Shared and Reciprocal Mechanisms Between Heart Failure and Cancer　- An Emerging Concept of Heart-Cancer Axis.

Epidemiological evidence of increased risks of cancer in heart failure (HF) patients and HF in cancer patients has suggested close relationships between the pathogenesis of both diseases. Indeed, HF and cancer share common risk factors, including aging and unhealthy lifestyles, and underlying mechanisms, including activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, chronic inflammation, and clonal hematopoiesis of indeterminate potential. Mechanistically, HF accelerates cancer development and progression via secreted factors, so-called cardiokines, and epigenetic remodeling of bone marrow cells into an immunosuppressive phenotype. Reciprocally, cancer promotes HF via cachexia-related wasting and metabolic remodeling in the heart, and possibly via cancer-derived extracellular vesicles influencing myocardial structure and function. The novel concept of the "heart-cancer axis" will help in our understanding of the shared and reciprocal relationships between HF and cancer, and provide innovative diagnostic and therapeutic approaches for both diseases.

Effect of renal function under left ventricular assist device support on the cardiac function and clinical events after heart transplantation.

AIM: We investigated the effects of pre-transplantation renal dysfunction under left ventricular assisted device (LVAD) support on post-transplantation cardiac function, and patient prognosis after heart transplantation (HTx). METHOD: All patients who were bridged by LVAD and underwent HTx at our hospital between 2007 and 2022 were included in this study. Patients were classified into two groups based on estimated glomerular filtration rate (eGFR) before HTx: renal dysfunction (RD) group (eGFR < 60 mL/min/1.73 m2 ) and non-renal dysfunction (NRD) group. RESULT: A total of 132 patients were analyzed, of whom 48 were classified into the RD group and 84 into the NRD group (RD group, 47.9 ± 10.1 years; NRD group, 38.4 ± 11.9 years, p < .0001). Under LVAD support before HTx, the RD group tended to have a history of right ventricular failure (RD group, nine (19%); NRD group, seven (8%); p = .098). After HTx, the echocardiographic parameters did not differ between the two groups in the long term. Furthermore, more concise hemodynamic parameters, exemplified by right heart catheterization, were not significantly different between the two groups. Regarding graft rejection, no significant differences were found in acute cellular rejection and cardiac allograft vasculopathy following HTx. In contrast, patients with RD before HTx had significantly increased mortality in the chronic phase after HTx and initiation of maintenance dialysis, without any overt changes in cardiac function. CONCLUSION: Pre-transplantation renal dysfunction under LVAD support significantly affected clinical course after HTx without any overt changes in graft cardiac function.

Prophylactic negative pressure wound therapy is not effective for preventing driveline infection following left ventricular assist device implantation.

BACKGROUND: Driveline infection (DLI) following left ventricular assist device (LVAD) implantation remains an unresolved problem. Negative pressure wound therapy (NPWT) promotes wound healing by applying negative pressure on the surface of the wound. Recently, the prophylactic application of NPWT to closed surgical incisions has decreased surgical site infections in various postsurgical settings. Therefore, we evaluated the efficacy and safety of prophylactic NPWT for preventing DLI in patients with LVAD implantation. METHODS: Prophylactic NPWT was provided to 50 patients who received continuous-flow LVADs as bridge-to-transplant therapy at our institution between May 2018 and October 2020 (NPWT group). The negative pressure dressing was applied immediately after surgery and retained on the driveline exit site for 7 days with a continuous application of -125 mm Hg negative pressure. The primary outcome was DLI within 1 year of LVAD implantation. We compared the rate of DLI incidence in the NPWT group with that in the historical control cohort (50 patients) treated with the standard dressing (SD) who received LVAD implantation between July 2015 and April 2018 (SD group). RESULTS: No severe complications were associated with the NPWT. During the follow-up period, DLI was diagnosed in 16 participants (32%) in the NPWT group and 21 participants (42%) in the SD group. The rates of DLI incidence and freedom from DLI did not differ between groups (p = 0.30 and p = 0.63). CONCLUSIONS: Prophylactic NPWT at the driveline exit site was safe following LVAD implantation. However, it did not significantly reduce the risk of DLI.

