Osteoporotic fracture risk in women with breast cancer treated with aromatase inhibitors: a health insurance claims database study in Japan.

BACKGROUND: Hormone therapy with aromatase inhibitors (AIs) for estrogen receptor-dependent breast cancer may expose patients to an increased osteoporosis risk. This study was performed to estimate fracture risk in women with breast cancer to whom AIs were prescribed in Japan. METHODS: This retrospective study used data from the Japanese Medical Data Vision database. Women with breast cancer prescribed AIs over a 12-month period were identified and matched to women not prescribed AIs using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared using a cause-specific Cox hazard model. The proportion of women undergoing bone density tests was retrieved. RESULTS: For all fractures sites combined, cumulative fracture incidence at 10 years was 0.19 [95%CI: 0.16-0.22] in women prescribed AIs and 0.18 [95%CI: 0.15-0.21] without AIs. AI prescription was not associated with any changes in risk (adjusted hazard ratio: 1.08 [95%CI: 0.99-1.17] p = 0.08). Women prescribed AI more frequently underwent bone density testing (31.9% [95% CI: 31.2%; 32.6%] versus 2.2% [95% CI: 2.0%; 2.4%]). CONCLUSIONS: The anticipated association between AI exposure and osteoporotic fracture risk in Japanese women with breast cancer was not seen clearly.

Androgen deprivation therapy-related fracture risk in prostate cancer: an insurance claims database study in Japan.

INTRODUCTION: Androgen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan. MATERIALS AND METHODS: Data were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry. RESULTS: 30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52-1.75]). CONCLUSION: ADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

Efficacy and safety of mirogabalin for chemotherapy-induced peripheral neuropathy: a prospective single-arm trial (MiroCIP study).

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks' intervention on chemotherapy completion and CIPN severity. METHODS: Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events. RESULTS: Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), - 1.7 (- 2.4 to - 1.0) (p < 0.001). Patients with baseline NRS of ≥ 6 experienced a 44.0% reduction in score from baseline to week 12 (LOCF): mean change (95% CI), - 3.3 (- 5.0 to - 1.5) (p = 0.002). Chemotherapy was discontinued in 18 (34.6%) patients; CIPN led to discontinuation in only 2 (3.8%). There was no notable worsening of CIPN severity in terms of Common Terminology Criteria for Adverse Events grade or Modified Total Neuropathy Score-reduced, although use of pain medications during chemotherapy might cause worsening of CIPN due to underestimation of subjective symptoms. QOL score based on the EuroQol five-dimensional descriptive system did not worsen during the 12 weeks. Thirty-one percent of patients experienced adverse drug reactions, and the most common event was somnolence (13.5%). Serious adverse events and death occurred in 3 patients and 1 patient, respectively; however, they were unrelated to mirogabalin treatment. CONCLUSIONS: Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021).

Relationship between the dose titration and adherence of mirogabalin in patients with peripheral neuropathic pain depending on renal function: a nationwide electronic medical record database study.

BACKGROUND: Mirogabalin has been attracting attention for treating peripheral neuropathic pain. The package insert recommends that mirogabalin should be titrated depending on renal function. Here, we investigated the relationship between dose titration patterns and adherence, and persistence of mirogabalin treatment. RESEARCH DESIGN AND METHODS: Peripheral neuropathic pain patients who initiated mirogabalin between March 2020 and May 2021 were identified using an electronic medical record database. The dose titration pattern was described according to degrees of renal function. Regression analyses were performed to compare adherence and persistence between the patients with and without titration. RESULTS: Of the 4,138 identified patients, 1,696 (41.0%) titrated the dose within 45 days and were more adherent than those without titration (Adjusted odds ratio: 1.75, 95% CI 1.21, 2.54). Of the total 952 patients with renal function parameters, 229 (24.1%) titrated to the effective dose within 45 days and were less likely to discontinue than those without titration (Adjusted hazard ratio: 0.57, 95% CI 0.40, 0.81). CONCLUSION: Mirogabalin dose titration was associated with better adherence and persistence. It is important for mirogabalin treatment to determine the initial prescription dose based on renal function and subsequent dose titration according to the package insert. TRIAL REGISTRATION: UMIN000047313.

Contrast defect of left atrial appendage on computed tomography is associated with higher risk of recurrence after catheter ablation in patients with paroxysmal atrial fibrillation.

