Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation.

Titin is the largest protein found in nature and spans half a sarcomere in vertebrate striated muscle. The protein has multiple functions, including in the organisation of the thick filament and acting as a molecular spring during the muscle contraction cycle. Missense variants in titin have been linked to both cardiac and skeletal myopathies. Titin is primarily composed of tandem repeats of immunoglobulin and fibronectin type III (Fn3) domains in a variety of repeat patterns; however, the vast majority of these domains have not had their high-resolution structure determined experimentally. Here, we present the crystal structures of seven wild type titin Fn3 domains and two harbouring rare missense variants reported in hypertrophic cardiomyopathy (HCM) patients. All domains present the typical Fn3 fold, with the domains harbouring variants reported in HCM patients retaining the wild-type conformation. The effect on domain folding and stability were assessed for five rare missense variants found in HCM patients: four caused thermal destabilization of between 7 and 13 °C and one prevented the folding of its domain. The structures also allowed us to locate the positions of residues whose mutations have been linked to congenital myopathies and rationalise how they convey their deleterious effects. We find no evidence of physiological homodimer formation, excluding one hypothesised mechanism as to how titin variants could exert pathological effects.

Left ventricular anatomy in obstructive hypertrophic cardiomyopathy: beyond basal septal hypertrophy.

AIMS: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic obstruction of the left ventricular (LV) outflow tract (LVOT). Although this may be mediated by interplay between the hypertrophied septal wall, systolic anterior motion of the mitral valve, and papillary muscle abnormalities, the mechanistic role of LV shape is still not fully understood. This study sought to identify the LV end-diastolic morphology underpinning oHCM. METHODS AND RESULTS: Cardiovascular magnetic resonance images from 2398 HCM individuals were obtained as part of the NHLBI HCM Registry. Three-dimensional LV models were constructed and used, together with a principal component analysis, to build a statistical shape model capturing shape variations. A set of linear discriminant axes were built to define and quantify (Z-scores) the characteristic LV morphology associated with LVOT obstruction (LVOTO) under different physiological conditions and the relationship between LV phenotype and genotype. The LV remodelling pattern in oHCM consisted not only of basal septal hypertrophy but a combination with LV lengthening, apical dilatation, and LVOT inward remodelling. Salient differences were observed between obstructive cases at rest and stress. Genotype negative cases showed a tendency towards more obstructive phenotypes both at rest and stress. CONCLUSIONS: LV anatomy underpinning oHCM consists of basal septal hypertrophy, apical dilatation, LV lengthening, and LVOT inward remodelling. Differences between oHCM cases at rest and stress, as well as the relationship between LV phenotype and genotype, suggest different mechanisms for LVOTO. Proposed Z-scores render an opportunity of redefining management strategies based on the relationship between LV anatomy and LVOTO.

Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT).

OBJECTIVE: Many patients presenting with suspected acute coronary syndrome (ACS) have high-sensitivity cardiac troponin (hs-cTn) concentrations between rule-in and rule-out thresholds and hence need serial testing, which is time consuming. The Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT) assessed the utility of coronary CT angiography (CCTA) in patients with suspected ACS, non-ischaemic ECG and intermediate initial hs-cTn concentration. METHODS: Patients were randomised to CCTA-guided management versus standard of care (SOC). The primary outcome was hospital length of stay (LOS). Secondary outcomes included cost of in-hospital stay and major adverse cardiac events (MACE) at 12 months of follow-up. Data are mean (SD); for LOS harmonic means, IQRs are shown. RESULTS: 250 (aged 55 (14) years, 25% women) patients were randomised. Harmonic mean (IQR) LOS was 7.53 (6.0-9.6) hours in the CCTA arm and 8.14 (6.3-9.8) hours in the SOC arm (p=0.13). Inpatient cost was £1285 (£2216) and £1108 (£3573), respectively, p=0.68. LOS was shorter in the CCTA group in patients with <25% stenosis, compared with SOC; 6.6 (5.6-7.8) hours vs 7.5 (6.1-9.4) hours, respectively; p=0.021. More referrals for cardiology outpatient clinic review and cardiac CT-related outpatient referrals occurred in the SOC arm (p=0.01). 12-month MACE rates were similar between the two arms (7 (5.6%) in the CCTA arm and 8 (6.5%) in the SOC arm-log-rank p=0.78). CONCLUSIONS: CCTA did not lead to reduced hospital LOS or cost, largely because these outcomes were influenced by the detection of ≥25% grade stenosis in a proportion of patients. TRIAL REGISTRATION NUMBER: NCT03583320.