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia.

Currently available anti-cytomegalovirus (CMV) agents are sometimes poorly tolerated, owing to their side effects. Letermovir is a novel anti-CMV drug that is only approved for CMV prophylaxis in hematopoietic stem cell transplant recipients, with fewer side effects. We report the case of a heart transplant recipient with UL97 mutation (L595F) ganciclovir-resistant cytomegalovirus colitis who was successfully treated with off-label use of letermovir. In treating CMV infection or disease with letermovir, a transient rise or lag in the clearance of CMV-DNA polymerase chain reaction levels has been observed. Our case suggests that CMV-pp65 antigenemia can be an additional marker of treatment efficacy.

Analysis of implant stability changes in immediate loading using a laser displacement sensor in vivo and comparison of its sensitivity with that of resonance frequency analysis.

OBJECTIVE: The aim of this study was to analyze the stability changes in immediately loaded implants by using an in vivo quantitative measurement of micromotion under functional dynamic loading and to verify the sensitivity of Resonance Frequency Analysis (RFA) as compared to that of actual micromotion. MATERIALS AND METHODS: The micromotions of immediately loaded implants placed in the tibia of 11 rabbits were monitored using a laser displacement sensor. Functional dynamic loading forces were applied 5 days a week for 6 weeks. The implant stability quotient (ISQ) was monitored using RFA. RESULTS: The micromotion of the almost-loaded implants increased to peak values the day after loading was started and subsequently reached a plateau gradually. The ISQ changes in the loaded implants closely correlated with the alterations of the actual micromotion (r = -0.98, p < .01). Although the ISQ value itself correlated with the measured micromotion at the time of initial fixation (r = 0.73, p < .05), it did not correlate with the micromotion of the implant that acquired integration. No close correlation was observed between the ISQ and the histomorphometrical data. CONCLUSION: The immediately loaded implants showed the lowest stability immediately after the start of loading, which gradually increased thereafter. RFA is considered a useful method for examining stability changes and initial stability; however, it cannot determine the absolute magnitude of the stability after integration.

Association between infectious event and de novo malignancy after heart transplantation.

The aim of the study was to investigate the incidence of and risk factors for de novo malignancy after heart transplantation (HTx) in a single center. We assessed 102 consecutive patients who received HTx and were followed-up in our center regularly for > 1 year from June 2006 to May 2018. We investigated the incidence of and risk factors for de novo malignancy. The cumulative incidence of each malignancy type during the follow-up period was one (0.98%) for skin cancer, four (3.92%) for nonskin solid organ cancer, and six (5.88%) for posttransplant lymphoproliferative disorder (PTLD). The percentage of patients with more than one infectious event ≤ 1 year after HTx was higher in the malignancy group than in the non-malignancy group. Furthermore, Kaplan-Meier analysis revealed that the incidence rate of infectious events was higher in patients with malignancies than in those without (log-rank P < 0.001). After dividing malignancies into a PTLD group and a solid organ malignancy group, we found that negative Epstein-Barr virus serostatus, cytomegalovirus-positive antigenemia, and the occurrence of any viral or gastrointestinal infectious event at ≤ 1 year were more frequent in patients with PTLD than in patients without it. The survival rate was significantly lower for patients with solid organ malignancy than for patients without malignancy. In conclusion, there was a correlation between infectious events and de novo malignancy, particularly in patients with PTLD. We should confirm this finding by conducting a larger cohort study.

Detection of Profound Myocardial Damage by Cardiac MRI in a Patient with Severe Cardiotoxicity Induced by Anti-HER2 Therapy.

