Cardiac magnetic resonance biomarkers as surrogate endpoints in cardiovascular trials for myocardial diseases.

Cardiac magnetic resonance offers multiple facets in the diagnosis, risk stratification, and management of patients with myocardial diseases. Particularly, its feature to precisely monitor disease activity lends itself to quantify response to novel therapeutics. This review critically appraises the value of cardiac magnetic resonance imaging biomarkers as surrogate endpoints for prospective clinical trials. The primary focus is to comprehensively outline the value of established cardiac magnetic resonance parameters in myocardial diseases. These include heart failure, cardiac amyloidosis, iron overload cardiomyopathy, hypertrophic cardiomyopathy, cardio-oncology, and inflammatory cardiomyopathies like myocarditis and sarcoidosis.

Evidence-based cardiovascular magnetic resonance cost-effectiveness calculator for the detection of significant coronary artery disease.

BACKGROUND: Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs. METHODS: We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography. RESULTS: CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model. CONCLUSIONS: Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.

Optimization of Ultrasonic-Assisted Extraction of Total Flavonoids from Abrus Cantoniensis (Abriherba) by Response Surface Methodology and Evaluation of Its Anti-Inflammatory Effect.

Abrus cantoniensis is a Chinese herbal medicine with efficacy in clearing heat and detoxification, as well as relieving liver pain. The whole plant, except the seeds, can be used and consumed. Flavonoids have been found in modern pharmacological studies to have important biological activities, such as anti-inflammatory, antibacterial and antioxidant properties. The antibacterial and antioxidant bioactivities of the total flavonoids of Abrus cantoniensis (ATF) have been widely reported in national and international journals, but there are fewer studies on their anti-inflammatory effects. The present study focused on the optimization of the ultrasonic extraction process of ATF by response surface methodology and the study of its anti-inflammatory effects in vitro and in vivo. The results showed that the factors that had a great impact on the ATF extraction were the material-to-liquid ratio, ultrasonic extraction cycles and ethanol concentration. The best extraction process used a material-to-liquid ratio of 1:47, ultrasonic extraction cycles of 4 times, an ethanol concentration of 50%, an ultrasonic extraction time of 40 min and an ultrasonic power of 125 W. Under these conditions, the actual extraction rate of total flavonoids was 3.68%, which was not significantly different from the predicted value of 3.71%. In an in vitro anti-inflammatory assay, ATF was found to be effective in alleviating LPS (lipopolysaccharide)-induced inflammation in mouse peritoneal macrophages. In an in vivo anti-inflammatory assay, ATF was found to have a significant inhibitory effect on xylene-induced ear swelling in mice and cotton ball granuloma in mice, and the inhibitory effect was close to that of the positive control drug dexamethasone. This may provide a theoretical basis for the further development of the medicinal value of Abrus cantoniensis.

Appropriateness of inpatient stress testing: Implications for development of clinical decision support mechanisms and future criteria.

BACKGROUND: An upcoming national mandate will require consultation of appropriate use criteria (AUC) through a clinical decision support mechanism (CDSM) for advanced imaging. We aimed to evaluate our current ability to ascertain test appropriateness. METHODS: We prospectively collected data on 288 consecutive stress tests and coronary computed tomography angiography studies for medical inpatients. Study appropriateness was determined independently by two physicians using the 2013 Multimodality AUC. RESULTS: The median age of the study population was 66 years [interquartile range (IQR) 56, 75], 40.8% were female, and 52.8% had a history of coronary artery disease. Review of the electronic health record (EHR) alone was sufficient to deem appropriateness for 87.2% of cases. The most common reason it was insufficient was inability to determine if the patient could exercise (59.5%). After reviewing the EHR and pilot CDSM data together, appropriateness could be determined for 95.8% of the cases. The most common reason appropriateness could not be determined was that the exam indication was not addressed by an AUC criterion (83.3%). CONCLUSION: In preparing for the mandate, it will be important for future CDSM to obtain information on the patient's ability to exercise and for future AUC to include additional indications that are not currently addressed.

Stress cardiac MRI in stable coronary artery disease.

