and function are altered in most heart failure (HF) patients, but there may be fundamental differences in LA properties between HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods and Results— One hundred ninety-eight HF patients (51% HFpEF, New York Heart Association 3.1±0.7) and 40 HF-free controls underwent catheterization, echocardiography, and follow-up. Compared with controls, HF patients had larger and more dysfunctional left atria. At identical mean LA pressure (20 versus 20 mm Hg; P =0.9), HFrEF patients had larger LA volumes (LA volume index 50 versus 41 mL/m 2 ; P <0.001), whereas HFpEF patients had higher LA peak pressures, lower LA minimal pressures, higher LA stiffness (0.79 versus 0.48 mm Hg/mL; P <0.001), greater LA pulsatility (19 versus 13 mm Hg; P <0.001), and higher wall stress variations. Despite smaller LA volumes, better function, and less mitral regurgitation, HFpEF patients had more atrial fibrillation (42 versus 26%; P =0.02). LA dysfunction was associated with increased pulmonary vascular resistance and right ventricular dysfunction in both HF phenotypes. After a median follow-up of 350 days, 31 HFpEF and 28 HFrEF patients died. LA function (total LA EF) was associated with lower mortality in HFpEF (hazard ratio 0.43; 95% confidence interval, 0.2–0.9; P <0.05), but not in HFrEF. Conclusions— HFrEF is characterized by greater eccentric LA remodeling, whereas HFpEF by increased LA stiffness, which might contribute to greater atrial fibrillation burden. LA function is associated with pulmonary vascular disease and right HF in both HF phenotypes, but is associated with outcome more closely in HFpEF, supporting efforts to improve LA function in this cohort.