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.

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.

Malignant Findings in Candidates for Transcatheter Aortic Valve Implantation.

BACKGROUND: In candidates for transcatheter aortic valve implantation (TAVI), preoperative computed tomography (CT) may detect clinically relevant non-cardiac findings. In particular, when malignant findings are detected, patients may be less likely to undergo the procedure. Additionally, they might require further examinations, which may prolong their time to treatment. We investigated how malignant findings affect candidacy for TAVI. METHODS: In this single-center retrospective study, 98 patients with severe aortic stenosis who had undergone preoperative CT between September 2013 and October 2016 were evaluated for malignant findings. RESULTS: Seven patients (7.1%) had malignant findings. 74 of 91 patients who did not have malignant findings underwent TAVI, SAVR, or balloon aortic valvuloplasty (81.3%). All patients who had malignant findings underwent TAVI or SAVR, and they underwent the procedure sooner after CT than the rest of the patients (mean time to TAVI or SAVR: 24.6 ± 16.8 versus 48.5 ± 45.4 days; P = .003). All 5 patients who had malignant findings without metastatic cancer and who underwent TAVI were still alive during the follow-up period (the mean duration of the follow-up period was 22.3 ± 8.8 months). However, 1 patient who had a malignant finding with metastatic cancer died 7 months after CT. CONCLUSION: Our outcomes indicated that the mean duration before TAVI or SAVR was reduced when malignant findings were detected by CT; and TAVI may be a safe and effective treatment for patients with aortic stenosis and a malignant tumor.

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.

Genome-wide detection of changes in allelic frequency in Landrace pigs selected for resistance to mycoplasma pneumonia of swine.

Closed-pig line breeding could change the genetic structure at a genome-wide scale because of the selection in a pig breeding population. We investigated the changes in population structure among generations at a genome-wide scale and the selected loci across the genome by comparing the observed and expected allele frequency changes in mycoplasma pneumonia of swine (MPS)-selected pigs. Eight hundred and seventy-four Landrace pigs, selected for MPS resistance without reducing average daily gain over five generations, had 37,299 single nucleotide polymorphisms (SNPs) and were used for genomic analyses. Regarding population structure, individuals in the first generation were the most widely distributed and then converged into a specific group, as they were selected over five generations. For allele frequency changes, 96 and 14 SNPs had higher allele frequency changes than the 99.9% and 99.99% thresholds of the expected changes, respectively. These SNPs were evenly spread across the genome, and a few of these selected regions overlapped with previously detected quantitative trait loci for MPS and immune-related traits. Our results indicated that the considerable changes in allele frequency were identified in many regions across the genome by closed-pig line breeding based on estimated breeding value.

Oral Administration of Euglena Gracilis Z Alleviates Constipation and Cardiac Dysfunction in a Mouse Model of Isoproterenol-Induced Heart Failure.

Background: Patients with heart failure (HF) often experience gastrointestinal problems such as constipation, diarrhea, and disturbances to drug absorption. In HF, hypoperfusion and congestion cause structural and functional changes in the gut, which, in turn, lead to impaired cardiac function. Euglena gracilis Z (hereafter "Euglena"), called Midorimushi in Japanese, is a microalga that is used as a food or nutritional supplement. It is unclear whether Euglena is beneficial for bowel habitus and cardiac function in subjects with HF. Methods and Results: We injected C57BL/6 male mice subcutaneously with isoproterenol (ISO) (20 mg/kg/day) for 7 days to examine bowel movement in HF. Euglena was orally administered to mice on an ad libitum-feeding to a normal chow containing 2% dietary mixture. ISO induced a decrease in bowel movement and an increase in fecal retention in the cecum, as well as a decrease in left ventricular (LV) contraction. Euglena accelerated intestinal transit, relieved fecal retention, and prevented the alterations in gut pathology in ISO-treated mice. Euglena also suppressed ISO-induced decreases in LV contraction, although it had no significant effect on LV hypertrophy. Conclusions: The results suggested that oral administration of Euglena alleviated constipation and cardiac dysfunction in a mouse model of ISO-induced HF, and highlight the potential clinical benefit of Euglena in patients with HF in preventing constipation and contractile deterioration.

Mechanisms and Management of Immune Checkpoint Inhibitor-Related Cardiac Adverse Events.

