Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension : a multicenter, prospective, exploratory study (DIANA)

Introduction Dotinurad is a newer urate-lowering agent that selectively inhibits urate transporter 1 in the renal proximal tubule and increases urinary urate excretion. Currently, little is known about the clinical efficacies of dotinurad in patients with hyperuricemia and hypertension. The aim of this study was to assess the clinical effects of a selective urate reabsorption inhibitor dotinurad on serum uric acid (SUA) levels and relevant vascular markers in patients with hyperuricemia and treated hypertension. Methods This investigator-initiated, multicenter, prospective, single-arm, open-label, exploratory clinical trial in Japan enrolled patients with hyperuricemia and treated hypertension who received a 24-week dotinurad therapy (a starting dose at 0.5 mg once daily and up-titrated to 2 mg once daily). The primary endpoint was a percentage change in the SUA level from baseline to week 24. The secondary endpoints were cardiovascular and metabolic measurements, including changes in the cardio-ankle vascular index (CAVI) and derivatives of reactive oxygen metabolites (d-ROMs) concentration at week 24. Results Fifty patients (mean age 70.5 ± 11.0 years, with 76.0% being men, and mean SUA level 8.5 ± 1.2 mg/dL) were included in the analysis. The percentage change from baseline in the SUA level at week 24 was − 35.8% (95% confidence interval [CI] − 39.7% to − 32.0%, P < 0.001), with approximately three quarters of patients achieving an SUA level of ≤ 6.0 mg/dL at week 24. The proportional changes from baseline in the geometric mean of CAVI and d-ROMs at week 24 were 0.96 (95% CI 0.92 to 1.00, P = 0.044) and 0.96 (95% CI 0.92 to 1.00, P = 0.044), respectively. Conclusion In addition to meaningful SUA-lowering effects, 24 weeks of dotinurad therapy may favorably affect arterial stiffness and oxidative stress markers, suggesting off-target vascular protection of dotinurad. Further research is expected to verify our findings and elucidate the entire off-target effects of dotinurad

Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis : the PROTECT study

Background: Type 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus. Methods: A total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50–100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies. Discussion: The PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Assessment of Bi-Ventricular and Bi-Atrial Areas Using Four-Chamber Cine Cardiovascular Magnetic Resonance Imaging: Fully Automated Segmentation with a U-Net Convolutional Neural Network

Four-chamber (4CH) cine cardiovascular magnetic resonance imaging (CMR) facilitates simultaneous evaluation of cardiac chambers; however, manual segmentation is time-consuming and subjective in practice. We evaluated deep learning based on a U-Net convolutional neural network (CNN) for fully automated segmentation of the four cardiac chambers using 4CH cine CMR. Cine CMR datasets from patients were randomly assigned for training (1400 images from 70 patients), validation (600 images from 30 patients), and testing (1000 images from 50 patients). We validated manual and automated segmentation based on the U-Net CNN using the dice similarity coefficient (DSC) and Spearman&rsquo;s rank correlation coefficient (&rho;); p &lt; 0.05 was statistically significant. The overall median DSC showed high similarity (0.89). Automated segmentation correlated strongly with manual segmentation in all chambers&mdash;the left and right ventricles, and the left and right atria (end-diastolic area: &rho; = 0.88, 0.76, 0.92, and 0.87; end-systolic area: &rho; = 0.81, 0.81, 0.92, and 0.83, respectively; p &lt; 0.01). The area under the curve for the left ventricle, left atrium, right ventricle, and right atrium showed high scores (0.96, 0.99, 0.88, and 0.96, respectively). Fully automated segmentation could facilitate simultaneous evaluation and detection of enlargement of the four cardiac chambers without any time-consuming analysis

Differentiation between mild and severe myocarditis using multiparametric cardiac magnetic resonance

