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The article discusses the procedure of autogenous bone-cartilage transplantation. Among the measures for cartilage repair include marrow stimulation, correction osteotomy and chondrocyte or stem cell transplantation. An overview of the indications and contraindications of autogenous bone-cartilage transplantation is provided, along with technical data about osteonecrosis of the knee, and complications and rehabilitation of the procedure.

Introduction: It has not been yet adequately addressed whether the addition of the non-statin low-density lipoprotein cholesterol (LDL-C) lowering agents on top of statins has the same magnitude of risk reduction in the cardiovascular events as compared with more intensive statin therapy. Methods: We performed a systematic review and meta-analysis of randomized controlled trials comparing the more- versus less-intensive lipid-lowering therapy (LLT) on clinical outcomes in patients with atherosclerotic cardiovascular risk. The primary outcome measure was major adverse cardiovascular events (MACE), which was equivalent to the composite of coronary heart death, non-fatal myocardial infarction, stroke, or coronary revascularization. Results: We included 23 studies involving 133,037 patients (more-intensive LLT: 67,691 patients, and less-intensive LLT: 65,346 patients). We evaluated 3 types of more- versus less-intensive LLT, including more- versus less-statins (12 studies, 57,672 patients), combination therapy of ezetimibe versus statins alone (4 studies, 20,688 patients) or a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors with statins versus statins alone (7 studies, 54,677 patients). The risk for MACE was significantly lower in the more-intensive LLT group compared with the less-intensive LLT group in the entire study population (odds ratio [OR] 0.84, 95% confidence interval [CI] [0.79-0.88], P<0.001), and in all the 3 categories of more intensive LLT strategies (more-intensive statin therapy: OR 0.83, 95%CI [0.76-0.90], P<0.001, ezetimibe: OR 0.90, 95%CI [0.85-0.96], P<0.001, and PCSK9 inhibitors: OR 0.81, 95%CI [0.73-0.90], P<0.001) with numerically greater relative risk reduction by more-intensive statin therapy and PCSK9 inhibitors than by ezetimibe. Relative risk reduction for MACE per 20mg/dl LDL-C reduction was also different across the 3 types of more-intensive LLT (more-intensive statin therapy: 17.4%, ezetimibe: 11.0%, and PCSK9 inhibitors: 6.6%). Conclusions: In this meta-analysis of 23 randomized controlled trials, more-intensive LLT as compared with less-intensive LLT was associated with significant risk reduction for MACE in the entire study population and in all the 3 categories of more-intensive LLT such as more-intensive statin therapy, ezetimibe, and PCSK9 inhibitors. However, overall relative risk reduction for MACE, as well as relative risk reduction for MACE per 20mg/dl LDL-C reduction were different across the 3 types of more-intensive LLT. [ABSTRACT FROM AUTHOR]

Introduction: Recently, we reported continuous elevation in the pro B-type natriuretic peptide (BNP) to total BNP ratio during hospitalization in patients with severe acute heart failure (HF). On the other hand, although atrial natriuretic peptide (ANP) is known to elevate acutely after cardiac stress, little is unknown about the clinical significance of proANP measurement on admission in patients with acute HF. Hypothesis: We hypothesized that the elevations in pro-natriuretic peptide (NP) family on admission have a greater predictability than BNP level measured by the conventional assay. Methods: We prospectively evaluated plasma levels of proANP, proBNP, and BNP, in 173 patients with acute HF (NYHA3-4) on admission by using our recently developed chemiluminescence enzyme immunoassay for each NP. Results: During follow-up (median: 469 days), composite clinical events (all causes of death or re-hospitalization for HF) occurred in 67 patients (38.7 %). Interestingly, the association with the frequency of composite events was strongest for proANP (hazard ratio: 1.18, 95% CI: 1.03, 1.34, p=0.017), although only borderline significances were found in the other two NPs on admission (proBNP, p=0.058; BNP, p=0.101). Then, we analyzed the clinical features of the patients with higher proANP/BNP ratio. The patients with above median proANP/BNP presented lower systolic blood pressure (BP), left ventricular ejection fraction (LVEF) and larger LV end-diastolic diameter (LVDd); Figure A-C, respectively; p<0.05 vs. below median proANP/BNP. The age- and sex-adjusted multivariate model for higher proANP ratio showed that the significance of systolic BP, LVEF and LVDd persisted (p<0.05). Conclusion: ProANP level on admission is a stronger predictor of future adverse events than BNP or proBNP level. Due to the association of higher proANP ratio with LV structure and function, proANP may be a better marker for hemodynamic stress to the LV than BNP in the acute heart failure. [ABSTRACT FROM AUTHOR]