Association of Titin Variations With Late-Onset Dilated Cardiomyopathy.

IMPORTANCE: Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM). OBJECTIVE: To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. DESIGN, SETTING, AND PARTICIPANTS: A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. MAIN OUTCOMES AND MEASURES: The study outcome was all-cause mortality. RESULTS: A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative. CONCLUSIONS AND RELEVANCE: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

Healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy.

OBJECTIVES: Our primary aim was to evaluate the healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy. Second, we aim to assess the effect of the number of diagnostic tests and clinical contact points on the total time and costs between symptom onset and diagnosis defining a quantitative hypothetical optimized diagnostic pathway. SETTING: Clinical and cost data were collected from patients presenting between 2010 and 2018 in a tertiary referral institution in South London involving two participating hospitals. PARTICIPANTS: Thirty-eight adult patients with a definite diagnosis of transthyretin amyloidosis cardiomyopathy were included, mostly male (n = 28, 74%) and of African-Caribbean descent (n = 23, 64%). We excluded patients without a confirmed transthyretin amyloidosis cardiomyopathy or those on inotersen, patisiran, or diflunisal at point of referral. PRIMARY AND SECONDARY OUTCOME MEASURES: The average time between first presentation and final diagnosis, and the cost per patient per month. By comparing to a more optimal clinical pathway towards diagnosis, we considered what could be the theoretical gain in terms of time to diagnosis and financial savings. RESULTS: The average time between first presentation and final diagnosis was 2.74 years. The average cost per patient per month was higher with progressive heart failure symptoms. A hypothetical optimal pathway reduces time to diagnosis of 1.65 to 1.74 years per patient. The potential financial savings are estimated within the range of £3000 to £4800 per patient. CONCLUSIONS: Patients diagnosed with transthyretin amyloidosis cardiomyopathy have substantial healthcare resource utilization and costs starting from symptom onset. Higher costs were observed with progression in symptoms and appear linked to a delayed diagnosis. The number of additional diagnostic tests and clinical contact points may contribute to this and could represent a path to explore further for important health and cost savings, with more efficient pathways for these patients to be managed.

Real-world evidence in a national health service: results of the UK CardioMEMS HF System Post-Market Study.

AIMS: The CardioMEMS HF System Post-Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic-guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. METHODS AND RESULTS: COAST is a prospective, international, multicentre, open-label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic-guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system-related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72-88%] than the previous 12 months (0.27 vs. 1.52 events/patient-year, respectively, P < 0.0001). Freedom from device/system-related complications and pressure sensor failure at 2 years was 100% and 99%, respectively. CONCLUSIONS: Remote haemodynamic-guided HF management, using frequent assessment of pulmonary artery pressures, was successfully implemented at 14 specialist centres in the UK. Haemodynamic-guided HF management was safe and significantly reduced hospitalization in a group of high-risk patients. These results support implementation of this innovative remote management strategy to improve outcome for patients with symptomatic HF. Clinical registration number: ClinicalTrials.gov identifier: NCT02954341.

Epidemiology of cardiomyopathies and incident heart failure in a population-based cohort study.