The pathophysiology of myocarditis is associated with mild inflammation and may progress silently, or in severe cases such as fulminant myocarditis, may lead to sudden hemodynamic compromise. An invasive myocardial biopsy is generally required for a definitive myocarditis diagnosis. Alternatively, cardiac magnetic resonance (CMR), which evaluates myocardial characteristics and cardiac function, can be used as a noninvasive tool for diagnosing myocarditis. We describe the cases of a 49-year-old woman with mild acute eosinophilic myocarditis and a 48-year-old man with severe acute lymphocytic myocarditis. CMR was performed during the acute and convalescent phases in both cases. Compared with mild myocarditis, CMR in severe myocarditis showed higher T2 values and decreased left ventricular and atrial volumes and strains; however, the right ventricular strain was preserved. Late gadolinium enhancement showed faint contrast enhancement in the whole and strong enhancement in the local myocardium. Follow-up CMR showed recovery from myocardial inflammation and cardiac function. Some late gadolinium enhancement persisted whereas acute inflammation-associated enhancement disappeared. This case report highlights the differences between the cardiac parameters of patients with mild and severe myocarditis. Severe myocardial inflammation can be caused by severe heart failure owing to the concurrent reduction of cardiac function and compliance. Additionally, preserved right ventricular strain may predict cardiac function recovery in acute myocarditis. Noninvasive and repeatable CMR provides information on myocardial characteristics, cardiac function, and hemodynamics in a single scan at that time, which is useful not only for diagnosis but also for severity assessment and patient management in acute myocarditis

Assessing myocardial circumferential strain using cardiovascular magnetic resonance after magnetic resonance-conditional cardiac resynchronization therapy

Nondrug therapy for arrhythmia patients had been developed dramatically until recent years. Cardiac resynchronization therapy (CRT), a nondrug therapy for arrhythmia, is especially utilized for the treatment of left ventricular (LV) severe heart failure caused by cardiac dyssynchrony. Prolonged QRS duration (≧130 ms) is strongly used as a CRT indication criterion, but QRS is not the direct clinical index of mechanical contraction delay of the LV myocardium. Therefore, identifying the presence of dyssynchrony by diagnostic imaging is necessary. Echocardiography is widely used for the assessment of dyssynchrony as a standard diagnostic imaging. Several studies have addressed the efficacy of cardiovascular magnetic resonance feature tracking (CMR-FT) in the diagnosis of dyssynchrony for arrythmia patients. In addition, cardiac implantable electronic devices (CIEDs) were not available to examine CMR until recent years; however, new MR-conditional CIEDs have become available for use before and after CRT. Recently, diagnostic imaging using CMR-FT has been attracting attention for the assessment of dyssynchrony. However, a strong metal artifact caused by CIEDs may make the analysis difficult after CRT implantation. Strain analysis using short-axis (SA) cine CMR overcame this issue of artifact by enabling slice selection by avoiding artifact. Moreover, circumferential strain has superiority over other strain methods with respect to sensitivity, and we focused on these advantages. This case illustrates that circumferential strain with CMR-FT using SA cine CMR is useful in the assessment of improvement of myocardial motion after CRT and can provide useful additional information with imaging to determine the responders of CRT

Assessment of Bi-Ventricular and Bi-Atrial Areas Using Four-Chamber Cine Cardiovascular Magnetic Resonance Imaging: Fully Automated Segmentation with a U-Net Convolutional Neural Network

Four-chamber (4CH) cine cardiovascular magnetic resonance imaging (CMR) facilitates simultaneous evaluation of cardiac chambers; however, manual segmentation is time-consuming and subjective in practice. We evaluated deep learning based on a U-Net convolutional neural network (CNN) for fully automated segmentation of the four cardiac chambers using 4CH cine CMR. Cine CMR datasets from patients were randomly assigned for training (1400 images from 70 patients), validation (600 images from 30 patients), and testing (1000 images from 50 patients). We validated manual and automated segmentation based on the U-Net CNN using the dice similarity coefficient (DSC) and Spearman’s rank correlation coefficient (ρ); p < 0.05 was statistically significant. The overall median DSC showed high similarity (0.89). Automated segmentation correlated strongly with manual segmentation in all chambers—the left and right ventricles, and the left and right atria (end-diastolic area: ρ = 0.88, 0.76, 0.92, and 0.87; end-systolic area: ρ = 0.81, 0.81, 0.92, and 0.83, respectively; p < 0.01). The area under the curve for the left ventricle, left atrium, right ventricle, and right atrium showed high scores (0.96, 0.99, 0.88, and 0.96, respectively). Fully automated segmentation could facilitate simultaneous evaluation and detection of enlargement of the four cardiac chambers without any time-consuming analysis