The previous study has shown that the contrast defect of the left atrial appendage (LAA) on contrast-enhanced cardiac computed tomography (CT) is associated with a higher rate of stroke in patients with atrial fibrillation (AF). This study aimed to investigate the association between LAA CT contrast defect and the risk of arrhythmia recurrence after catheter ablation (CA) in patients with paroxysmal AF. A total of 283 paroxysmal AF patients [age: 67 ± 10 years, 185 (65%) males] who underwent cardiac CT before CA were retrospectively analyzed. The presence or absence of LAA CT contrast defect was visually assessed using early phase CT images. Recurrence was an episode of atrial arrhythmia beyond the first 90 days post-ablation. LAA flow velocity was measured using transesophageal echocardiography in 246 paroxysmal AF patients. Sixty-eight (24%) patients had an LAA CT contrast defect. LAA flow velocity was significantly reduced in patients with LAA CT defect compared to those without (56.8 ± 28.7 cm/s vs. 41.1 ± 19.1 cm/s, p < 0.001). During a median follow-up period of 858 days, arrhythmia recurrence was identified in 85 (30%) patients. On a Kaplan Meier curve, patients with LAA CT contrast defect had significantly higher recurrence rates than those without (p = 0.043). On a multivariable Cox regression analysis, LAA CT contrast defect was a significant and independent predictor after adjustment of age, sex and left atrial volume index (hazard ratio: 1.79, 95% confidence interval: 1.03-3.07, p = 0.036). LAA CT contrast defect was associated with decreased LAA flow velocity and a higher rate of arrhythmia recurrence after CA, suggesting its usefulness as a non-invasive predictor for high-risk AF patients resistant to CA therapy.

Machine learning to predict left ventricular reverse remodeling by guideline-directed medical therapy by utilizing texture feature of extracellular volume fraction in patients with non-ischemic dilated cardiomyopathy.

Extracellular volume fraction (ECV) by cardiac magnetic resonance (CMR) allows for the non-invasive quantification of diffuse myocardial fibrosis. Texture analysis and machine learning are now gathering attention in the medical field to exploit the ability of diagnostic imaging for various diseases. This study aimed to investigate the predictive value of texture analysis of ECV and machine learning for predicting response to guideline-directed medical therapy (GDMT) for patients with non-ischemic dilated cardiomyopathy (NIDCM). A total of one-hundred and fourteen NIDCM patients [age: 63 ± 12 years, 91 (81%) males] were retrospectively analyzed. We performed texture analysis of ECV mapping of LV myocardium using dedicated software. We calculated nine histogram-based features (mean, standard deviation, maximum, minimum, etc.) and five gray-level co-occurrence matrices. Five machine learning techniques and the fivefold cross-validation method were used to develop prediction models for LVRR by GDMT based on 14 texture parameters on ECV mapping. We defined the LVRR as follows: LVEF increased ≥ 10% points and decreased LVEDV ≥ 10% on echocardiography after GDMT > 12 months. Fifty (44%) patients were classified as non-responders. The area under the receiver operating characteristics curve for predicting non-responder was 0.82 for eXtreme Gradient Boosting, 0.85 for support vector machine, 0.76 for multi-layer perception, 0.81 for Naïve Bayes, 0.77 for logistic regression, respectively. Mean ECV value was the most critical factor among texture features for differentiating NIDCM patients with LVRR and those without (0.28 ± 0.03 vs. 0.36 ± 0.06, p < 0.001). Machine learning analysis using the support vector machine may be helpful in detecting high-risk NIDCM patients resistant to GDMT. Mean ECV is the most crucial feature among texture features.

Native T1 heterogeneity for predicting reverse remodeling in patients with non-ischemic dilated cardiomyopathy.

