Association of Multiple Nonhypertrophic Cardiomyopathy-Related Genetic Variants and Outcomes in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient. OBJECTIVES: In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants. METHODS: The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants." RESULTS: Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010). CONCLUSIONS: Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

Association Between Clonal Hematopoiesis and Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy.

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

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.

The first case report of de novo Crohn's disease after heart transplantation successfully treated with ustekinumab.

Inflammatory bowel disease (IBD) is a complex chronic inflammatory intestinal disease. The development of de novo IBD after solid organ transplantation with immunosuppressive agents has been rarely reported. We present the case of a 65-year-old man with repeated colitis after heart transplantation (HTx) who was diagnosed with Crohn's disease (CD). The patient underwent HTx due to non-ischemic dilated cardiomyopathy. Six months after HTx, he developed serious diarrhea and a transient fever, which persisted for about 6 months. Valganciclovir or any antibiotic agents were not effective for his symptoms and longitudinal ulcers in colonoscopy aggravated during the course, so that we made a diagnosis of CD. We started 5-aminosalicylic acid and found improvement in his symptoms and colonoscopic findings. However, 7 months after improvement, CD worsened. We started ustekinumab by which his condition successfully went into remission again. While oral immunosuppressive drugs are thought to suppress autoimmune diseases in general, IBD should be included in the differential diagnoses for recurring enterocolitis after HTx. Poorly controlled CD can lead to serious and potentially fatal complications, but in this case, ustekinumab has been used safely and effectively for the treatment of CD. Learning objective: Colitis is a common complication after heart transplantation (HTx). Although cytomegalovirus colitis or posttransplant lymphoproliferative disorder are observed commonly, de novo inflammatory bowel disease (IBD) should be considered when serious refractory colitis occurs. Not only 5-aminosalicylic acid but also ustekinumab, which is a monoclonal antibody to the p40 subunit of interleukin (IL)-12 and IL-23, may be a safe and effective treatment for de novo IBD after HTx.

Right Heart Reserve Function Assessed With Fluid Loading Predicts Late Right Heart Failure After Left Ventricular Assist Device Implantation.

BACKGROUND: A left ventricular assist device (LVAD) is an effective therapeutic option for advanced heart failure. Late right heart failure (LRHF) is a complication after LVAD implantation that is associated with increasing morbidity and mortality; however, the assessment of right heart function, including right heart reserve function after LVAD implantation, has not been established. We focused on a fluid-loading test with right heart catheterization to evaluate right heart preload reserve function and investigate its impact on LRHF. METHODS: Patients aged > 18 years who received a continuous-flow LVAD between November 2007 and December 2022 at our institution, and underwent right heart catheterization with saline loading (10 mL/kg for 15 minutes) 1 month after LVAD implantation, were included. RESULTS: Overall, 31 cases of LRHF or death (right heart failure [RHF] group) occurred in 149 patients. In the RHF vs the non-RHF groups, the pulmonary artery pulsatility index (PAPi) at rest (1.8 ± 0.89 vs 2.5 ± 1.4, P = 0.02) and the right ventricular stroke work index (RVSWi) change ratio with saline loading (0.96 ± 0.32 vs 1.1 ± 0.20, P = 0.03) were significantly different. The PAPi at rest and the RVSWi change ratio with saline loading were identified as postoperative risks for LRHF and death. The cohort was divided into 3 groups based on whether the PAPi at rest and the RVSWi change ratio were low. The event-free curve differed significantly among the 3 groups (P < 0.001). CONCLUSIONS: Hemodynamic assessment with saline loading can evaluate the right ventricular preload reserve function of patients with an LVAD. A low RVSWi change with saline loading was a risk factor for LRHF following LVAD implantation.

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.

Multivessel Coronary Artery Dissection in a Patient with Co-Occurrence of Aortic Dissection and Dilated Cardiomyopathy in the Postpartum Period.

The co-occurrence of dilated cardiomyopathy (DCM) and aortic dissection has been rarely reported. Here, we present the case of a patient with co-occurrence of DCM and aortic dissection, wherein multivessel coronary artery dissection eventually occurred, thereby leading to advanced heart failure. She suffered from co-occurrence of DCM and aortic dissection 6 years ago. After the heart failure had briefly stabilized, the myocardial infarction due to coronary artery dissection led to worsening mitral regurgitation and decreased right ventricular function, thereby worsening the status of her heart failure. In addition to cardiovascular abnormalities, the patient was also complicated by short stature (145 cm), mild scoliosis, nonfunctioning pituitary adenoma of 1 cm in size, and retinitis pigmentosa. Coronary artery dissection is a possible complication in patients with co-occurrence of DCM and aortopathy, which could dramatically affect the clinical course of advanced heart failure.