PURPOSE OF REVIEW: Non-invasive testing is often the first step in the evaluation of stable coronary artery disease (CAD). Stress cardiac magnetic resonance imaging (CMR) is an established modality with high diagnostic accuracy and prognostic value. This review will focus on the recent advances in understanding how stress CMR can help guide patient care. RECENT FINDINGS: Diagnostic accuracy of stress CMR has been validated against coronary angiography with fractional flow reserve (FFR) in patients with stable CAD. Large registry data have shown stress CMR to have important prognostic importance and that its cost-effectiveness compares favorably to alternatives. In patients with stable CAD, guidance using a CMR based strategy led to equivalent outcomes when compared to coronary angiography with FFR. SUMMARY: In persons with stable CAD, Stress CMR is an accurate and cost-effective imaging modality that should be considered in patients at intermediate pre-test probability of CAD. Prognostic studies have shown it to have excellent negative predictive value and that it can safely serve as a "gatekeeper" for invasive angiography.

MRI in Patients with Cardiac Implantable Electronic Devices.

Indications for MRI have grown considerably in recent years. However, many patients with cardiac implantable electronic devices are denied imaging due to physician misinterpretation of the risks associated with MRI. This review discusses the theoretical basis for the perceived risk by exploring preclinical literature. It then presents a detailed examination of the true rates of adverse events in clinical studies across both MR nonconditional (legacy) and MR conditional devices. Indeed, many of these adverse events are rare, nonexistent, and/or clinically insignificant in the wealth of published data. The authors then address image quality and the constituents of a safety checklist that institutions should consider when performing MRI in patients with a cardiac implantable electronic device. Lastly, the authors conclude with an overview of future directions for advancement in the field.

Peptide Bond Synthesis by a Mechanism Involving an Enzymatic Reaction and a Subsequent Chemical Reaction.

We recently reported that an amide bond is unexpectedly formed by an acyl-CoA synthetase (which catalyzes the formation of a carbon-sulfur bond) when a suitable acid and l-cysteine are used as substrates. DltA, which is homologous to the adenylation domain of nonribosomal peptide synthetase, belongs to the same superfamily of adenylate-forming enzymes, which includes many kinds of enzymes, including the acyl-CoA synthetases. Here, we demonstrate that DltA synthesizes not only N-(d-alanyl)-l-cysteine (a dipeptide) but also various oligopeptides. We propose that this enzyme catalyzes peptide synthesis by the following unprecedented mechanism: (i) the formation of S-acyl-l-cysteine as an intermediate via its "enzymatic activity" and (ii) subsequent "chemical" S → N acyl transfer in the intermediate, resulting in peptide formation. Step ii is identical to the corresponding reaction in native chemical ligation, a method of chemical peptide synthesis, whereas step i is not. To the best of our knowledge, our discovery of this peptide synthesis mechanism involving an enzymatic reaction and a subsequent chemical reaction is the first such one to be reported. This new process yields peptides without the use of a thioesterified fragment, which is required in native chemical ligation. Together with these findings, the same mechanism-dependent formation of N-acyl compounds by other members of the above-mentioned superfamily demonstrated that all members most likely form peptide/amide compounds by using this novel mechanism. Each member enzyme acts on a specific substrate; thus, not only the corresponding peptides but also new types of amide compounds can be formed.

Circulating CD34(+) progenitor cell frequency is associated with clinical and genetic factors.

Circulating blood CD34(+) cells consist of hematopoietic stem/progenitor cells, angiogenic cells, and endothelial cells. In addition to their clinical use in hematopoietic stem cell transplantation, CD34(+) cells may also promote therapeutic neovascularization. Therefore, understanding the factors that influence circulating CD34(+) cell frequency has wide implications for vascular biology in addition to stem cell transplantation. In the present study, we examined the clinical and genetic characteristics associated with circulating CD34(+) cell frequency in a large, community-based sample of 1786 Framingham Heart Study participants.Among subjects without cardiovascular disease (n = 1595), CD34(+) frequency was inversely related to older age, female sex, and smoking. CD34(+) frequency was positively related to weight, serum total cholesterol, and statin therapy. Clinical covariates accounted for 6.3% of CD34(+) variability. CD34(+) frequency was highly heritable (h(2) = 54%; P < .0001). Genome-wide association analysis of CD34(+) frequency identified suggestive associations at several loci, including OR4C12 (chromosome 11; P = 6.7 × 10(-7)) and ENO1 and RERE (chromosome 1; P = 8.8 × 10(-7)). CD34(+) cell frequency is reduced in older subjects and is influenced by environmental factors including smoking and statin use. CD34(+) frequency is highly heritable. The results of the present study have implications for therapies that use CD34(+) cell populations and support efforts to better understand the genetic mechanisms that underlie CD34(+) frequency.