A recent study has shown that the heterogeneity of native T1 mapping may be a new prognostic factor for patients with non-ischemic dilated cardiomyopathy (NIDCM). This study aimed to investigate the predictive value of native T1 heterogeneity of the left ventricular (LV) myocardium, as assessed by pixel-wise histogram analysis, for predicting left ventricular reverse remodeling (LVRR) by medical therapy in patients with NIDCM. A total of one hundred and thirteen NIDCM patients (mean age: 63 ± 12 years; 91 males and 22 females; mean LV ejection fraction (EF): 37 ± 10%) were retrospectively analyzed. T1 mapping images were acquired using a modified look-locker inversion recovery (MOLLI) sequence. We performed histogram analysis of native T1 mapping of LV myocardium, mean (T1-mean) and standard deviation (T1-STD) of native T1 time from each pixel were calculated. Extracellular volume fraction (ECV) was also evaluated. LVRR was defined as LVEF increased ≥ 10% points and decrease in LV end-diastolic volume ≥ 10% at 12 months from initiation of medical therapy. Cutoff value of T1-mean and T1-STD was set as median value of each parameter. Sixty (53%) NIDCM patients reached LVRR. Area under the receiver-operating characteristics curve for predicting LVRR was 0.763 (95% confidence interval (CI) 0.679-0.847) for %LGE, 0.757 (95% CI 0.663-0.850) for T1-mean, 0.724 (95% CI 0.625-0.823) for T1-STD, 0.800 (95% CI 0.717-0.882) for ECV, respectively. Proportion of LVRR was significantly lower in NIDCM patients with high T1-mean and high T1-STD (12%) compared to NIDCM with high T1-mean and low T1-STD (65%) (p < 0.001). Adding T1-STD to T1-mean improved AUC from 0.757 to 0.806, comparable to AUC of ECV. Combination of T1-mean and T1-STD, a parameter of heterogeneity of native T1 of the LV myocardium, may be a useful for prediction of LVRR by medical therapy without use of gadolinium contrast for patients with NIDCM.

Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.

In this systematic review and meta-analysis, we sought to evaluate the prevalence of cardiac involvement in patients with COVID-19 using cardiac magnetic resonance imaging. A literature review was performed to investigate the left ventricular (LV) and right ventricular (RV) ejection fraction (EF), the prevalence of LV late gadolinium enhancement (LGE), pericardial enhancement, abnormality on T1 mapping, and T2 mapping/T2-weighted imaging (T2WI), and myocarditis (defined by modified Lake Louis criteria). Pooled mean differences (MD) between COVID-19 patients and controls for LVEF and RVEF were estimated using random-effects models. We included data from 10.462 patients with COVID-19, comprising 1.010 non-athletes and 9.452 athletes from 29 eligible studies. The meta-analysis showed a significant difference between COVID-19 patients and controls in terms of LVEF [MD = - 2.84, 95% confidence interval (CI) - 5.11 to - 0.56, p < 0.001] and RVEF (MD = - 2.69%, 95% CI - 4.41 to - 1.27, p < 0.001). However, in athletes, no significant difference was identified in LVEF (MD = - 0.74%, 95% CI - 2.41 to - 0.93, p = 0.39) or RVEF (MD = - 1.88%, 95% CI - 5.21 to 1.46, p = 0.27). In non-athletes, the prevalence of LV LGE abnormalities, pericardial enhancement, T1 mapping, T2 mapping/T2WI, myocarditis were 27.5% (95%CI 17.4-37.6%), 11.9% (95%CI 4.1-19.6%), 39.5% (95%CI 16.2-62.8%), 38.1% (95%CI 19.0-57.1%) and 17.6% (95%CI 6.3-28.9%), respectively. In athletes, these values were 10.8% (95%CI 2.3-19.4%), 35.4% (95%CI - 3.2 to 73.9%), 5.7% (95%CI - 2.9 to 14.2%), 1.9% (95%CI 1.1-2.7%), 0.9% (0.3-1.6%), respectively. Both LVEF and RVEF were significantly impaired in COVID-19 patients compared to controls, but not in athletes. In addition, the prevalence of myocardial involvement is not negligible in patients with COVID-19.

Cardiovascular magnetic resonance assessment of coronary flow reserve improves risk stratification in heart failure with preserved ejection fraction.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been proposed as a novel mechanism for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). Recent studies have suggested the potential utility of coronary flow reserve (CFR) as a marker of CMD in patients with HFpEF. Phase contrast (PC) cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to quantify CFR. We aimed to investigate the prognostic value of CMR-derived CFR in patients with HFpEF. METHODS: Data from 163 HFpEF patients (73 ± 9 years; 86 [53%] female) were retrospectively analyzed. Coronary sinus blood flow was measured in all patients, and myocardial blood flow was calculated as coronary sinus blood flow divided by left ventricular mass. CFR was calculated as the myocardial blood flow during adenosine triphosphate infusion divided by that at rest. Adverse events were defined as all-cause death and hospitalization due to HF exacerbation. Event-free survival stratified according to CFR < 2.0 was estimated with Kaplan-Meier survival methods and Log-rank test. RESULTS: During a median follow-up of 4.1 years, 26 patients (16%) experienced adverse events. CMR-derived CFR was significantly lower in HFpEF with adverse events compared with those without (1.93 ± 0.38 vs. 2.67 ± 0.52, p < 0.001). On a Kaplan Meier curve, the rates of adverse events were significantly higher in HFpEF patients with CFR < 2.0 compared with HFpEF with CFR ≥ 2.0 (p < 0.001). The area under the curve of CFR for predicting adverse events was significantly higher than that of LGE (0.881 vs. 0.768, p = 0.037) and GLS (0.881 vs. 0.747, p = 0.036). CONCLUSIONS: CFR assessed using coronary sinus PC cine CMR may be useful as a non-invasive prognostic marker for HFpEF patients.