Anti-HER2 therapy has greatly improved the long-term prognosis of patients with HER2-positive breast cancer. Meanwhile, by interfering with the protective effects of neuregulin-1/HER2 signaling on stressed cardiomyocytes, anti-HER2 therapy occasionally induces reversible cancer therapeutics-related cardiac dysfunction (CTRCD). Cardiac magnetic resonance (CMR) parametric mapping or myocardial feature-tracking, in combination with late gadolinium enhancement (LGE) imaging, has the potential to detect changes in the myocardium in anti-HER2 therapy-related cardiac dysfunction. Here we report a breast cancer patient who experienced life-threatening CTRCD after treatment with trastuzumab plus pertuzumab. This case showed multiple transmural LGE-positive myocardial lesions in CMR imaging and high native T1 and T2 values in CMR parametric mapping, which was apparently more extensive than those observed in most patients with anti-HER2 therapy-related cardiac dysfunction. Consistent with profound myocardial damage indicated by CMR, her cardiac function was not fully restored despite intensive care and cardioprotective drug therapy. These findings suggest the potential usefulness of LGE imaging and parametric mapping by CMR for the assessment of myocardial injury to determine the clinical severity of anti-HER2 therapy-related cardiac dysfunction.

Cancer Therapeutics-Related Cardiac Dysfunction　- Insights From Bench and Bedside of Onco-Cardiology.

Improvements in the long-term survival of cancer patients have led to growing awareness of the clinical importance of cancer therapeutics-related cardiac dysfunction (CTRCD), which can have a considerable effect on the prognosis and quality of life of cancer patients and survivors. Under such circumstances, onco-cardiology/cardio-oncology has emerged as a new discipline, with the aim of best managing cardiovascular complications, including CTRCD. Despite the recent accumulation of epidemiological and clinical information regarding CTRCD, the molecular mechanisms underlying the pathogenesis of CTRCD by individual drugs remain to be determined. To achieve the goal of preventing cardiovascular complications in cancer patients and survivors, it is important to elucidate the pathogenic mechanisms and to establish diagnostic strategies with risk prediction and mechanism- and evidence-based therapies against CTRCD.

A Fatal Case of Myocarditis Following Myositis Induced by Pembrolizumab Treatment for Metastatic Upper Urinary Tract Urothelial Carcinoma.

We report a case of lethal myocarditis and myositis after pembrolizumab treatment for advanced upper urinary tract urothelial carcinoma. A 69-year-old man underwent pembrolizumab therapy as a second-line treatment. He had myalgia and a slightly elevated creatinine kinase (CK) on the day of the second administration of pembrolizumab. Five days later, the patient was admitted with severe fatigue and an abnormal gait. Physical examination revealed reduced muscle reflexes and proximal muscle weakness. An electrocardiogram (ECG) demonstrated a wide QRS complex ventricular rhythm. A marked elevation of cardiac enzymes, including CK, myoglobin, and cardiac troponin I, was detected. Myocardial biopsy revealed inflammatory cell infiltration and the partial impairment of myocardial tissue. The electromyogram was normal, but inflammation in myofibers was noted in a muscle biopsy. Myocarditis and myositis as immune-related adverse events (irAEs) were suspected, and the patient began intravenous steroid therapy and plasma exchange. However, the patient underwent cardiac arrest three days after admission and began extracorporeal membrane oxygenation and intra-aortic balloon pumping therapy. Despite steroid pulse therapy, the patient demonstrated no sign of improvement and subsequently died 17 days after admission. Immune-mediated myocarditis is a rare but fatal irAE of an immune checkpoint inhibitor (ICI). The present case suggests that myositis precedes myocarditis. Therefore, if myositis is suspected, subsequent myocarditis may need attention. In conclusion, we found that myositis and myocarditis developed in a patient with advanced urothelial carcinoma after pembrolizumab treatment. A routine follow-up of CK and cardiac troponin I, as well as an ECG, should be performed to identify any possible ICI-induced myocarditis and myositis quickly.

Structural Series in the Ternary A-Mn-As System (A = Alkali Metal): Double-Layer-Type CsMn4As3 and RbMn4As3 and Tunnel-Type KMn4As3.