[DUOX2 mutations in children with congenital hypothyroidism].

OBJECTIVE: To study the features of DUOX2 mutations and genotype-phenotype relationship in children with congenital hypothyroidism (CH), in order to provide evidence for gene diagnosis and gene treatment of CH. METHODS: Blood samples were collected from 10 CH children with thyromegaly. Genomic DNA was extracted from peripheral blood leukocytes. All exons of DUOX2 gene were analyzed using PCR and direct sequencing. RESULTS: G3632A mutation in the exon 28 of DUOX2 that may result in arginine to histidine substitution at codon 1211 was found in one patient. T2033C mutation in the exon 17 of DUOX2 that may result in histidine to arginine substitution at codon 678 was found in three patients. They were all heterozygous mutations. CONCLUSIONS: Heterozygous mutations in DUOX2 may affect protein function and cause CH. The relationship between DUOX2 genotypes and clinical phenotypes is unclear and needs further studies.

Downregulation of KDR expression induces apoptosis in breast cancer cells.

Angiogenesis plays a crucial role in the growth, invasion and metastasis of breast cancer. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are the key regulators of tumor angiogenesis. VEGFR-2, known as the kinase insert domain receptor (KDR), is a key receptor involved in malignant angiogenesis. We previously showed that knocking down KDR with short interference RNA (KDR-siRNA) markedly decreased KDR expression and suppressed tumor growth in a xenograft model. However, the mechanisms underlying the anti-cancer effects of KDR-siRNA are not clearly understood. This study aimed to elucidate the molecular mechanisms that induce apoptosis in human breast cancer MCF-7 cells after transfection with KDR-siRNA. We studied the effects of KDR-siRNA on proliferation, apoptosis, antiapoptotic and pro-apoptotic proteins, mitochondrial membrane permeability, cytochrome c release and caspase-3 activity. The results indicated that KDR-siRNA treatment significantly inhibited the proliferation and induced the apoptosis of MCF-7 cells, reduced the levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xl, and increased the level of the pro-apoptotic protein Bax, resulting in a decreased Bcl-2/Bax ratio. KDR-siRNA also enhanced the mitochondrial membrane permeability, induced cytochrome c release from the mitochondria, upregulated apoptotic protease-activating factor-1 (Apaf-1), cleaved caspase-3, and increased caspase-3 activity in MCF-7 cells. Furthermore, KDR-siRNA-induced apoptosis in MCF-7 cells was blocked by the caspase inhibitor Z-VAD-FMK, suggesting a role of caspase activation in the induction of apoptosis. These results indicate that the Bcl-2 family proteins and caspase-related mitochondrial pathways are primarily involved in KDR-siRNAinduced apoptosis in MCF-7 cells and that KDR might be a potential therapeutic target for human breast cancer treatments.

Cardiac Magnetic Resonance Evaluation of LV Remodeling Post-Myocardial Infarction: Prognosis, Monitoring and Trial Endpoints.

Adverse left ventricular remodeling (ALVR) and subsequent heart failure after myocardial infarction (MI) remain a major cause of patient morbidity and mortality worldwide. Overt inflammation has been identified as the common pathway underlying myocardial fibrosis and development of ALVR post-MI. With its ability to simultaneously provide information about cardiac structure, function, perfusion, and tissue characteristics, cardiac magnetic resonance (CMR) is well poised to inform prognosis and guide early surveillance and therapeutics in high-risk cohorts. Further, established and evolving CMR-derived biomarkers may serve as clinical endpoints in prospective trials evaluating the efficacy of novel anti-inflammatory and antifibrotic therapies. This review provides an overview of post-MI ALVR and illustrates how CMR may help clinical adoption of novel therapies via mechanistic or prognostic imaging markers.

Head-to-Head Comparison and Temporal Trends of Cardiac MRI Recommendations in ESC versus ACC/AHA Guidelines: A Systematic Review and Meta-Analysis.