Prognostic value of resting coronary sinus flow determined by phase-contrast cine cardiovascular magnetic resonance in patients with known or suspected coronary artery disease.

BACKGROUND: Phase-contrast cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to measure coronary sinus blood flow (CSBF) and coronary flow reserve (CFR). We aimed to compare the prognostic value of resting CSBF and CFR for predicting major adverse cardiac events (MACE) in patients with known or suspected coronary artery disease (CAD) who underwent vasodilator stress CMR. METHODS: We studied 693 patients with known CAD and 519 patients with suspected CAD admitted to our hospital between 2009 and 2019. The CFR was calculated as the CSBF during adenosine triphosphate infusion divided by CSBF at rest. MACE was defined as composite of cardiovascular death, acute coronary syndrome, heart failure hospitalization, and sustained ventricular tachyarrhythmia. RESULTS: During a median follow-up of 4.6 years, 92 patients (8%) experienced MACE. The resting CSBF was significantly higher in patients with MACE than in patients without MACE (114.7 ± 44.9 mL/min vs. 84.7 ± 30.9 mL/min, p < 0.001 for known CAD; 122.2 ± 33.3 mL/min vs. 86.6 ± 36.7 mL/min, p < 0.001 for suspected CAD). The resting CSBF remained a significant predictor for MACE after adjusting clinical and CMR variables (hazard ratio [HR] of resting CSBF higher than the median: 3.18, p = 0.0083 for known CAD; HR: 23.3, p < 0.001 for suspected CAD). The area under the curve for predicting MACE was 0.73 for resting CSBF, 0.72 for CFR (p = 0.78) in patients with known CAD, and 0.82 for resting CSBF, 0.83 (p = 0.58) for CFR in patients with suspected CAD. CONCLUSIONS: The resting CSBF may be a useful non-invasive method for the risk stratification of patients with known or suspected CAD without any radiation exposure, contrast media, or pharmacological vasodilator agents.

Extracellular volume fraction by T1 mapping predicts improvement of left ventricular ejection fraction after catheter ablation in patients with non-ischemic dilated cardiomyopathy and atrial fibrillation.

Absence of myocardial fibrosis on late gadolinium enhanced (LGE) magnetic resonance imaging (MRI) is associated with improvement of left ventricular systolic function after catheter ablation (CA) for atrial fibrillation (AF) with non-ischemic dilated cardiomyopathy (NIDCM). Extracellular volume fraction (ECV) by T1 mapping has emerges as a non-invasive mean to quantify severity of myocardial fibrosis. The aim of this study was to assess the incremental value of ECV over LGE-MRI for the improvement of LVEF(∆EF) after CA in NIDCM patients. A total of thirty-two patients with NIDCM and AF (mean age 67.4 ± 9.3 years; 29 (91%) male) were retrospectively studied. Using a 1.5 T MR scanner and 32 channel cardiac coils, LGE-MRI, pre- and post-T1 mapping images of LV wall at mid-ventricular level (modified look-locker inversion recovery sequence) were acquired. All patients successfully underwent CA for AF, and the improvement of LVEF after CA were evaluated by echocardiography. All patients restored sinus rhythm after CA at the time of echocardiography. The mean LVEF was 35.1 ± 9.7% before CA and 52.2 ± 10.2% after CA (p < 0.001), resulting an increase of 17.4 ± 12.6%. Significant correlation was found between ∆LVEF and % LGE (r = - 0.49, p = 0.004), ∆LVEF and extracellular volume fraction (ECV) (r = - 0.47, p = 0.010). Area under the receiver operating characteristics curve (AUC) of combination of %LGE and ECV for predicting improvement of LVEF > 10% was substantially higher than that of %LGE alone (AUC: 0.830 vs 0.602). In NIDCM patients with AF, ECV had incremental value over %LGE for predicting improvement of EF by CA, suggesting that the assessment of diffuse interstitial fibrosis may be important to forecast the response of CA.