New manganese arsenides CsMn4As3, RbMn4As3, and KMn4As3 were synthesized by solid-state reaction. They consist of edge-sharing MnAs4 tetrahedra, which are a building block similar to those of Fe-based superconductors. CsMn4As3 and RbMn4As3 adopt the KCu4S3-type structure (tetragonal P4/ mmm space group, No. 123) with a Mn4As3 double layer, while KMn4As3 has the CaFe4As3-type structure (orthorhombic Pnma space group, No. 62) with a Mn4As3 tunnel framework. The structural change from CsMn4As3 and RbMn4As3 to KMn4As3 as well as the structural trend of the other ternary A-Mn-As (A = alkali metal) and AE-Mn-As (AE = alkaline-earth metal) compounds is understood as a consequence of reduction of the coordination number around the A and AE sites owing to the decrease of the ionic radius from Cs+ to Mg2+. Electrical resistivity measurements confirm that the three new phases are Mott insulators with band gaps of 0.52 (CsMn4As3), 0.43 (RbMn4As3), and 0.31 eV (KMn4As3). Magnetic and heat capacity measurements revealed that CsMn4As3 and RbMn4As3 are antiferromagnets without apparent phase transitions below 400 K, which is similar to the magnetism of LaMnAsO and BaMn2As2, while the existence of the ferromagnetic component was indicated in KMn4As3 with a magnetic transition at 179 K.

Direct adjustment for confounding by smoking reduces radiation-related cancer risk estimates of mortality among male nuclear workers in Japan, 1999-2010.

A causal relationship between protracted exposure to low-dose rate radiation and health effects remains unclear despite extensive international studies of nuclear workers. One potential reason is that radiation epidemiological studies that adjust for tobacco smoking, which heavily influences mortality, have been limited. In the present study, we examined radiation-related cancer risk by directly assessing the possible confounding effect of smoking, using data from two questionnaire surveys performed among Japanese nuclear workers in 1997 and 2003. Mortality follow-up was carried out for 71 733 male respondents for an average of 8.2 years during the observation period of 1999-2010. The mean cumulative dose was 25.5 mSv at the end of the follow-up period. Estimates of excess relative risk per Sv (ERRs/Sv) were obtained by Poisson regression. By adjusting for smoking directly on the basis of a linear dose-response model, we quantified the confounding effects of smoking on radiation risks. Statistically significant ERRs/Sv were found for all causes, all diseases, all non-cancer diseases, and liver cancer: 0.97 (90% confidence interval: 0.23, 1.78), 1.32 (0.40, 2.34), 1.87 (0.47, 3.49), and 4.78 (0.09, 11.68), respectively, without adjustment for smoking. However, the ERRs/Sv were no longer statistically significant after adjustment for smoking: 0.45 (-0.22, 1.19), 0.77 (-0.08, 1.72), 1.28 (-0.03, 2.79), and 3.89 (-0.46, 10.34), respectively. The ERRs/Sv for all cancers excluding leukaemia and lung cancer were not significant before adjustment for smoking, but declined after adjustment for smoking. The present study demonstrates that in this cohort of workers, smoking heavily distorts radiation risk estimates of mortality. The possibility of confounding by smoking depends on how strongly smoking is correlated with radiation exposure. If a correlation between smoking and radiation dose is suggested, smoking is an important confounder when assessing the radiation and health risks.

Corrigendum: direct adjustment for confounding by smoking reduces radiation-related cancer risk estimates of mortality among male nuclear workers in Japan, 1999-2010.

We found some trivial errors which might confuse reader. The errors can be identified as the following two types. (1) The one is that misuse of "ERR" and "ERR/Sv". We denoted "Table 4 shows ERRs/Sv and 90% CIs ..." in line 7 of page 366. While we denoted "ERR and 90% CI for all cancers, excluding leukaemia, by dose category ..." in title of Table 4. The values described in Table 4 were ERR by dose category and not ERR/Sv. In addition, the explanation about the model that derived ERR by dose category is better to be added. Therefore, the description mentioned above should be changed as follows. (Misprinted) Table 4 shows ERRs/Sv and 90% CIs for all cancers excluding leukaemia by dose category. (Corrected) Table 4 shows ERRs which were defined as follow equation and 90% CIs for all cancers excluding leukaemia by dose category. λ=λ0 (a,c,y,r,s)exp(α1z1+α2z2+α3z3) (1+ßi di) where di is the dose category, and ßi is the ERR by dose category. The lowest dose category was set as reference. (2) The other were errors in surface caput of several tables. We described "ERR without adjustment for smoking" and "ERR with adjustment for smoking" in Table 4. These are correct description. However, "ERR with adjustment for smoking" was described as "For smoking" in Table 2. In addition, "Without adjustment" and "With adjustment" denoted in the surface caput of Table 5, 6, 7 should be denoted as "Without adjustment for smoking" and "With adjustment for smoking". The author wishes to apologies for the errors. .