Onco-cardiology recently emerged as a novel discipline to provide effective cardioprotective care against cancer therapeutics-related cardiac adverse events (CAEs) and support the continuity of optimal cancer treatment. Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and dramatically improved outcomes in patients with advanced or refractory cancers. However, ICIs intrinsically stimulate systemic immune responses and can potentially induce a spectrum of immune-related adverse events (irAEs), which can affect any organs of the body. The manifestation of cardiac irAEs includes myocarditis, arrhythmias and conduction abnormalities, and pericardial diseases. Takotsubo-like cardiomyopathy is also included as a manifestation of ICI-related CAEs, but the pathophysiological relevance is unclear. Although the incidence is rare, ICI-related CAEs are life-threatening and potentially fatal. Elucidating pathophysiology and establishing management measures of ICI-related CAEs are one of the most urgent challenges in the field of onco-cardiology.

Axitinib Induces and Aggravates Hypertension Regardless of Prior Treatment With Tyrosine Kinase Inhibitors.

Background: Axitinib is a tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor signaling and is approved for second-line treatment of advanced renal cell carcinoma (RCC). Although the occurrence of hypertension with axitinib use has been documented, it is unclear whether a first-line TKI regimen can significantly affect the development of hypertension when axitinib is used as second-line therapy. Methods and Results: In this single-center retrospective study, advanced RCC patients treated with axitinib after first-line chemotherapy were divided into 2 groups according to the use of TKIs as part of first-line treatment before the initiation of axitinib. Clinical outcomes were compared between patients who were treated with (TKI(+); n=11) or without (TKI(-); n=11) a TKI. Although 63.6% of all patients had hypertension at baseline, axitinib-induced hypertension developed in 81.8% of patients, and 36.4% of patients experienced Grade 3 hypertension. After initiation of axitinib, both systolic and diastolic blood pressures and the hypertension grade were significantly elevated both in the TKI(+) and TKI(-) groups, and the number of antihypertensive drugs was significantly increased among all patients. Conclusions: This study suggests the need for proper monitoring and management of blood pressure in RCC patients treated with axitinib, regardless of a prior regimen with or without TKIs.

Genome-wide association studies for production, respiratory disease, and immune-related traits in Landrace pigs.

Identification of a quantitative trait locus (QTL) related to a chronic respiratory disease such as Mycoplasmal pneumonia of swine (MPS) and immune-related traits is important for the genetic improvement of disease resistance in pigs. The objective of this study was to detect a novel QTL for a total of 22 production, respiratory disease, and immune-related traits in Landrace pigs. A total of 874 Landrace purebred pigs, which were selected based on MPS resistance, were genotyped using the Illumina PorcineSNP60 BeadChip. We performed single nucleotide polymorphism (SNP)-based and haplotype-based genome-wide association studies (GWAS) to detect a novel QTL and to evaluate the possibility of a pleiotropic QTL for these traits. SNP-based GWAS detected a total of six significant regions in backfat thickness, ratio of granular leucocytes to lymphatic cells, plasma concentration of cortisol at different ages, and complement alternative pathway activity in serum. The significant region detected by haplotype-based GWAS was overlapped across the region detected by SNP-based GWAS. Most of these detected QTL regions were novel regions with some candidate genes located in them. With regard to a pleiotropic QTL among traits, only three of these detected QTL regions overlapped among traits, and many detected regions independently affected the traits.

Differences in distribution of single nucleotide polymorphisms among intracellular pattern recognition receptors in pigs.

Pathogens localized extracellularly or incorporated into endosomes are recognized mainly by Toll-like receptors, whereas pathogens and pathogen-derived molecules that invade into the cytoplasm of host cells typically are recognized by intracellular pattern recognition receptors (PRRs), such as retinoic acid-inducible gene (RIG)-like helicases (RLHs) and nucleotide-binding oligmerization domain (NOD)-like receptors (NLRs). RIG-I and melanoma differentiation-associated gene 5 (MDA5), which belong to the RLH family, recognize viral genomic RNA, whereas NOD2, a member of the NLR family, responds to microbial peptidoglycans. These receptors may play an important role in pig opportunistic infectious diseases, such as pneumonia and diarrhea, which markedly impair livestock productivity, such that polymorphisms of these receptor genes are potential targets of pig breeding to increase disease resistance. Here, we report single nucleotide polymorphisms (SNPs) in porcine DDX58, IFIH1, and NOD2, which encode RIG-I, MDA5, and NOD2, respectively. Interestingly, compared with DDX58 and IFIH1, NOD2 abounded in nonsynonymous SNPs both throughout the coding sequence and in sequences encoding domains important for ligand recognition, such as helicase domains for RIG-I and MDA5 and leucine-rich repeats in NOD2. These differences in the distribution of SNPs in intracellular PRRs may parallel the diversity of their ligands, which include nucleic acids and peptidoglycans.