Purpose To provide a comprehensive head-to-head comparison and temporal analysis of cardiac MRI indications between the European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines to identify areas of consensus and divergence. Materials and Methods A systematic review and meta-analysis was conducted. ESC and ACC/AHA guidelines published until May 2023 were systematically screened for recommendations related to cardiac MRI. The class of recommendation (COR) and level of evidence (LOE) for cardiac MRI recommendations were compared between the two guidelines and between newer versus older versions of each guideline using χ2 or Fisher exact tests. Results ESC guidelines included 109 recommendations regarding cardiac MRI, and ACC/AHA guidelines included 90 recommendations. The proportion of COR I and LOE B was higher in ACC/AHA versus ESC guidelines (60% [54 of 90] vs 46.8% [51 of 109]; P = .06 and 53% [48 of 90] vs 35.8% [39 of 109], respectively; P = .01). The increase in the number of cardiac MRI recommendations over time was significantly higher in ESC guidelines (from 63 to 109 for ESC vs from 65 to 90 for ACC/AHA; P = .03). The main areas of consensus were found in heart failure and hypertrophic cardiomyopathy, while the main divergences were in valvular heart disease, arrhythmias, and aortic disease. Conclusion ESC guidelines included more recommendations related to cardiac MRI use, whereas the ACC/AHA recommendations had higher COR and LOE. The number of cardiac MRI recommendations increased significantly over time in both guidelines, indicating the increasing role of cardiac MRI evaluation and management of cardiovascular disease. Keywords: Cardiovascular Magnetic Resonance, Guideline, European Society of Cardiology, ESC, American College of Cardiology/American Heart Association, ACC/AHA Supplemental material is available for this article. © RSNA, 2024.

Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer.

BACKGROUND: Cancer cell differentiation is an important characteristic of malignant tumor and has a great impact on prognosis and therapeutic decision for patients. The N-myc downstream regulated gene 1 (NDRG1), a putative tumor suppression gene, is involved in the regulation of human cell differentiation and metastasis in various cancers. Changes in the status of methylation of the NDRG1 gene have not been studied in detail in human breast cancer. RESULTS: The MDA-MB-231 breast tumor cell line could express NDRG1. However, it was only expressed after treatment with 5-Aza-2'-deoxycytidine (AZA) in T47D cell line, which revealed that NDRG1 expression could modulated by DNA methylation. Therefore, the fragment surrounding the transcript start site of NDRG1 gene promoter was cloned after sodium bisulfite DNA treatment. A high density (66%) of methylation for human NDRG1 gene promoter was detected in T47D; however, there was only 16% of methylated CpG dinucleotides in the NDRG1 gene promoter in MDA-MB-231. DNA methylation in the NDRG1 promoter was detected in 31.1% of primary breast cancer samples. Furthermore, the NDRG1 promoter methylation correlated with the Tumor Node Metastasis (TNM) at stage III/IV, metastasis, lymph invasion, moderate and poor histological grade in the breast cancer patients. CONCLUSION: These findings suggest that the DNA methylation status of NDRG1 gene may play an important role in the pathogenesis and/or development of breast cancer, and the expression could be regulated by aberrant DNA methylation.

Diagnostic Impact and Prognostic Value of Cardiac Magnetic Resonance in Patients With Ventricular Arrhythmias.

BACKGROUND: Cardiac magnetic resonance (CMR) characterizes myocardial substrate relevant to sudden cardiac death (SCD). However, its clinical value in patients presenting with ventricular arrhythmias is still being defined. OBJECTIVES: The authors sought to examine the diagnostic and prognostic value of multiparametric CMR in a cohort of consecutive patients referred for assessment of ventricular arrhythmias. METHODS: Consecutive patients undergoing CMR for nonsustained ventricular tachycardia (NSVT) (n = 345) or sustained ventricular tachycardia (VT)/aborted SCD (n = 297) were followed over a median of 4.4 years. Major adverse cardiac events included death, recurrent VT/ventricular fibrillation requiring therapy, and hospitalization for congestive heart failure. RESULTS: Of the 642 patients, 256 were women (40%), mean age was 54 ± 15 years, and median left ventricular ejection fraction was 58% (IQR: 49%-63%). A structurally abnormal heart by CMR assessment was detected in 40% of patients with NSVT and 66% in those with VT/SCD (P < 0.001). CMR assessment yielded a diagnostic change in 27% of NSVT patients vs 41% of those with VT/SCD (P < 0.001). During follow-up, 51 patients (15%) with NSVT and 104 patients (35%) with VT/SCD experienced major adverse cardiac events (MACE). An abnormal CMR was associated with a higher annual rate for MACE for both NSVT (0.7% vs 7.7%; P < 0.001) and VT/SCD (3.8% vs 13.3%; P < 0.001) patients. In a multivariate model including left ventricular ejection fraction, an abnormal CMR remained strongly associated with MACE in NSVT (HR: 5.23 [95% CI: 2.28-12.0]; P < 0.001) and VT/SCD (HR: 1.88 [95% CI: 1.07-3.30]; P = 0.03). Adding CMR assessment to the multivariable model for MACE yielded a significant improvement in the integrated discrimination improvement and an improvement in the C-statistic in the NSVT cohort. CONCLUSIONS: In patients presenting with ventricular arrhythmias, multiparametric CMR assessment provides diagnostic clarification and effective risk stratification beyond current standard of care.