A Circularly Arranged Sextuple Triptycene Gear Molecule.

Herein we report the synthesis of a circularly arranged sextuple triptycene gear molecule, hexakis(10-dodecyloxy-9-triptycyl)ethynylbenzene, via the trimerization of the corresponding triyne with a cobalt catalyst. The six triptycene gears are closely engaged with each other as confirmed by single crystal X-ray structure analysis, and their motion in solution was established by NMR spectroscopy. Notably, when one bulky RuCp* complex was attached to one triptycene gear, the whole movement of the six gears was highly restricted via their mechanical engagement. Development of such a multigear molecule would provide a structural basis for molecular motion transmission systems with a switching function.

Repurposing of approved cardiovascular drugs.

Research and development of new drugs requires both long time and high costs, whereas safety and tolerability profiles make the success rate of approval very low. Drug repurposing, applying known drugs and compounds to new indications, has been noted recently as a cost-effective and time-unconsuming way in developing new drugs, because they have already been proven safe in humans. In this review, we discuss drug repurposing of approved cardiovascular drugs, such as aspirin, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, cardiac glycosides and statins. Regarding anti-tumor activities of these agents, a number of experimental studies have demonstrated promising pleiotropic properties, whereas all clinical trials have not shown expected results. In pathological conditions other than cancer, repurposing of cardiovascular drugs is also expanding. Numerous experimental studies have reported possibilities of drug repurposing in this field and some of them have been tried for new indications ('bench to bedside'), while unexpected results of clinical studies have given hints for drug repurposing and some unknown mechanisms of action have been demonstrated by experimental studies ('bedside to bench'). The future perspective of experimental and clinical studies using cardiovascular drugs are also discussed.

Structural changes of water in poly(vinyl alcohol) hydrogel during dehydration.

To investigate the mechanism of structural changes of water and polymer networks with drying and swelling, we measured the Raman spectra of a physically cross-linked poly(vinyl alcohol) (PVA) hydrogel synthesized using the freezing-thawing method. The results show that the vibrational frequencies of the O-H and C-H stretching modes decrease with dehydration. The frequency shifts observed are attributed to reduction of free water inside the polymer network. The C-H bonds elongate as the water density decreases, and the average length of the O-H bonds increases with increasing proportion of bound water to the total amount of water. On the basis of the dependence of the frequency shifts on the PVA concentration of the original solution, it was found that the structure of the polymer network in the reswollen hydrogel becomes inhomogeneous due to shrinkage of the polymer network with drying. Furthermore, to investigate the effects of the cross-linking structure on the drying process, these results were compared with those of a chemically cross-linked PVA hydrogel synthesized using glutaraldehyde as a cross-linker. The result shows that the vibrational frequency of the O-H stretching mode for the chemically cross-linked hydrogel increases with dehydration, whereas that of the C-H stretching mode decreases. The opposite trend observed in the O-H stretching mode between the physically and chemically cross-linked hydrogels is due to the difference in the shrinkage rate of the polymer network. Because the rate of shrinking is slow compared with that of dehydration in the chemically cross-linked hydrogel, water density in the polymer network decreases. For the physically cross-linked hydrogel, the polymer network structure can be easily shrunken, and the average strength of hydrogen bonds increases with dehydration. The results show that the structures of the polymer network and water change with the gel preparation process, cross-linking method, and drying and reswelling processes. The structure of the polymer network and the behavior of water accommodated in the network are important factors governing the chemical and physical properties of gel materials.

Successful treatment of fulminant and recurrent lymphocytic myocarditis with calcineurin inhibitors.

Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.