We examined the effects of sumo on their knee joints, and investigated the relationship between radiological changes and knee joints symptoms, and the relationship between knee radiological changes and the physical characteristics of the wrestlers. Fifty-six high-school and 128 college freshman sumo wrestlers who belonged to the Japanese Sumo Federation. To evaluate radiological changes in the knee joints of high-school and college freshmen sumo wrestlers. They underwent routine radiographic examination of their knee joints and were instructed to answer a questionnaire regarding their knee symptoms as a medical check. The mean height, weight, body mass index (BMI), and sumo career/experience of the participants were 174.1 cm, 106.9 kg, 35.1 kg/m2, and 7.9 years, respectively. Twenty-five high-school (44.6%) and 54 collegiate (42.2%) sumo wrestlers had some knee symptoms, which was significantly associated with sumo career as a risk factor. Five high-school (8.9 %) and 18 collegiate (14.1 %) sumo wrestlers had joint space narrowing. Considering the relationship between knee symptoms and radiological changes, significant correlations between osteophyte formation and bony sclerosis and knee symptoms were observed. According to the Kellgren-Laurence (KL) classification, 7 high-school (12.5%) and 26 collegiate (20.3%) sumo wrestlers were grade 2, 3, or 4. The risk factors of degenerative radiographic changes in the knee joints of the participants were heavyweight, large BMI, and older age. The knee osteoarthritic changes had already appeared in 12.5% high-school sumo wrestlers at the admission., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: During the development of heart failure, a fetal cardiac gene program is reactivated and accelerates pathological cardiac remodeling. We previously reported that a transcriptional repressor, NRSF (neuron restrictive silencer factor), suppresses the fetal cardiac gene program, thereby maintaining cardiac integrity. The underlying molecular mechanisms remain to be determined, however., Methods: We aim to elucidate molecular mechanisms by which NRSF maintains normal cardiac function. We generated cardiac-specific NRSF knockout mice and analyzed cardiac gene expression profiles in those mice and mice cardiac-specifically expressing a dominant-negative NRSF mutant., Results: We found that cardiac expression of Gα o , an inhibitory G protein encoded in humans by GNAO1 , is transcriptionally regulated by NRSF and is increased in the ventricles of several mouse models of heart failure. Genetic knockdown of Gnao1 ameliorated the cardiac dysfunction and prolonged survival rates in these mouse heart failure models. Conversely, cardiac-specific overexpression of GNAO1 in mice was sufficient to induce cardiac dysfunction. Mechanistically, we observed that increasing Gα o expression increased surface sarcolemmal L-type Ca 2+ channel activity, activated CaMKII (calcium/calmodulin-dependent kinase-II) signaling, and impaired Ca 2+ handling in ventricular myocytes, which led to cardiac dysfunction., Conclusions: These findings shed light on a novel function of Gα o in the regulation of cardiac Ca 2+ homeostasis and systolic function and suggest Gα o may be an effective therapeutic target for the treatment of heart failure.