AIMS: The population prevalence of cardiomyopathies and the natural history of symptomatic heart failure (HF) and arrhythmia across cardiomyopathy phenotypes is poorly understood. Study aims were to estimate the population-diagnosed prevalence of cardiomyopathies and describe the temporal relationship between a diagnosis of cardiomyopathy with HF and arrhythmia. METHODS: People with cardiomyopathy (n=4116) were identified from linked electronic health records (~9 million individuals; 2000-2018) and categorised into hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM) and cardiac amyloidosis (CA). Cardiomyopathy point prevalence, rates of symptomatic HF and arrhythmia and timing relative to a diagnosis of cardiomyopathy were determined. RESULTS: In 2018, DCM was the most common cardiomyopathy. DCM and HCM were twice as common among men, with the reverse trend for ARVC. Between 2010 and 2018, prevalence increased for ARVC by 180% and HCM by 9%. At diagnosis, more patients with CA (66%), DCM (56%) and RCM (62%) had pre-existing HF compared with ARVC (29%) and HCM (27%). Among those free of HF at diagnosis of cardiomyopathy, annualised HF incidence was greatest in CA and DCM. Diagnoses of all cardiomyopathies clustered around the time of HF onset. CONCLUSIONS: The recorded prevalence of all cardiomyopathies increased over the past decade. Recognition of CA is generally preceded by HF, whereas individuals with ARVC or HCM more often developed HF after their cardiomyopathy diagnosis suggesting a more indolent course or better asymptomatic recognition. The clustering of HF and cardiomyopathy diagnoses suggests opportunities for presymptomatic or earlier diagnosis.

A case of mistaken arrhythmogenic identity during pregnancy.

Atypical LVOT ectopy can present with an RVOT morphology on ECG and differentiation to reveal this focus is in favor of benign idiopathic ventricular ectopy over an arrhythmogenic cardiomyopathy.

The alcohol-induced cardiomyopathy: A cardiovascular magnetic resonance characterization.

BACKGROUND: Alcoholic cardiomyopathy(ACM) is part of the non-ischaemic dilated cardiomyopathy(NI-DCM) spectrum. Little is known about cardiovascular magnetic resonance(CMR) features in ACM patients. The aim of this study is to describe CMR findings and their prognostic impact in ACM patients. METHODS: Consecutive ACM patients evaluated in five referral CMR centres from January 2005 to December 2018 were enrolled. CMR findings and their prognostic value were compared to idiopathic NI-DCM(iNI-DCM) patients. The main outcome was a composite of death/heart transplantation/life-threatening arrhythmias. RESULTS: Overall 114 patients (52 with ACM and 62 with iNI-DCM) were included. ACM patients were more often males compared to iNI-DCM (90% vs 64%, respectively, p ≤ 0.001) and were characterized by a more pronounced biventricular adverse remodelling than iNI-DCM, i.e. lower LVEF (31 ± 12% vs 38 ± 11% respectively, p = 0.001) and larger left ventricular end-diastolic volume (116 ± 40 ml/m2 vs 67 ± 20 ml/m2 respectively, p < 0.001). Similarly to iNI-DCM, late gadolinium enhancement (LGE), mainly midwall, was present in more than 40% of ACM patients but, conversely, it was not associated with adverse outcome(p = 0.15). LGE localization was prevalently septal (87%) in ACM vs lateral in iNI-DCM(p < 0.05). Over a median follow-up of 42 months [Interquartile Range 24-68], adverse outcomes were similar in both groups(p = 0.67). CONCLUSIONS: ACM represents a specific phenotype of NI-DCM, with severe morpho-functional features at the onset, but similar long-term outcomes compared to iNI-DCM. Despite the presence and pattern of distribution of LGE was comparable, ACM and iNI-DCM showed a different LGE localization, mostly septal in ACM and lateral in iNI-DCM, with different prognostic impact.

The Role of AI in Characterizing the DCM Phenotype.

