NAD+ Levels Are Augmented in Aortic Tissue of ApoE-/- Mice by Dietary Omega-3 Fatty Acids.

BACKGROUND: Maintaining bioenergetic homeostasis provides a means to reduce the risk of cardiovascular events during chronological aging. Nicotinamide adenine dinucleotide (NAD+) acts as a signaling molecule, and its levels were used to govern several biological pathways, for example, promoting angiogenesis by SIRT1 (sirtuin 1)-mediated inhibition of Notch signaling to rejuvenate capillary density of old-aged mice. NAD+ modulation shows promise in the vascular remodeling of endothelial cells. However, NAD+ distribution in atherosclerotic regions remains uncharacterized. Omega-3 polyunsaturated fatty acids consumption, such as docosahexaenoic acid and eicosapentaenoic acid, might increase the abundance of cofactors in blood vessels due to omega-3 polyunsaturated fatty acids metabolism. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice were fed a Western diet, and the omega-3 polyunsaturated fatty acids-treated groups were supplemented with docosahexaenoic acid (1%, w/w) or eicosapentaenoic acid (1%, w/w) for 3 weeks. Desorption electrospray ionization mass spectrometry imaging was exploited to detect exogenous and endogenous NAD+ imaging. RESULTS: NAD+, NADH, NADP+, NADPH, FAD+, FADH, and nicotinic acid adenine dinucleotide of the aortic arches were detected higher in the omega-3 polyunsaturated fatty acids-treated mice than the nontreated control. Comparing the distribution in the outer and inner layers of the arterial walls, only NADPH was detected slightly higher in the outer part in eicosapentaenoic acid-treated mice. CONCLUSIONS: Supplementation of adding docosahexaenoic acid or eicosapentaenoic acid to the Western diet led to a higher NAD+, FAD+, and their metabolites in the aortic arch. Considering the pleiotropic roles of NAD+ in biology, this result serves as a beneficial therapeutic strategy in the animal model counter to pathological conditions.

Diagnostic value of heart-to-mediastinum ratio in 99mTc-pyrophospate SPECT/CT for transthyretin cardiac amyloidosis.

BACKGROUND: In transthyretin cardiac amyloidosis (ATTR-CA), 99mTc-pyrophosphate myocardial scintigraphy (99mTc-PYP) is a diagnostic tool that utilizes visual and quantitative evaluation. However, false positive cases can occur because of tracer accumulation in the blood. We investigated the effectiveness of the heart-to-mediastinum (H/M) ratio of 99mTc-PYP in ATTR-CA diagnosis. METHODS: We retrospectively included 164 patients who underwent 99mTc-PYP single-photon emission computed tomography/computed tomography between March 2019 and January 2022. The diagnostic accuracy of ATTR-CA was examined by the heart-to-contralateral lung (H/CL) and H/M ratio calculated at 3 hours post-tracer administration. RESULTS: After the exclusion of patients who did not undergo endomyocardial biopsy, 30 patients (15 each with ATTR-CA and without ATTR-CA) were included. The receiver operating characteristic curve used to distinguish ATTR-CA from non-ATTR-CA patients revealed an area under the curve of 0.986 and 0.943, respectively. A H/M ratio of > 1.41 identified ATTR-CA patients with a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100, 93.3, 93.3, and 100%, respectively. Conversely, an H/CL ratio of > 1.3 identified ATTR-CA patients with 100% sensitivity, 40.0% specificity, 62.5% PPV, and 100% NPV. CONCLUSION: The H/M ratio obtained at 3 hours post-injection has the potential to be a novel indicator for ATTR-CA.

Early changes of pulmonary arterial hemodynamics in patients with systemic sclerosis: flow pattern, WSS, and OSI analysis with 4D flow MRI.