Background: It has not been yet adequately addressed whether the addition of the nonstatin LDL-C (low-density lipoprotein cholesterol)-lowering agents on top of statins has the same magnitude of risk reduction in the cardiovascular events as compared with more-intensive statin therapy., Methods and Results: We performed a systematic review and meta-analysis of RCTs (randomized controlled trials) comparing more- versus less-intensive lipid-lowering therapy (LLT) on clinical outcomes in patients with atherosclerotic cardiovascular risk. We included 23 studies involving 133 037 patients (more-intensive LLT: 67 691 patients and less-intensive LLT: 65 346 patients). We evaluated 3 types of more- versus less-intensive LLT including more versus less statins (57 672 patients), combination therapy of ezetimibe versus statins alone (20 688 patients), or a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor with statins versus statins alone (54 677 patients). The odds for major adverse cardiovascular events (MACE; equivalent to the composite of coronary heart death, nonfatal myocardial infarction, stroke, or coronary revascularization) were significantly lower in the more-intensive LLT group compared with the less-intensive LLT group in the entire study population (odds ratio, 0.84; 95% CI, 0.79-0.88; P<0.001), and in all the 3 categories of more-intensive LLT strategies (more-intensive statin therapy: odds ratio, 0.83; 95% CI, 0.76-0.90; P<0.001, ezetimibe: odds ratio, 0.90; 95% CI, 0.85-0.96; P<0.001, and PCSK9 inhibitors: odds ratio, 0.81; 95% CI, 0.73-0.90; P<0.001) with numerically greater relative odds reduction by more-intensive statin therapy and PCSK9 inhibitors than by ezetimibe. Odds reduction for MACE per 20 mg/dL LDL-C reduction was also different across the 3 types of more-intensive LLT (more-intensive statin therapy: 17.4%, ezetimibe: 11.0%, and PCSK9 inhibitors: 6.6%)., Conclusions: In this meta-analysis, more-intensive LLT as compared with less-intensive LLT was associated with significant odds reduction for MACE in the entire study population and in all the 3 categories of more-intensive LLT such as more-intensive statin therapy, ezetimibe, and PCSK9 inhibitors. However, overall odds reduction for MACE and odds reduction for MACE per 20 mg/dL LDL-C reduction were different across the 3 types of more-intensive LLT. Registration: URLs: https://www.crd.york.ac.uk/PROSPERO/ and http://www.umin.ac.jp/ctr. Unique identifiers: PROSPERO: CRD42018081196, and UMIN-CTR: R000036229.

Clinical guidance on the choice of anesthetic modality vis-à-vis the risk of perioperative venous thromboembolism (VTE) is largely lacking because of a paucity of recent evidence. A comparative effect of general anesthesia and neuraxial blockade on the perioperative incidence of VTE has not been well-investigated.We compared the effects of different types of anesthetic modalities on the risk of VTE after total hip arthroplasty (THA) and total knee arthroplasty (TKA).This is a secondary analysis of the Japanese Study of Prevention and Actual Situation of Venous Thromboembolism after Total Arthroplasty (J-PSVT). Data pertaining to a total of 2162 patients who underwent THA and TKA at 34 hospitals were included in this analysis. We compared the different anesthetic modalities with respect to the incidence of VTE. The composite end-point was asymptomatic/symptomatic deep vein thrombosis detected using scheduled bilateral ultrasonography up to postoperative day (POD) 10 and fatal/non-fatal pulmonary embolism up to POD 10.The study groups were as follows: general anesthesia (n = 646), combined epidural/general anesthesia (n = 1004), epidural anesthesia (n = 87), and spinal anesthesia (n = 425). On multivariate analysis, only spinal anesthesia was associated with a significant increase in the risk of VTE as compared with that associated with general anesthesia. Propensity score-matched analysis for "combined epidural/general anesthesia group" versus "spinal anesthesia group" demonstrated a 48% higher incidence of VTE (relative risk = 1.48, 95% confidence interval [CI] 1.18-1.85) in the latter.Spinal anesthesia was associated with a higher risk of postoperative VTE, as compared with that associated with combined epidural/general anesthesia, in patients undergoing total arthroplasty.

Background: The proliferation of cardiomyocytes is highly restricted after postnatal maturation, limiting heart regeneration. Elucidation of the regulatory machineries for the proliferation and growth arrest of cardiomyocytes is imperative. Chemical biology is efficient to dissect molecular mechanisms of various cellular events and often provides therapeutic potentials. We have been investigating cardiovascular differentiation with pluripotent stem cells. The combination of stem cell and chemical biology can provide novel approaches to investigate the molecular mechanisms and manipulation of cardiomyocyte proliferation., Methods and Results: To identify chemicals that regulate cardiomyocyte proliferation, we performed a screening of a defined chemical library based on proliferation of mouse pluripotent stem cell-derived cardiomyocytes and identified 4 chemical compound groups: inhibitors of glycogen synthase kinase-3, p38 mitogen-activated protein kinase, and Ca(2+)/calmodulin-dependent protein kinase II, and activators of extracellular signal-regulated kinase. Several appropriate combinations of chemicals synergistically enhanced proliferation of cardiomyocytes derived from both mouse and human pluripotent stem cells, notably up to a 14-fold increase in mouse cardiomyocytes. We also examined the effects of identified chemicals on cardiomyocytes in various developmental stages and species. Whereas extracellular signal-regulated kinase activators and Ca(2+)/calmodulin-dependent protein kinase II inhibitors showed proliferative effects only on cardiomyocytes in early developmental stages, glycogen synthase kinase-3 and p38 mitogen-activated protein kinase inhibitors substantially and synergistically induced re-entry and progression of cell cycle in neonatal but also as well as adult cardiomyocytes., Conclusions: Our approach successfully uncovered novel molecular targets and mechanisms controlling cardiomyocyte proliferation in distinct developmental stages and offered pluripotent stem cell-derived cardiomyocytes as a potent tool to explore chemical-based cardiac regenerative strategies.