Incremental prognostic value of coronary flow reserve determined by phase-contrast cine cardiovascular magnetic resonance of the coronary sinus in patients with diabetes mellitus.

BACKGROUND: Although non-invasive assessment of coronary flow reserve (CFR) by cardiovascular magnetic resonance (CMR) provides prognostic information for patients with diabetes mellitus (DM), the incremental prognostic value of CMR-derived CFR remains unclear. PURPOSE: To evaluate the incremental prognostic value of CMR-derived CFR for patients with DM who underwent stress CMR imaging. MATERIALS AND METHODS: A total of 309 patients with type 2 DM [69 ± 9 years; 244 (78%) male] assessed between 2009 and 2019 were retrospectively reviewed. Coronary sinus blood flow (CSBF) was measured using phase contrast (PC) cine CMR. CFR was calculated as the CSBF during adenosine triphosphate infusion divided by that at rest. Major adverse cardiac events (MACE) were defined as death, acute coronary syndrome, hospitalization due to heart failure exacerbation, or sustained ventricular tachycardia. The incremental prognostic value of CFR over clinical and CMR variables was assessed by calculating the C-index and net reclassification improvement (NRI). RESULTS: During a median follow-up of 3.8 years, 42 patients (14%) experienced MACE. The annualized event rate was significantly higher among patients with CFR < 2.0, regardless of the presence of late gadolinium enhancement (LGE) (1.4% vs. 9.8%, p = 0.011 in the LGE (-) group; 1.8% vs. 16.9%, p < 0.001 in the LGE (+) group). In addition, this trend was maintained in the subgroups stratified by presence or absence of ischemia (0.3% vs. 6.7%, p = 0.007 in the ischemia (-) group; 3.9% vs. 17.1%, p = 0.001 in the ischemia (+) group). Adding CFR to the risk model (age + gender + left ventricular ejection fraction + %LGE + %ischemia) resulted in a significant increase of the C-index from 0.838 to 0.870 (p = 0.038) and an NRI of 0.201 (0.004-0.368, p = 0.012). CONCLUSION: PC cine CMR-derived CFR of the coronary sinus may be useful as a prognostic marker for DM patients, incremental to common clinical and CMR parameters. Due to the high prevalence of coronary microvascular dysfunction, the addition of CFR to conventional vasodilator stress CMR imaging may improve risk stratification for patients with DM.

Relationship between the cardiac magnetic resonance derived extracellular volume fraction and feature tracking myocardial strain in patients with non-ischemic dilated cardiomyopathy.

BACKGROUND: Feature tracking (FT) has emerged as a promising method to quantify myocardial strain using conventional cine magnetic resonance imaging (MRI). Extracellular volume fraction (ECV) by T1 mapping enables quantification of myocardial fibrosis. To date, the correlation between FT-derived left ventricular strain and ECV has not been elucidated yet. The aim of this study was to evaluate the relationship between myocardial strain by FT and ECV by T1 mapping in patients with non-ischemic dilated cardiomyopathy (NIDCM). METHODS: A total of 57 patients with NIDCM (61 ± 12 years; 46 (81%) male)) and 15 controls (62 ± 11 years; 11 (73%) male)) were studied. Using a 1.5 T magnetic resonance scanner, pre- and post- T1 mapping images of the LV wall at the mid-ventricular level were acquired to calculate the ECV by a modified Look-Locker inversion recovery (MOLLI) sequence. The radial strain (RS), circumferential strain (CS), and longitudinal strain (LS) were assessed by the FT technique. The ECV and myocardial strain were compared using a 6-segment model at the mid-ventricular level. RESULTS: The ECV and myocardial strain were evaluable in all 432 segments in 72 subjects. On a patient-based analysis, NIDCM patients had a significantly higher ECV (0.30 ± 0.07 vs. 0.28 ± 0.06, p = .007) and impaired myocardial strain than the control subjects (RS, 22.7 ± 10.3 vs. 30.3 ± 18.2, p < .01; CS, -6.47 ± 1.89 vs. -9.52 ± 5.15, p < .001; LS -10.2 ± 3.78 vs. -19.8 ± 4.30, p < .001, respectively). A significant linear correlation was found between the RS and ECV (r = -0.38, p < .001) and CS and ECV, (r = 0.38, p < .001). LS and ECV also correlated (r = 0.31, p < 0.001). On a segment-based analysis, there was a significant correlation between the ECV and RS and ECV and CS (all p values < .05). The intraclass correlation coefficient was good for the strain measurement (>0.80). CONCLUSIONS: In patients with NIDCM, significant correlation was found between myocardial strain and ECV, suggesting the FT-derived myocardial strain might be useful as a non-invasive imaging marker for the detection of myocardial fibrosis without any contrast media.