Prognostic Value of Different Thresholds for Myocardial Scar Quantification on Cardiac MRI Late Gadolinium Enhancement Images in Patients Receiving Implantable Cardioverter Defibrillators.

Purpose: To compare the predictive value of different myocardial scar quantification thresholds using cardiac MRI for appropriate implantable cardioverter defibrillator (ICD) shock and mortality. Materials and Methods: In this retrospective, two-center observational cohort study, patients with ischemic or nonischemic cardiomyopathy underwent cardiac MRI prior to ICD implantation. Late gadolinium enhancement (LGE) was first determined visually and then quantified by blinded cardiac MRI readers using different SDs above the mean signal of normal myocardium, full-width half-maximum, and manual thresholding. The intermediate signal "gray zone" was calculated as the differences between different SDs. Results: Among 374 consecutive eligible patients (mean age, 61 years ± 13 [SD]; mean left ventricular ejection fraction, 32% ± 14; secondary prevention, 62.7%), those with LGE had a higher rate of appropriate ICD shock or death than those without (37.5% vs 26.6%, log-rank P = .04) over a median follow-up of 61 months. In multivariable analysis, none of the thresholds for quantifying scar was a significant predictor of mortality or appropriate ICD shock, while the extent of gray zone was an independent predictor (adjusted hazard ratio per 1 g = 1.025; 95% CI: 1.008, 1.043; P = .005) regardless of the presence or absence of ischemic heart disease (P interaction = .57). Model discrimination was highest for the model incorporating the gray zone (between 2 SD and 4 SD). Conclusion: Presence of LGE was associated with a higher rate of appropriate ICD shock or death. Although none of the scar quantification techniques predicted outcomes, the gray zone both in infarct and nonischemic scar was an independent predictor and may refine risk stratification.Keywords: MRI, Scar Quantification, Implantable Cardioverter Defibrillator, Sudden Cardiac Death Supplemental material is available for this article. © RSNA, 2023.

Sex-Specific Stress Perfusion Cardiac Magnetic Resonance Imaging in Suspected Ischemic Heart Disease: Insights From SPINS Retrospective Registry.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of mortality in women, but current noninvasive cardiac imaging techniques have sex-specific limitations. OBJECTIVES: In this study, the authors sought to investigate the effect of sex on the prognostic utility and downstream invasive revascularization and costs of stress perfusion cardiac magnetic resonance (CMR) for suspected CVD. METHODS: Sex-specific prognostic performance was evaluated in a 2,349-patient multicenter SPINS (Stress CMR Perfusion Imaging in the United States [SPINS] Study) Registry. The primary outcome measure was a composite of cardiovascular death and nonfatal myocardial infarction; secondary outcomes were hospitalization for unstable angina or heart failure, and late unplanned coronary artery bypass grafting. RESULTS: SPINS included 1,104 women (47% of cohort); women had higher prevalence of chest pain (62% vs 50%; P < 0.0001) but lower use of medical therapies. At the 5.4-year median follow-up, women with normal stress CMR had a low annualized rate of primary composite outcome similar to men (0.54%/y vs 0.75%/y, respectively; P = NS). In contrast, women with abnormal CMR were at higher risk for both primary (3.74%/y vs 0.54%/y; P < 0.0001) and secondary (9.8%/y vs 1.6%/y; P < 0.0001) outcomes compared with women with normal CMR. Abnormal stress CMR was an independent predictor for the primary (HR: 2.64 [95% CI: 1.20-5.90]; P = 0.02) and secondary (HR: 2.09 [95% CI: 1.43-3.08]; P < 0.0001) outcome measures. There was no effect modification for sex. Women had lower rates of invasive coronary angiography (3.6% vs 7.3%; P = 0.0001) and downstream costs ($114 vs $171; P = 0.001) at 90 days following CMR. There was no effect of sex on diagnostic image quality. CONCLUSIONS: Stress CMR demonstrated excellent prognostic performance with lower rates of invasive coronary angiography referral in women. Stress CMR should be considered as a first-line noninvasive imaging tool for the evaluation of women. (Stress CMR Perfusion Imaging in the United States [SPINS] Study [SPINS]; NCT03192891).