Rationale: Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized., Objective: We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca(2+) channel known to positively regulate prohypertrophic calcineurin-nuclear factor of activated T cells (NFAT) signaling., Methods and Results: In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca(2+) influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II-induced cardiac hypertrophy in mice., Conclusions: Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.

Rationale: It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized., Objective: We have now investigated the physiological function of p300 in adult hearts., Methods and Results: We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300DeltaC/H3 transgenic [TG] mice). p300DeltaC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300DeltaC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300DeltaC/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300DeltaC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300DeltaC/H3-TG mice, and p300DeltaC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1alpha promoter activity and disrupted the transcriptional activity of PGC-1alpha in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300DeltaC/H3-TG hearts., Conclusions: Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.

Background: Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however., Methods and Results: We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction., Conclusions: T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Background: Recent clinical trials have shown that systemic infusion of nesiritide, a recombinant human brain natriuretic peptide (BNP), improves hemodynamic parameters in acutely decompensated hearts. This suggests that BNP exerts a direct cardioprotective effect and might thus be a useful therapeutic agent with which to treat acute myocardial infarction (MI). In the present study, we used BNP-transgenic (BNP-Tg) mice with elevated plasma BNP to determine whether and how BNP contributes to left ventricular remodeling and healing after MI., Methods and Results: We examined the accumulation of neutrophils and the expression and activation of matrix metalloproteinase (MMP)-9 in the ventricles of male BNP-Tg mice and their nontransgenic (non-Tg) littermates during the early phase after acute MI. The numbers of neutrophils infiltrating the infarcted area were significantly increased in BNP-Tg mice 3 days after MI. In addition, both the gene expression and zymographic activity of MMP-9, but not MMP-2, were significantly higher in BNP-Tg than non-Tg mice. Double immunostaining revealed that neutrophils are the main source of the MMP-9, although doxycycline, an MMP inhibitor, had no effect on neutrophil infiltration of the infarcted area in BNP-Tg mice., Conclusions: These results demonstrate that elevated plasma BNP facilitates neutrophil infiltration of the infarcted area after MI and increases the activity of the MMP-9 they produce. This suggests that BNP plays a key role in the processes of extracellular matrix remodeling and wound-healing during the early phase after acute MI.

Background: Angiotensin II plays a prominent role in the progression of heart failure after acute myocardial infarction (AMI). Although both angiotensin type 1 (AT1) and type 2 (AT2) receptors are known to be present in the heart, comparatively little is known about the latter. We therefore examined the role played by AT2 receptors in post-AMI heart failure., Methods and Results: In wild-type mice subjected to AMI by coronary artery ligation, AT2 receptor immunoreactivity is upregulated in the infarct and border areas. Among AT2 receptor-null (-/-) mice, the 7-day survival rate after AMI was significantly lower than among wild-type mice (43% versus 67%; P<0.05). All sham-operated animals of both genotypes survived through the study. Ventricular mRNA levels for brain natriuretic peptide were elevated in both genotypes 24 hours after coronary occlusion, with levels in AT2-/- significantly higher than in wild-type mice, as were their lung weights, and histological examination revealed marked pulmonary congestion in the AT2-/- mice. Cardiac function was significantly decreased in AT2-/- mice 2 days after AMI., Conclusions: AT2 receptor deficiency exacerbates short-term death rates and heart failure after experimental AMI in mice. The AT2 receptor may thus exert a protective effect on the heart after AMI.

Background: Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice., Methods and Results: We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals., Conclusions: These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.