OBJECTIVES: To study the pulmonary artery (PA) hemodynamics in patients with systemic sclerosis (SSc) using 4D flow MRI (4D-flow). METHODS: Twenty-three patients with SSc (M/F: 2/21, 57 ± 15 years, 3 manifest PA hypertension (PAH) by right heart catheterization) and 10 control subjects (M/F: 1/9, 55 ± 17 years) underwent 4D-flow for the in vivo measurement of 3D blood flow velocities in the PA. Data analysis included area-averaged flow quantification at the main PA, 3D wall shear stress (WSS), oscillatory shear index (OSI) calculation along the PA surface, and Reynolds number. The composite outcome of all-cause death and major adverse cardiac events was also investigated. RESULTS: The maximum PA flow at the systole did not differ, but the minimum flow at the diastole was significantly greater in patients with SSc compared with that in control subjects (7.7 ± 16.0 ml/s vs. ­ 13.0 ± 17.3 ml/s, p < 0.01). The maximum WSS at the peak systole was significantly lower and OSI was significantly greater in patients with SSc compared with those in control subjects (maximum WSS: 1.04 ± 0.20 Pa vs. 1.33 ± 0.34 Pa, p < 0.01, OSI: 0.139 ± 0.031 vs. 0.101 ± 0.037, p < 0.01). The cumulative event-free rate for the composite event was significantly lower in patients with minimum flow in main PA ≤ 9.22 ml/s (p = 0.012) and in patients with Reynolds number ≤ 2560 (p < 0.001). CONCLUSIONS: 4D-flow has the potential to detect changes of PA hemodynamics noninvasively and predict the outcome in patients with SSc at the stage before manifest PAH. KEY POINTS: • The WSS at the peak systolic phase was significantly lower (p < 0.05), whereas OSI was greater (p < 0.01) in patients with SSc without manifest PAH than in controls. • The hemodynamic change detected by 4D-flow may help patient management even at the stage before manifest PAH in SSc. • The minimum PA flow and Reynolds number by 4D-flow will serve as a predictive marker for SSc.

Cardiac Insulin Resistance in Heart Failure: The Role of Mitochondrial Dynamics.

Heart failure (HF) frequently coexists with conditions associated with glucose insufficiency, such as insulin resistance and type 2 diabetes mellitus (T2DM), and patients with T2DM have a significantly high incidence of HF. These two closely related diseases cannot be separated on the basis of their treatment. Some antidiabetic drugs failed to improve cardiac outcomes in T2DM patients, despite lowering glucose levels sufficiently. This may be, at least in part, due to a lack of understanding of cardiac insulin resistance. Basic investigations have revealed the significant contribution of cardiac insulin resistance to the pathogenesis and progression of HF; however, there is no clinical evidence of the definition or treatment of cardiac insulin resistance. Mitochondrial dynamics play an important role in cardiac insulin resistance and HF because they maintain cellular homeostasis through energy production, cell survival, and cell proliferation. The innovation of diagnostic tools and/or treatment targeting mitochondrial dynamics is assumed to improve not only the insulin sensitivity of the myocardium and cardiac metabolism, but also the cardiac contraction function. In this review, we summarized the current knowledge on the correlation between cardiac insulin resistance and progression of HF, and discussed the role of mitochondrial dynamics on the pathogenesis of cardiac insulin resistance and HF. We further discuss the possibility of mitochondria-targeted intervention to improve cardiac metabolism and HF.

Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats.

BACKGROUND: Hypertension promotes cardiac hypertrophy which finally leads to cardiac dysfunction. Although aberrant mitochondrial dynamics is known to be a relevant contributor of pathogenesis in heart disease, little is known about the relationship between mitochondrial dynamics and cardiac hypertrophy. We investigated the pathophysiological roles of Dynamin-related protein1 (Drp1, a mitochondrial fission protein) on the hypertensive cardiac hypertrophy. METHODS & RESULTS: Dahl salt-sensitive rats were fed with a low-salt (0.3% NaCl) or a high-salt (8% NaCl) chow to promote hypertension with and without administration of mdivi1 (an inhibitor of Drp1: 1 mg/kg/every alternative day), and then the hypertensive cardiac hypertrophy was assessed. High-salt fed rats exhibited left ventricular hypertrophy (LVH), myocytes hypertrophy, and cardiac fibrosis, and mdivi-1 suppressed them without alteration of the blood pressure. Mdivi1 also reduced ROS production by hypertension, which subsequently suppressed the Ca2+-activated protein phosphatase calcineurin and Ca2+/calmodulin-dependent kinase II (CaMKII). CONCLUSIONS: Our results suggest that Drp1 contributes to the pathogenesis of hypertensive cardiac hypertrophy via ROS production and the Drp1 suppression may be effective to prevent the hypertensive cardiac hypertrophy.

Ventricular Thrombus Formation Caused by Subendomyocardial Inflammation in Eosinophilic Granulomatosis With Polyangiitis.

Cardiac involvement of eosinophilic granulomatosis with polyangiitis is a rare but life-threatening complication. We present a case of eosinophilic granulomatosis with polyangiitis with moderately impaired ventricular function forming a ventricular thrombus. Pathological assessment of endomyocardial biopsy specimen revealed aggregated eosinophils in the subendocardium, suggesting ventricular endothelial damage leading to thrombus formation.

Rationale and protocol of the LAQUA-HF trial: a factorial randomised controlled trial evaluating the effects of neurohormonal and diuretic agents on health-status reported outcomes in heart failure patients.