Modeling the Cost and Health Impacts of Diagnostic Strategies in Patients with Suspected Transthyretin Cardiac Amyloidosis.

Background Transthyretin cardiac amyloidosis (ATTR-CMP) is an increasingly recognized and treatable cause of heart failure with preserved ejection fraction. Multimodality cardiac imaging is recommended for ATTR-CMP diagnosis, but its cost-effectiveness in current clinical practice has not been well studied. Methods and Results Using a microsimulation model, we compared the cost-effectiveness of a combination of strategies involving 99mtechnetium pyrophosphate (PYP), cardiac magnetic resonance imaging, and endomyocardial biopsy for the diagnosis of ATTR-CMP. We developed a decision analytic model to project health care costs and lifetime quality-adjusted life years for symptomatic, older patients who present with congestive heart failure, with an increased left ventricular wall thickness and a 13% prevalence of ATTR-CMP. Rates of clinical events, costs, and quality-of-life values were estimated from published literature. The analysis was conducted from a US health care system perspective with health and cost outcomes discounted annually at 3%. In the base-case scenario, using a fixed tafamidis price of $16 000 annually (previously identified cost-effective price), total health care costs per person were lowest for the PYP-only strategy ($209 415) and highest for endomyocardial biopsy strategy ($215 881). Of the 7 strategies examined, the PYP-only strategy had the highest net monetary benefit using a willingness-to-pay threshold of $100 000/quality-adjusted life year. Results were sensitive to variations in model inputs for PYP and cardiac magnetic resonance imaging specificity, cost of tafamidis, and willingness-to-pay thresholds. Conclusions Our model-based analyses showed that a PYP-only strategy to diagnose ATTR-CMP is the most cost-effective strategy, at willingness-to-pay threshold of $100 000/quality-adjusted life year. At higher threshold ($150 000/quality-adjusted life year), sequential tests involving PYP and cardiac magnetic resonance imaging may be considered cost effective.

Entropy as a Measure of Myocardial Tissue Heterogeneity in Patients With Ventricular Arrhythmias.

OBJECTIVES: The authors investigated the incremental prognostic value of entropy, a novel measure of myocardial tissue heterogeneity by cardiac magnetic resonance (CMR) imaging in patients presenting with ventricular arrhythmias (VAs). BACKGROUND: CMR can characterize myocardial areas serving as arrhythmogenic substrate. METHODS: Consecutive patients undergoing CMR imaging for VAs were followed for major adverse cardiac events (MACEs) defined by all-cause death, incident VAs requiring therapy, or heart failure hospitalization. Entropy was derived from the probability distribution of pixel signal intensities of the left ventricular (LV) myocardium. RESULTS: A total of 583 patients (age 54 ± 15 years, female 39%, left ventricular ejection fraction [LVEF] 54 ± 13%) were followed for a median of 4.4 years and experienced 141 MACEs. Entropy showed strong unadjusted association with MACE (HR: 1.88; 95% CI: 1.63-2.17; P < 0.001). In a multivariable model including LVEF, QRS duration, late gadolinium enhancement, and presenting arrhythmia, entropy maintained independent association with MACE (HR: 1.61; 95% CI: 1.32-1.96; P < 0.001). Entropy was further significantly associated with MACE in patients without myocardial scar (HR: 2.43; 95% CI: 1.55-3.82; P < 0.001) and in those presenting with nonsustained VAs (HR: 2.16; 95% CI: 1.43-3.25; P < 0.001). Addition of LV entropy to the baseline multivariable model significantly improved model performance (C-statistic improvement: 0.725 to 0.754; P = 0.003) and risk reclassification. CONCLUSIONS: In patients with VAs, CMR-assessed LV entropy was independently associated with MACE and provided incremental prognostic value, on top of LVEF and late gadolinium enhancement. LV entropy assessment may help risk stratification in patients with absence of myocardial scar or with nonsustained VAs.