Enormous Aneurysm in Coronary Artery Fistula With Immunoglobulin G4-Related Disease.

We report the first case of coronary artery fistula with aneurysmal change in a patient with immunoglobulin G4-related disease (IgG4-RD). This case revealed concomitant coronary artery dilation, pericardial inflammatory nodules, and coronary-pulmonary fistula aneurysm in addition to several IgG4-RD lesions. Each of these features was located in close proximity to the thickened pericardium. These lesions might result from inflammation of the pericardial space, which extended to the coronary-pulmonary artery vessels, leading to aneurysmal formation. This case will enhance our understanding of the pathological mechanisms of IgG4-RD inflammation.

Correlated response of peripheral blood cytokines with selection for reduced mycoplasma pneumonia of swine lesions in Landrace pigs.

Mycoplasma pneumonia of swine (MPS) is responsible for significant economic losses in the swine industry. We selected Landrace pigs for reduced MPS pulmonary lesions over five generations, and measured concentrations of the following cytokines: interleukin (IL)-10, IL-13, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ to estimate their correlation with MPS lesions. Sheep red blood cells (SRBC) were injected twice intramuscularly at 70 and 95 kg body weight. Blood serum samples were collected after 1 week of secondary SRBC inoculation and cytokine concentrations were analyzed by ELISA. Genetic parameters and breeding values were estimated. The heritability estimates of IL-10, IL-13, IL-17, TNF-α and IFN-γ were 0.20 ± 0.06, 0.12 ± 0.06, 0.27 ± 0.07, 0.20 ± 0.10 and 0.05 ± 0.03, respectively. Genetic correlations of IL-17 and TNF-α with pulmonary MPS lesions were high (-0.86 ± 0.13 and 0.69 ± 0.29, respectively) and those of IFN-γ and IL-13 with MPS lesions were moderately negative (-0.45). Through selection, the breeding values of IL-17 and IFN-γ increased substantially and those of TNF-α decreased. These results suggest that innate and cellular immunity are more important for the suppression of pulmonary lesions in MPS than humoral-mediated immunity, such as antibody response.

Correlated responses of respiratory disease and immune capacity traits of Landrace pigs selected for Mycoplasmal pneumonia of swine (MPS) lesion.

Five generations of Landrace pigs selected for average daily gain, backfat thickness, Mycoplasmal pneumonia of swine (MPS) lesion score, and plasma cortisol levels, was executed to decrease the MPS lesion score. Genetic parameters and correlated genetic responses for respiratory disease and peripheral blood immune traits were estimated in 1395 Landrace pigs. We estimated the negative genetic correlation of MPS lesion score with phagocytic activity (PA) at 7 weeks of age (-0.67). The breeding values of PA at 7 weeks of age and 105 kg body weight and the correlated selection response of the ratio of granular leukocytes to lymphocytes at 105 kg body weight were significantly increased, and sheep red blood cell-specific antibody production (AP) was significantly decreased in a selection-dependent manner. Increasing of natural immunological indicators (e.g. PA) and decreasing of humoral immunological indicator (e.g. AP) were observed due to genetically decreasing MPS lesion score.

Effect of VRTN gene polymorphisms on Duroc pig production and carcass traits, and their genetic relationships.

The thoracic vertebral number is associated with body length and carcass traits, and represents one of the most important traits in the pig industry. Recent studies have shown that vertnin (VRTN) gene is associated with variations in the vertebral number in commercial European pigs. However, the genetic relationships and effect of this VRTN gene in pig production and carcass traits remain uncertain. Therefore, we investigated the genetic relationships among traits such as vertebral numbers, carcass weight and length-related traits, and meat production traits, and the effect of VRTN gene polymorphisms on these traits in a Duroc purebred population selected for its meat production traits. Highly positive genetic correlations were obtained between the thoracic vertebral numbers and length-related traits (0.56 to 0.84), whereas low correlations were obtained with production traits and carcass weight (-0.16 to 0.05). VRTN gene polymorphisms indicated that the number of thoracic vertebrae and length-related traits were significantly associated with the VRTN genotype, but had no significant effect on production traits and carcass weight. The results indicate that VRTN gene may be used as an effective selection marker to obtain pigs with high thoracic vertebral numbers and length-related traits, without adversely affecting meat production traits.