INTRODUCTION: The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects. METHODS AND ANALYSIS: In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients' QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients' health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint. ETHICS AND DISSEMINATION: The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses. TRIAL REGISTRATION NUMBER: UMIN000045229.

Sweat lactate sensor for detecting anaerobic threshold in heart failure: a prospective clinical trial (LacS-001).

A simple method for determining the anaerobic threshold in patients with heart failure (HF) is needed. This prospective clinical trial (LacS-001) aimed to investigate the safety of a sweat lactate-monitoring sensor and the correlation between lactate threshold in sweat (sLT) and ventilatory threshold (VT). To this end, we recruited 50 patients with HF and New York Heart Association functional classification I-II (mean age: 63.5 years, interquartile range: 58.0-72.0). Incremental exercise tests were conducted while monitoring sweat lactate levels using our sensor. sLT was defined as the first steep increase in lactate levels from baseline. Primary outcome measures were a correlation coefficient of ≥ 0.6 between sLT and VT, similarities as assessed by the Bland-Altman analysis, and standard deviation of the difference within 15 W. A correlation coefficient of 0.651 (95% confidence interval, 0.391-0.815) was achieved in 32/50 cases. The difference between sLT and VT was -4.9 ± 15.0 W. No comparative error was noted in the Bland-Altman plot. No device-related adverse events were reported among the registered patients. Our sweat lactate sensor is safe and accurate for detecting VT in patients with HF in clinical settings, thereby offering valuable additional information for treatment.

Machine learning-based detection of sleep-disordered breathing in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is often concomitant with sleep-disordered breathing (SDB), which can cause adverse cardiovascular events. Although an appropriate approach to SDB prevents cardiac remodelling, detection of concomitant SDB in patients with HCM remains suboptimal. Thus, we aimed to develop a machine learning-based discriminant model for SDB in HCM. METHODS: In the present multicentre study, we consecutively registered patients with HCM and performed nocturnal oximetry. The outcome was a high Oxygen Desaturation Index (ODI), defined as 3% ODI >10, which significantly correlated with the presence of moderate or severe SDB. We randomly divided the whole participants into a training set (80%) and a test set (20%). With data from the training set, we developed a random forest discriminant model for high ODI based on clinical parameters. We tested the ability of the discriminant model on the test set and compared it with a previous logistic regression model for distinguishing SDB in patients with HCM. RESULTS: Among 369 patients with HCM, 228 (61.8%) had high ODI. In the test set, the area under the receiver operating characteristic curve of the discriminant model was 0.86 (95% CI 0.77 to 0.94). The sensitivity was 0.91 (95% CI 0.79 to 0.98) and specificity was 0.68 (95% CI 0.48 to 0.84). When the test set was divided into low-probability and high-probability groups, the high-probability group had a higher prevalence of high ODI than the low-probability group (82.4% vs 17.4%, OR 20.9 (95% CI 5.3 to 105.8), Fisher's exact test p<0.001). The discriminant model significantly outperformed the previous logistic regression model (DeLong test p=0.03). CONCLUSIONS: Our study serves as the first to develop a machine learning-based discriminant model for the concomitance of SDB in patients with HCM. The discriminant model may facilitate cost-effective screening tests and treatments for SDB in the population with HCM.

Phenotyping of Elderly Patients With Heart Failure Focused on Noncardiac Conditions: A Latent Class Analysis From a Multicenter Registry of Patients Hospitalized With Heart Failure.

Background The burden of noncardiovascular conditions is becoming increasingly prevalent in patients with heart failure (HF). We aimed to identify novel phenogroups incorporating noncardiovascular conditions to facilitate understanding and risk stratification in elderly patients with HF. Methods and Results Data from a total of 1881 (61.2%) patients aged ≥65 years were extracted from a prospective multicenter registry of patients hospitalized for acute HF (N=3072). We constructed subgroups of patients with HF with preserved ejection fraction (HFpEF; N=826, 43.9%) and those with non-HFpEF (N=1055, 56.1%). Latent class analysis was performed in each subgroup using 17 variables focused on noncardiovascular conditions (including comorbidities, Clinical Frailty Scale, and Geriatric Nutritional Risk Index). The latent class analysis revealed 3 distinct clinical phenogroups in both HFpEF and non-HFpEF subgroups: (1) robust physical and nutritional status (Group 1: HFpEF, 41.2%; non-HFpEF, 46.0%); (2) multimorbid patients with renal impairment (Group 2: HFpEF, 40.8%; non-HFpEF, 41.9%); and (3) malnourished patients (Group 3: HFpEF, 18.0%; non-HFpEF, 12.1%). After multivariable adjustment, compared with Group 1, patients in Groups 2 and 3 had a higher risk for all-cause death over the 1-year postdischarge period (hazard ratio [HR], 2.79 [95% CI, 1.64-4.81] and HR, 2.73 [95% CI, 1.39-5.35] in HFpEF; HR, 1.96 [95% CI, 1.22-3.14] and HR, 2.97 [95% CI, 1.64-5.38] in non-HFpEF; respectively). Conclusions In elderly patients with HF, the phenomapping focused on incorporating noncardiovascular conditions identified 3 phenogroups, each representing distinct clinical outcomes, and the discrimination pattern was similar for both patients with HFpEF and non-HFpEF. This classification provides novel risk stratification and may aid in clinical decision making.