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.

A new assessment method for right ventricular diastolic function using right heart catheterization by pressure-volume loop.

Diastolic stiffness coefficient (ß) and end-diastolic elastance (Eed) are ventricular-specific diastolic parameters. However, the diastolic function of right ventricle had not been investigated sufficiently due to the lack of established evaluation method. We evaluated the validity of these parameters calculated using only data of right heart catheterization (RHC) and assessed it in patients with restrictive cardiomyopathy (RCM) and cardiac amyloidosis. We retrospectively analyzed 46 patients with heart failure who underwent RHC within 10 days of cardiac magnetic resonance (CMR). Right ventricular end-diastolic volume and end-systolic volume were calculated using only RHC data, which were found to be finely correlated with those obtained from CMR. ß and Eed calculated by this method were also significantly correlated with those derived from conventional method using CMR. By this method, ß and Eed were significantly higher in RCM with amyloidosis group than dilated cardiomyopathy group. In addition, the ß and Eed calculated by our method were finely correlated with E/A ratio on echocardiography. We established an easy method to estimate ß and Eed of right ventricle from only RHC. The method finely demonstrated right ventricular diastolic dysfunction in patients with RCM and amyloidosis.

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.

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.

Summation of Precordial R Wave Amplitudes, a Clinical Parameter for Detecting Early TTR Amyloidosis Cardiac Involvement.

There have been several reports on the identification of the stage of transthyretin amyloid cardiomyopathy (ATTR-CM); however, a staging system for ATTR-CM has not yet been established. An 83-year-old woman was referred to our department about ten years ago. Recently, she was diagnosed with ATTR-CM. The electrocardiogram showed characteristic changes that take place over the duration of ATTR-CM progression. Among these, the precordial R amplitudes abruptly decreased before the development of increased ventricular thickness. This case suggested that the decrease in the precordial R wave amplitudes may represent a new diagnostic clue reflecting early myocardial damage due to ATTR-CM.

The effect of immunosuppressive therapy on cardiac involvements in anti-mitochondrial antibody-positive myositis.

AIMS: Anti-mitochondrial antibody (AMA)-positive myositis is frequently associated with various cardiac involvements, such as arrhythmia and left ventricular (LV) dysfunction. However, the efficacy of immunosuppressive therapy in these complications remains unknown. This study aimed to investigate the cardiac response to immunosuppressive therapy in patients with AMA-positive myositis. METHODS AND RESULTS: The clinical data of 15 AMA-positive myositis patients with cardiac involvement were retrospectively collected at our centre. To evaluate the effects of immunosuppressive therapy, echocardiographic and laboratory data of patients who received glucocorticoid therapy with additional immunosuppressants (n = 6) and those who did not (n = 6) were compared. Also, the characteristics of patients with or without >5% LV ejection fraction (LVEF) decline during the follow-up period (n = 5 vs. n = 7) were compared. Thirteen patients (87%) had arrhythmias, and eight patients (53%) had LV wall motion abnormalities. Although arrhythmias decreased after treatment, reduced LVEF and LV wall motion abnormalities persisted. Further investigation revealed an increased LV end-systolic dimension and reduced LVEF in patients without additional immunosuppressive therapy, while those in patients with additional immunosuppressive therapy were maintained. Six of seven patients (86%) without LVEF decline received additional immunosuppressive therapy, whereas no patients with LVEF decline had additional immunosuppressive therapy. CONCLUSIONS: Cardiac involvement in AMA-positive myositis may worsen even with glucocorticoid monotherapy, and there might be some associations between the change of LV function and additional immunosuppressive therapy.

Successful treatment of recurrent cardiac sarcoidosis with the combination of corticosteroid and methotrexate monitored by 18F-fluoro-2-deoxyglucose positron emission tomography: case series.

Background: The standard treatment for cardiac sarcoidosis (CS) is corticosteroids, including prednisolone (PSL). Previous studies have shown that the addition of methotrexate (MTX) to PSL is effective for steroid-refractory and recurrent cases. 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is an essential tool for the diagnosis of CS. However, it is unclear whether FDG-PET is useful for detecting recurrence of CS and monitoring the effectiveness of PSL and MTX combination therapy. Case summary: We detected CS recurrence during PSL treatment using FDG-PET. Patient 1 was accompanied by increased FDG uptake in other organs, Patient 2 was complicated with a decrease in left ventricular ejection fraction, and Patient 3 showed enlargement of the late gadolinium enhancement area, which was compatible with the recurrence of CS. We successfully monitored the inflammation activity by FDG-PET and treated recurrent CS by increasing the PSL dose and adding MTX to suppress inflammation. Discussion: FDG-PET is useful for detecting CS recurrence and monitoring the effectiveness of PSL and MTX combination therapy. Serial FDG-PET scans indicated that it might be more difficult to suppress inflammation in recurrent CS than in the initial treatment. The use of FDG-PET is necessary to monitor long-term disease activity.