Prognostic Value of T1 Mapping and Feature Tracking by Cardiac Magnetic Resonance in Patients With Signs and Symptoms Suspecting Heart Failure and No Clinical Evidence of Coronary Artery Disease.

Background The ability of left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) by cardiac magnetic resonance for risk stratification in suspected heart failure is limited. We aimed to evaluate the incremental prognostic value of cardiac magnetic resonance-assessed extracellular volume fraction (ECV) and global longitudinal strain (GLS) in patients with signs and symptoms suspecting heart failure and no clinical evidence of coronary artery disease. Methods and Results A total of 474 consecutive patients (57±21 years of age, 56% men) with heart failure-related symptoms and absence of coronary artery disease underwent cardiac magnetic resonance. After median follow-up of 18 months, 59 (12%) experienced the outcome of all-cause death or heart failure hospitalization (DeathCHF). In univariate analysis, cardiac magnetic resonance-assessed LVEF, LGE, GLS, and ECV were all significantly associated with DeathCHF. Adjusted for a multivariable baseline model including age, sex, LVEF and LGE, ECV, and GLS separately maintained a significant association with DeathCHF (ECV, hazard ratio [HR], 1.44 per 1 SD increase; 95% CI 1.13-1.84; P=0.003, and GLS, HR, 1.78 per 1 SD increase; 95% CI, 1.06-2.96; P=0.028 respectively). Adding both GLS and ECV to the baseline model significantly improved model discrimination (C statistic from 0.749 to 0.782, P=0.017) and risk reclassification (integrated discrimination improvement 0.046 [0.015-0.076], P=0.003; continuous net reclassification improvement 0.378 [0.065-0.752], P<0.001) for DeathCHF, beyond LVEF and LGE. Conclusions In patients with signs and symptoms suspecting heart failure and no clinical evidence of coronary artery disease, joint assessment of GLS and ECV provides incremental prognostic value for DeathCHF, independent of LVEF and LGE.

Cost-Minimization Analysis for Cardiac Revascularization in 12 Health Care Systems Based on the EuroCMR/SPINS Registries.

OBJECTIVES: The aim of this study was to compare the costs of a noninvasive cardiac magnetic resonance (CMR)-guided strategy versus 2 invasive strategies with and without fractional flow reserve (FFR). BACKGROUND: Coronary artery disease (CAD) is a major contributor to the public health burden. Stress perfusion CMR has excellent accuracy to detect CAD. International guidelines recommend as a first step noninvasive testing of patients in stable condition with known or suspected CAD. However, nonadherence in routine clinical practice is high. METHODS: In the EuroCMR (European Cardiovascular Magnetic Resonance) registry (n = 3,647, 59 centers, 18 countries) and the U.S.-based SPINS (Stress-CMR Perfusion Imaging in the United States) registry (n = 2,349, 13 centers, 11 states), costs were calculated for 12 health care systems (8 in Europe, the United States, 2 in Latin America, and 1 in Asia). Costs included diagnostic examinations (CMR and x-ray coronary angiography [CXA] with and without FFR), revascularizations, and complications during 1-year follow-up. Seven subgroup analyses covered low- to high-risk cohorts. Patients with ischemia-positive CMR underwent CXA and revascularization at the treating physician's discretion (CMR+CXA strategy). In the hypothetical invasive CXA+FFR strategy, costs were calculated for initial CXA and FFR in vessels with ≥50% stenoses, assuming the same proportion of revascularizations and complications as with the CMR+CXA strategy and FFR-positive rates as given in the published research. In the CXA-only strategy, costs included CXA and revascularizations of ≥50% stenoses. RESULTS: Consistent cost savings were observed for the CMR+CXA strategy compared with the CXA+FFR strategy in all 12 health care systems, ranging from 42% ± 20% and 52% ± 15% in low-risk EuroCMR and SPINS patients with atypical chest pain, respectively, to 31% ± 16% in high-risk SPINS patients with known CAD (P < 0.0001 vs 0 in all groups). Cost savings were even higher compared with CXA only, at 63% ± 11%, 73% ± 6%, and 52% ± 9%, respectively (P < 0.0001 vs 0 in all groups). CONCLUSIONS: In 12 health care systems, a CMR+CXA strategy yielded consistent moderate to high cost savings compared with a hypothetical CXA+FFR strategy over the entire spectrum of risk. Cost savings were consistently high compared with CXA only for all risk groups.