Prevalence and Characteristics of Inspiration-Induced Negative Left Atrial Pressure during Pulmonary Vein Isolation.

BACKGROUND: Atrial fibrillation (AF) ablation is performed under deep sedation, which may cause inspiration-induced negative left atrial pressure (INLAP) associated with deep inspiration. INLAP could be the cause of periprocedural complications. METHODS: We retrospectively enrolled 381 patients with AF (mean age, 63.9 ± 10.8 years; 76 women; 216 cases of paroxysmal AF) who underwent CA under deep sedation using an adaptive servo ventilator (ASV). Patients whose LAP was not obtained were excluded. INLAP was defined as <0 mmHg of mean LAP during inspiration immediately after the transseptal puncture. The primary and secondary endpoints were the presence of INLAP and the incidence of periprocedural complications. RESULTS: Among 381 patients, INLAP was observed in 133 (34.9%). Patients with INLAP had higher CHA2DS2-Vasc scores (2.3 ± 1.5 vs. 2.1 ± 1.6) and 3% oxygen desaturation indexes (median 18.6 (interquartile range 11.2-31.1) vs. 15.7 (8.1-25.3)), and higher prevalence of diabetes mellitus (23.3 vs. 13.3%) than patients without INLAP. Air embolism occurred in four patients with INLAP (3.0 vs. 0.0%). CONCLUSION: INLAP is not rare in patients undergoing CA for AF under deep sedation with ASV. Much attention should be paid to the possibility of air embolism in patients with INLAP.

Association of an Increased Abnormal Mitochondria Ratio in Cardiomyocytes with a Prolonged Oxygen Uptake Time Constant during Cardiopulmonary Exercise Testing of Patients with Non-ischemic Cardiomyopathy.

Objective The cardiac function, blood distribution, and oxygen extraction in the muscles as well as the pulmonary function determine the oxygen uptake (VO2) kinetics at the onset of exercise. This factor is called the VO2 time constant, and its prolongation is associated with an unfavorable prognosis for heart failure (HF). The mitochondrial function of skeletal muscle is known to reflect exercise tolerance. Morphological changes and dysfunction in cardiac mitochondria are closely related to HF severity and its prognosis. Although mitochondria play an important role in generating energy in cardiomyocytes, the relationship between cardiac mitochondria and the VO2 time constant has not been elucidated. Methods We calculated the ratio of abnormal cardiac mitochondria in human myocardial biopsy samples using an electron microscope and measured the VO2 time constant during cardiopulmonary exercise testing. The VO2 time constant was normalized by the fat-free mass index (FFMI). Patients Fifteen patients with non-ischemic cardiomyopathy (NICM) were included. Patients were divided into two groups according to their median VO2 time constant/FFMI value. Results Patients with a low VO2 time constant/FFMI value had a lower abnormal mitochondria ratio than those with a high VO2 time constant/FFMI value. A multiple linear regression analysis revealed that the ratio of abnormal cardiac mitochondria was independently associated with a high VO2 time constant/FFMI. Conclusion An increased abnormal cardiac mitochondria ratio might be associated with a high VO2 time constant/FFMI value in patients with NICM.

The association between the clinical severity of heart failure and docosahexaenoic acid accumulation in hypertrophic cardiomyopathy.

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is a common genetic disease with diverse morphology, symptoms, and prognosis. Hypertrophied myocardium metabolism has not been explored in detail. We assessed the association between myocardium lipid metabolism and clinical severity of heart failure (HF) in HCM using imaging mass spectrometry (IMS). RESULTS: We studied 16 endomyocardial biopsy (EMB) specimens from patients with HCM. Analysis was conducted using desorption electrospray ionization IMS. The samples were assigned into two cohorts according to the period of heart biopsy (cohort 1, n = 9 and cohort 2, n = 7). In each cohort, samples were divided into two groups according to the clinical severity of HF in HCM: clinically severe and clinically mild groups. Signals showing a significant difference between the two groups were analyzed by volcano plot. In cohort 1, the volcano plot identified four signals; the intensity in the clinically severe group was more than twice that of the mild group. Out of the four signals, docosahexaenoic acid (DHA) showed significant differences in intensity between the two groups in cohort 2 (10,575.8 ± 2750.3 vs. 19,839.3 ± 4803.2, P = 0.025). The intensity of DHA was significantly higher in EMB samples from the clinically severe HCM group than in those from the mild group.