Dilated Cardiomyopathy is conventionally defined by left ventricular dilatation and dysfunction in the absence of coronary disease. Emerging evidence suggests many patients remain vulnerable to major adverse outcomes despite clear therapeutic success of modern evidence-based heart failure therapy. In this era of personalized medical care, the conventional assessment of left ventricular ejection fraction falls short in fully predicting evolution and risk of outcomes in this heterogenous group of heart muscle disease, as such, a more refined means of phenotyping this disease appears essential. Cardiac MRI (CMR) is well-placed in this respect, not only for its diagnostic utility, but the wealth of information captured in global and regional function assessment with the addition of unique tissue characterization across different disease states and patient cohorts. Advanced tools are needed to leverage these sensitive metrics and integrate with clinical, genetic and biochemical information for personalized, and more clinically useful characterization of the dilated cardiomyopathy phenotype. Recent advances in artificial intelligence offers the unique opportunity to impact clinical decision making through enhanced precision image-analysis tasks, multi-source extraction of relevant features and seamless integration to enhance understanding, improve diagnosis, and subsequently clinical outcomes. Focusing particularly on deep learning, a subfield of artificial intelligence, that has garnered significant interest in the imaging community, this paper reviews the main developments that could offer more robust disease characterization and risk stratification in the Dilated Cardiomyopathy phenotype. Given its promising utility in the non-invasive assessment of cardiac diseases, we firstly highlight the key applications in CMR, set to enable comprehensive quantitative measures of function beyond the standard of care assessment. Concurrently, we revisit the added value of tissue characterization techniques for risk stratification, showcasing the deep learning platforms that overcome limitations in current clinical workflows and discuss how they could be utilized to better differentiate at-risk subgroups of this phenotype. The final section of this paper is dedicated to the allied clinical applications to imaging, that incorporate artificial intelligence and have harnessed the comprehensive abundance of data from genetics and relevant clinical variables to facilitate better classification and enable enhanced risk prediction for relevant outcomes.

ESC EORP Cardiomyopathy Registry: real-life practice of genetic counselling and testing in adult cardiomyopathy patients.

AIMS: Cardiomyopathies comprise a heterogeneous group of diseases, often of genetic origin. We assessed the current practice of genetic counselling and testing in the prospective European Society of Cardiology EURObservational Research Programme Cardiomyopathy Registry. METHODS AND RESULTS: A total of 3208 adult patients from 69 centres in 18 countries were enrolled. Genetic counselling was performed in 60.8% of all patients [75.4% in hypertrophic cardiomyopathy (HCM), 39.2% in dilated cardiomyopathy (DCM), 70.8% in arrhythmogenic right ventricular cardiomyopathy (ARVC), and 49.2% in restrictive cardiomyopathy (RCM), P < 0.001]. Comparing European geographical areas, genetic counselling was performed from 42.4% to 83.3% (P < 0.001). It was provided by a cardiologist (85.3%), geneticist (15.1%), genetic counsellor (11.3%), or a nurse (7.5%) (P < 0.001). Genetic testing was performed in 37.3% of all patients (48.8% in HCM, 18.6% in DCM, 55.6% in ARVC, and 43.6% in RCM, P < 0.001). Index patients with genetic testing were younger at diagnosis and had more familial disease, family history of sudden cardiac death, or implanted cardioverter defibrillators but less co-morbidities than those not tested (P < 0.001 for each comparison). At least one disease-causing variant was found in 41.7% of index patients with genetic testing (43.3% in HCM, 33.3% in DCM, 51.4% in ARVC, and 42.9% in RCM, P = 0.13). CONCLUSIONS: This is the first detailed report on the real-life practice of genetic counselling and testing in cardiomyopathies in Europe. Genetic counselling and testing were performed in a substantial proportion of patients but less often than recommended by European guidelines and much less in DCM than in HCM and ARVC, despite evidence for genetic background.

Differentiation between athlete's heart and dilated cardiomyopathy in athletic individuals.

