Icing after skeletal muscle injury with necrosis in a small fraction of myofibers limits inducible nitric oxide synthase-expressing macrophage invasion and facilitates muscle regeneration.

Growing evidence from animal experiments suggests that icing after skeletal muscle injury is harmful to muscle regeneration. However, these previous experimental models yielded massive necrotic myofibers, whereas muscle injury with necrosis in a small myofiber fraction (<10%) frequently occurs in human sports activities. Although macrophages play a proreparative role during muscle regeneration, they exert a cytotoxic effect on muscle cells through an inducible nitric oxide synthase (iNOS)-mediated mechanism. In this study, we established an animal injury model with necrosis limited to a small myofiber fraction and investigated the effect of icing on muscle regeneration with a focus on macrophage-related events. Icing after muscle injury of this model resulted in an enlarged size of regenerating myofibers compared with those in untreated animals. During the regenerative process, icing attenuated the accumulation of iNOS-expressing macrophages, suppressed iNOS expression in the whole damaged muscle, and limited the expansion of the injured myofiber area. In addition, icing increased the ratio of M2 macrophages within the injured site at an earlier time point than that in untreated animals. Following these phenomena in icing-treated muscle regeneration, an early accumulation of activated satellite cells within the damaged/regenerating area occurred. The expression level of myogenic regulatory factors, such as MyoD and myogenin, was not affected by icing. Taken together, our results suggest that icing after muscle injury with necrosis limited to a small fraction of myofibers facilitates muscle regeneration by attenuating iNOS-expressing macrophage invasion, limiting muscle damage expansion, and accelerating the accumulation of myogenic cells which form regenerating myofibers.

Icing after skeletal muscle injury decreases M1 macrophage accumulation and TNF-α expression during the early phase of muscle regeneration in rats.

Following skeletal muscle injury, both myogenic and immune cells interact closely during the regenerative process. Although icing is still a common acute treatment for sports-related skeletal muscle injuries, icing after muscle injury has been shown to disrupt macrophage accumulation and impair muscle regeneration in animal models. However, it remains unknown whether icing shortly after injury affects macrophage-related phenomena during the early stages of muscle regeneration. Therefore, we focused on the distribution of M1/M2 macrophages and cytokines expressed predominantly by macrophages during the early stages of muscle regeneration after muscle crush injury. Icing resulted in a decrease, not retardation, in the accumulation of M1 macrophages, but not M2 macrophages, in injured muscles. Consistent with the decrease in M1 macrophage accumulation, icing led to a reduction, instead of delay, in the level of tumor necrosis factor-α (TNF-α) expression. Additionally, at subsequent timepoints, icing decreased the number of myogenic precursor cells in the regenerating area and the size of centrally nucleated regenerating myofibers. Together, our findings suggest that icing after acute muscle damage by crushing disturbs muscle regeneration through hindering tM1 macrophage-related phenomena.

Icing after eccentric contraction-induced muscle damage perturbs the disappearance of necrotic muscle fibers and phenotypic dynamics of macrophages in mice.

Icing is still one of the most common treatments to acute skeletal muscle damage in sports medicine. However, previous studies using rodents reported the detrimental effect of icing on muscle regeneration following injury. This study aimed to elucidate the critical factors governing the impairment of muscle regeneration by icing with a murine model of eccentric contraction-induced muscle damage by electrical stimulation. Because of icing after muscle injury, the infiltration of polynuclear and mononuclear cells into necrotic muscle fibers was retarded and attenuated, leading to the persistent presence of necrotic cellular debris. These phenomena coincided with the delayed emergence and sustained accumulation of Pax7+ myogenic cells within the regenerating area. In addition, due to icing, delayed and/or sustained infiltration of M1 macrophages was noted in accordance with the perturbed expression patterns of inflammation-related factors, including tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The key myogenic regulatory factors (i.e., MyoD and myogenin) involved in the activation/proliferation and differentiation of myogenic precursor cells were not altered by icing during the regenerative process. A detailed analysis of regenerating myofibers by size distribution at day 14 after muscle damage showed that the ratio of small regenerating fibers to total regenerating fibers was higher in icing-treated animals than in untreated animals. These findings suggest that icing following muscle damage blunts the efficiency of muscle regeneration by perturbing the removal of necrotic myofibers and phenotypic dynamics of macrophages rather than affecting myogenic factors.NEW & NOTEWORTHY Icing blunted the muscle regeneration by perturbing the infiltration of polynuclear and mononuclear cells into necrotic myofibers and the phenotypic dynamics of macrophages rather than affecting the myogenic regulatory factors. Because of icing, the disappearance of necrotic muscle debris was retarded, coinciding with the delayed emergence and sustained accumulation of Pax7+ cells within the regenerating area. The expression patterns of TNF-α and IL-10 were altered by icing consistent with the perturbation of the macrophage phenotype.

Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension.

OBJECTIVE: We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). METHODS: Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. RESULTS: The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. CONCLUSION: Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.

Associations between lipid profiles and MACE in hemodialysis patients with percutaneous coronary intervention: from the FU-Registry.

BACKGROUND: It is well known that percutaneous coronary intervention (PCI) in hemodialysis (HD) patients is associated with higher rates of in-stent restenosis and major adverse cardiovascular events (MACE) compared to that in non-HD patients, even if the target value in cholesterol management is achieved. METHODS: To evaluate the factors that are associated with MACE in HD patients, we selected 142 HD patients (164 lesions) without acute coronary syndrome (ACS) from 2148 patients (2568 lesions) who underwent PCI in our database of the FU-Registry [UMIN000005679, Fukuoka University Hospital EC/IRB:10-1-08(09-105)], and compared 52 patients (53 lesions) with MACE [MACE(+)] to 90 patients (111 lesions) without MACE [MACE(-)]. RESULTS: Total cholesterol (TC: 150±30mg/dL vs 166±39mg/dL, p<0.05) and high-density lipoprotein cholesterol (HDL-C: 40.1±14.7mg/dL vs 47.8±13.5mg/dL, p<0.01) levels were significantly lower in the MACE(+) group at follow-up. No significant differences were observed in other parameters, including triglyceride, low-density lipoprotein cholesterol (LDL-C; LDL-C/HDL-C ratio, and % changes in HDL-C, non-HDL-C, LDL-C), and hemoglobin A1c (US National Glycohemoglobin Standardization Program) between before and after PCI. TC, LDL-C, and non-HDL-C at the time of PCI and TC, and HDL-C at the 9-month follow-up were negatively correlated with MACE, while body mass index (BMI) [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.68-0.95)], prior coronary artery bypass graft (CABG) (OR: 3.89; 95%CI: 1.29-12.6), and insulin use (OR: 3.17; 95%CI: 1.23-8.55) were strongly correlated with MACE in a multivariate analysis. CONCLUSION: BMI, CABG, and insulin use, but not LDL-C, are independent predictors of MACE in HD patients, suggesting that the application of lipid management for non-HD patients to HD patients at the time of PCI may not necessarily be beneficial for medium-term clinical outcomes.

Efficacy and safety of a single-pill fixed-dose combination of high-dose telmisartan/hydrochlorothiazide in patients with uncontrolled hypertension.

OBJECTIVE: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. METHODS: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. RESULTS: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. CONCLUSION: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.