Pre-procedural predictors of left atrial low-voltage zones in patients undergoing catheter ablation of atrial fibrillation.

Pulmonary vein isolation has become a cornerstone treatment for catheter ablation of atrial fibrillation (AF). Recent reports show that additional ablation targeting low-voltage zones reduces AF recurrence. However, the pre-procedural predictors of low-voltage zones remain elusive. We retrospectively enrolled 359 patients (mean age 63.7 ± 10.8 years; 73 females; and 149 had persistent atrial fibrillation) who underwent catheter ablation for AF and left atrial (LA) voltage mapping during sinus rhythm or atrial pacing. Low-voltage zones were defined as area of > 5 cm2 with a bipolar electrogram amplitude of < 0.50 mV. Overall, 51 (14.2%) patients had low-voltage zones. Patients with low-voltage zones were older (67.9 ± 9.9 vs. 63.0 ± 10.8 years; P = 0.003), predominantly female (33.3% vs. 18.2%; P = 0.013), had higher prevalence of dilated cardiomyopathy (DCM) (11.8% vs. 1.6%; P = 0.002) and hypertrophic cardiomyopathy (HCM) (9.8% vs. 2.6%; P = 0.025), and had larger LA volumes (153.6 ± 46.4 vs. 117.7 ± 67.8 mL; P < 0.001) than those without low-voltage zones. Multivariate logistic regression analysis revealed that age (OR 1.060; 95% CI 1.022-1.101, P = 0.002), female sex (OR 2.978; 95% CI 1.340-6.615, P = 0.007), DCM (OR 8.341; 95% CI 1.381-50.372, P = 0.021), HCM (OR 5.044; 95% CI 1.314-19.363, P = 0.018), persistent AF (OR 4.188; 95% CI 1.928-9.100, P < 0.001), and larger LA volume (OR 3.215; 95% CI 1.378-7.502, P = 0.007) were independently associated with the presence of low-voltage zones. Patient age, female sex, DCM, HCM, persistent AF and larger LA volume may predict the presence of low-voltage zones and could be useful in selecting the appropriate ablation strategy for AF.

Association between plasma xanthine oxidoreductase activity and in-hospital outcomes in patients with stable coronary artery disease after percutaneous coronary intervention.

OBJECTIVES: Reactive oxygen species generated by xanthine oxidoreductase (XOR) are associated with the progression of atherosclerosis. However, changes in plasma XOR (pXOR) activity after percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) remains unknown. METHODS: Herein, we compared the change in the pXOR activity in patients undergoing PCI with that in patients undergoing coronary angiography (CAG) and further evaluated the relation between changes in pXOR activity and in-hospital and long-term outcomes of patients undergoing PCI. The pXOR activity of 80 consecutive patients who underwent PCI and 25 patients who underwent CAG during the hospitalization was analyzed daily. The percentage changes from baseline regulated time interval was evaluated. RESULTS: We found that although pXOR activity decreased after PCI, and remained low until discharge, no significant changes were observed in patients undergoing CAG. Furthermore, among the patients undergoing PCI, those who experienced in-hospital adverse events, had a higher percentage of pXOR reduction 3 days after PCI. There was no association between these changes and long-term events. CONCLUSIONS: A significant change in pXOR activity was observed in patients undergoing PCI than in patients undergoing CAG, and there seems to be a correlation between the in-hospital outcomes and the percentage reduction from baseline in pXOR activity.

Cardiotoxicity of Carfilzomib in Two Japanese Patients with Relapsed Multiple Myeloma.

Although multiple myeloma (MM) had been an incurable hematological malignancy with a poor prognosis, recent advances in novel anti-neoplastic agents, including carfilzomib (a proteasome inhibitor), have improved the prognosis. We herein report two cases of congestive heart failure in patients treated with carfilzomib. Although there are some reports on the cardiotoxicity of carfilzomib, to our knowledge, this is the first report on the cardiac involvement of carfilzomib in Japanese MM patients. We review the critical points from our two cases, with the aim of avoiding carfilzomib-associated heart failure in MM patients.