Residual Pulmonary Vascular Resistance Increase Under Left Ventricular Assist Device Support Predicts Long-Term Cardiac Function After Heart Transplantation.

Aims: We compared hemodynamics and clinical events after heart transplantation (HTx) in patients stratified by the severity of residual pulmonary vascular resistance (PVR) after left ventricular assist device (LVAD) implantation for bridge to transplantation. Methods: We retrospectively analyzed patients who had undergone HTx at the University of Tokyo Hospital. We defined the high PVR group as patients with PVR of >3 Wood Units (WU) as measured by right heart catheterization performed 1 month after LVAD implantation. Results: We included 85 consecutive HTx recipients, 20 of whom were classified in the high PVR group and 65 in the low PVR group. The difference in PVR between the two groups became apparent at 2 years after HTx (the high PVR group: 1.77 ± 0.41 WU, the low PVR group: 1.24 ± 0.59 WU, p = 0.0009). The differences in mean pulmonary artery pressure (mPAP), mean right arterial pressure (mRAP), and mean pulmonary capillary wedge pressure (mPCWP) tended to increase from the first year after HTx, and were all significantly higher in the high PVR group at 3 years after HTx (mPAP: 22.7 ± 9.0 mm Hg vs. 15.4 ± 4.3 mm Hg, p = 0.0009, mRAP: 7.2 ± 3.6 mm Hg vs. 4.1 ± 2.1 mm Hg, p = 0.0042, and mPCWP: 13.4 ± 4.5 mm Hg, 8.8 ± 3.3 mm Hg, p = 0.0040). In addition, pulmonary artery pulsatility index was significantly lower in the high PVR group than in the low PVR group at 3 years after HTx (2.51 ± 1.00 vs. 5.21 ± 3.23, p = 0.0033). The composite event including hospitalization for heart failure, diuretic use, and elevated intracardiac pressure (mRAP ≥ 12 mm Hg or mPCWP ≥ 18 mm Hg) between the two groups was significantly more common in the high PVR group. Residual high PVR was still an important predictor (hazard ratio 6.5, 95% confidence interval 2.0-21.6, and p = 0.0023) after multivariate Cox regression analysis. Conclusion: Our study demonstrates that patients with residual high PVR under LVAD implantation showed the increase of right and left atrial pressure in the chronic phase after HTx.

Determining the factors for interhospital transfer in advanced heart failure cases.

Background: There are some patients with advanced heart failure (HF), for whom implantable left ventricular assist device (LVAD) or heart transplantation (HTx) should be considered. Some of them need to be transferred between hospitals. There are few reports on the interhospital transfer of patients with advanced HF and their subsequent clinical course.In this study, we investigated the characteristics and clinical course of patients transferred to a LVAD/HTx center, focusing on the distance between hospitals. Methods: We retrospectively examined 141 patients who were transferred to our hospital, considering the indications of LVAD implantation or HTx. We divided the patients into two groups: those referred <33 km (short-distance) and those referred more than 33 km (long-distance). The primary outcome was the composite outcome of increased catecholamine dose, mechanical support, or renal dysfunction within 1 week of transfer. Results: Continuous catecholamine infusion was significantly more common in patients in the long-distance group, whereas extracorporeal membrane oxygenation (ECMO) placement was significantly more common in short-distance group.Patients transferred via long distance had significantly higher rates of increased catecholamine doses, mechanical support including intra-aortic balloon pumping (IABP) and ECMO, and renal dysfunction within 1 week of transfer than patients transferred via short distance. Multivariate analysis showed that low body mass index (BMI) and long distance were independent predictive factors for the primary outcome. Conclusions: When patients with advanced HF are transferred from far distant hospitals or with low BMI, it may be necessary to devise various measures for interhospital transport.

Recovery of sinus rhythm by tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy with atrial arrhythmias.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening infiltrative disease in elderly patients. Atrial arrhythmias (AAr) are common in patients with ATTR-CM. However, AAr treatment in these patients is challenging. In this case, a patient diagnosed with wild-type ATTR-CM suffered atrial fibrillation (AF) for ~1 year, according to the data of his self-monitoring and regular electrocardiogram. This AF reverted to normal sinus rhythm a few months after the initiation of tafamidis without administering an antiarrhythmic drug. Tafamidis may be beneficial as alternative antiarrhythmic therapy in patients with ATTR-CM.