Combination of extracellular volume fraction by cardiac magnetic resonance imaging and QRS duration for the risk stratification for patients with non-ischemic dilated cardiomyopathy.

The extracellular volume fraction (ECV) by T1 mapping can quantify diffuse myocardial fibrosis, and useful as a non-invasive marker for risk stratification for patients with non-ischemic dilated cardiomyopathy (NIDCM). Prolonged QRS interval on electrocardiogram is related to worse clinical outcome for heart failure patients. The purpose of this study was to evaluate the prognostic value of the combination of ECV and QRS duration for NIDCM patients. A total of 60 NIDCM patients (mean age 61 ± 12 years, mean left ventricular ejection fraction 37 ± 10%, mean QRS duration 110 ± 19 ms) were enrolled. Using a 1.5-T MR scanner and 32-channel cardiac coils, the mean ECV value of six myocardial segments at the mid-ventricular level was measured by the modified look-locker inversion recovery method. Adverse events were defined as follows: cardiac death; recurrent hospitalization due to heart failure. Patients were allocated into three groups based on ECV value and QRS duration (group 1: ECV â‰¦ 0.30 and QRS â‰¦ 120 ms; group 2: ECV > 0.30 or QRS > 120 ms; group 3: ECV > 0.30 and QRS > 120 ms). During a median follow-up duration of 370 days, 7 of 60 (12%) NIDCM patients experienced adverse events. NIDCM patients with events had longer QRS duration (134 ± 31 ms vs. 106 ± 14 ms, p = 0.01) and higher ECV (0.34 ± 0.07 vs 0.29 ± 0.05, p = 0.026) compared with those without events. On Kaplan-Meier curve analysis, significant difference was found between group 1 and group 3 (p < 0.001, log-rank test). No significant difference was found between group 1 and group 2 (p = 0.053), group 2 and group 3 (p = 0.115). The area under the receiver operating characteristic curve (AUC) for predicting adverse events was 0.778 (95% confidence interval CI 0.612-0.939) for ECV, 0.792 (95% CI 0.539-0.924) for QRS duration, 0.822 (95% CI 0.688-0.966) for combination of ECV and QRS duration. NIDCM patients with high ECV and prolonged QRS duration had significantly worse prognosis compared to those with normal ECV and normal QRS duration. The combination of ECV and QRS duration could be useful as a non-invasive method for better risk stratification for patients with NIDCM.

Identification and functional characterization of novel nonsynonymous variants in the human multidrug and toxin extrusion 2-K.

This study was performed to identify genetic polymorphisms in multidrug and toxin extrusion 2-K (MATE2-K, SLC47A2), a proton/organic cation antiporter that plays a role in the transport of organic cations across the apical membrane in kidney epithelial cells into the urine, and to demonstrate their effects on MATE2-K functions in vitro. Four of the thirty single nucleotide polymorphisms (SNPs) we identified in three ethnic groups (Caucasian, African American, and Japanese) were novel [308C>G (P103R), c.487-8C>T, 818A>G (Y273C), and c.1018+14T>C]. The transport activities of the prototypical substrates, tetraethylammonium and metformin, for four nonsynonymous SNPs (P103R, P162L, G211V, and Y273C) were significantly different from those of the wild-type. In particular, transport activity was higher in P103R than in the wild-type, which is the first time elevated transport activity was demonstrated due to these coding SNPs. Kinetic analysis revealed that P103R had a higher Vmax value, whereas Y273C had a lower value than that in the wild-type. Cell surface protein expression levels were higher for P103R than for the wild-type, whereas Y273C expression was decreased. Immunofluorescence analysis revealed that the P103R protein was localized to the plasma membrane, whereas Y273C showed cytoplasmic localization. Therefore, the difference in transport activities between P103R and Y273C variants was suggested to be responsible for the different protein expression levels observed at the plasma membrane. Four nonsynonymous SNPs in this study showed relatively low allelic frequencies (0.5 to 2.1%), but these were associated with markedly reduced or increased MATE2-K function.