Mapping QTL for fat area ratios and serum leptin concentrations in a Duroc purebred population.

The reduction of extra subcutaneous, intermuscular and abdominal fat is important to increase the carcass lean percentage of pigs. Image analyses of fat area ratios were effective for estimation of separated fat in pig carcasses. Serum concentrations of leptin are useful as physiological predictors of fat accumulation in pigs. The objectives of the present study were to perform a quantitative trait locus (QTL) analysis for fat area ratios and serum leptin concentrations in a Duroc purebred population. Pigs (n = 226 to 538) were measured for fat area ratios of carcass cross-sections at the fifth to sixth thoracic vertebrae, half body length and last thoracic vertebra using an image analysis system, and serum leptin concentration. In total, animals were genotyped for 129 markers and used for QTL analysis. For fat area ratios, four significant and 12 suggestive QTLs were detected on chromosomes 1, 6, 7, 8, 9, 12 and 13. Significant QTLs were detected on the same region of chromosome 6, which was located near a leptin receptor gene. For serum leptin concentrations, two significant and two suggestive QTLs were detected on chromosomes 6, 9, and 16, and the QTLs on chromosome 6 were also in the same region for fat area ratios.

Effects of porcine leptin receptor gene polymorphisms on backfat thickness, fat area ratios by image analysis, and serum leptin concentrations in a Duroc purebred population.

The leptin receptor (LEPR) gene is considered a candidate gene for fatness traits. It is located on SSC 6 in a region in which quantitative trait loci (QTLs) for backfat thickness (BF), fat area ratios, and serum leptin concentration (LEPC) have previously been detected in a Duroc purebred population. The objectives of the present study were to identify porcine LEPR polymorphisms and examine the effects of LEPR polymorphisms on fatness traits in this same population. The Duroc pigs (226 to 953 pigs) were evaluated for BF, fat area ratios using image analysis, and LEPC. A total of seven single nucleotide polymorphisms (SNPs) in the full-length LEPR coding region were identified in pigs from the base population. Four non-synonymous SNPs of the LEPR gene and 15 microsatellite markers on SSC 6 were then genotyped in all pigs. During candidate gene analysis, we detected significant effects of the non-synonymous SNP c.2002C>T in exon 14 on all traits. In fine mapping analysis, significant QTLs for BF, fat area ratios, and LEPC were detected near the LEPR gene in the same region. These results indicated that the c.2002C>T SNP of LEPR has a strong effect on BF, fat area ratios and LEPC.

Influence of polymorphisms in porcine NOD2 on ligand recognition.

Nucleotide oligomerization domain 2 (NOD2) is a cytosolic pattern recognition receptor (PRR) that responds to muramyldipeptide (MDP), a component of peptidoglycans of gram positive and negative bacteria. NOD2 is involved in the modulation of signaling pathways for other PRRs, such as Toll-like receptors. Polymorphisms in NOD2 may evoke bowel disorders, and human Crohn's disease is significantly correlated with mis-sense insertion of the NOD2 gene. Such polymorphisms affecting ligand recognition in the NOD2 gene may also influence bowel flora in livestock, which is compromised by bowel diseases such as diarrhea. We investigated the functional variance of mis-sense polymorphisms in ligand recognition by porcine NOD2. The 1949T>C polymorphism, located in the region encoding the hinge domain of the molecule, notably diminished the functional response of porcine NOD2 to MDP. By comparison, the 2197A>C polymorphism, localized in the region corresponding to leucine-rich repeats, significantly augmented the response of porcine NOD2 to the ligand. The 1949C allele was rare among pig breeds, suggesting that this mutation is a disadvantage to pigs in their immune response to microbes. The 2197C allele, in contrast, was widely distributed among Western breeds and is most likely to be derived from wild boars in Asia. This is the first report of a causal relationship between molecular function and polymorphisms in PRRs in non-primate, non-rodent mammals. These findings suggest that the 2197C allele might confer an immune response advantage in modern pig breeds and may be a useful marker for breeding aimed at disease resistance in pigs.