OBJECTIVE: Distinguishing early dilated cardiomyopathy (DCM) from physiological left ventricular (LV) dilatation with LV ejection fraction <55% in athletes (grey zone) is challenging. We evaluated the role of a cascade of investigations to differentiate these two entities. METHODS: Thirty-five asymptomatic active males with DCM, 25 male athletes in the 'grey zone' and 24 male athletes with normal LV ejection fraction underwent N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement, ECG and exercise echocardiography. Grey-zone athletes and patients with DCM underwent cardiovascular magnetic resonance (CMR) and Holter monitoring. RESULTS: Larger LV cavity dimensions and lower LV ejection fraction were the only differences between grey-zone and control athletes. None of the grey-zone athletes had abnormal NT-proBNP, increased ectopic burden/complex arrhythmias or pathological late gadolinium enhancement on CMR. These features were also absent in 71%, 71% and 50% of patients with DCM, respectively. 95% of grey-zone athletes and 60% of patients with DCM had normal ECG. During exercise echocardiography, 96% grey-zone athletes increased LV ejection fraction by >11% from baseline to peak exercise compared with 23% of patients with DCM (p<0.0001). Peak LV ejection fraction was >63% in 92% grey-zone athletes compared with 17% patients with DCM (p<0.0001). Failure to increase LV ejection fraction >11% from baseline to peak exercise or achieve a peak LV ejection fraction >63% had sensitivity of 77% and 83%, respectively, and specificity of 96% and 92%, respectively, for predicting DCM. CONCLUSION: Comprehensive assessment using a cascade of routine investigations revealed that exercise stress echocardiography has the greatest discriminatory value in differentiating between grey-zone athletes and asymptomatic patients with DCM. Our findings require validation in larger studies.

CMR imaging biosignature of cardiac involvement due to cancer-related treatment by T1 and T2 mapping.

BACKGROUND: Cancer-related treatment is associated with development of heart failure and poor outcome in cancer-survivors. T1 and T2 mapping by cardiovascular magnetic resonance (CMR) may detect myocardial injury due to cancer-related treatment. METHODS: Patients receiving cancer-related treatment regimes underwent screening of cardiac involvement with CMR, either within 3 months (early Tx) or >12 months (late Tx) post-treatment. T1 and T2 mapping, cardiac function, strain, ischaemia-testing, scar-imaging and serological cardiac biomarkers were obtained. RESULTS: Compared to age/gender matched controls (n = 57), patients (n = 115, age (yrs): median(IQR) 48(28-60), females, n = 60(52%) had reduced left ventricular ejection fraction (LV-EF) and strain, and higher native T1 and T2. The early Tx group (n = 52) had significantly higher native T1, T2 and troponin levels compared to the late Tx group, indicating myocardial inflammation and oedema (p < 0.01). On the contrary, late Tx patients showed raised native T1, increased LV-end-systolic volumes, reduced LV-EF and deformation, and elevated NT-proBNP, suggesting myocardial fibrosis and remodelling (p < 0.05). Prospective validation of these results in an independent cohort of patients with similar treatment regimens (n = 25) and longitudinal assessments revealed high concordance of CMR imaging signatures of early and late cardiac involvement. CONCLUSIONS: Native T1 and T2 mapping can be valuable in detecting and monitoring of cardiac involvement with cancer-related treatment, providing distinct biosignatures of early inflammatory involvement (raised native T1 and T2) and interstitial fibrosis and remodelling (raised native T1 but not T2), respectively. Our findings may provide an algorithm allowing to identify susceptible myocardium to potentially guide cardio-protective treatment measures.

High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus.

BACKGROUND: Cardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR). METHODS AND RESULTS: This is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement. CONCLUSIONS: Patients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement. TRIAL REGISTRATION NUMER: NCT02407197; Results.

Native T1 and ECV of Noninfarcted Myocardium and Outcome in Patients With Coronary Artery Disease.

BACKGROUND: Coronary artery disease (CAD) remains the major cause of cardiac morbidity and mortality worldwide, despite the advances in treatment with coronary revascularization and modern antiremodeling therapy. Risk stratification in CAD patients is primarily based on left ventricular volumes, ejection fraction (LVEF), risk scores, and the presence and extent of late gadolinium enhancement (LGE). The prognostic role of T1 mapping in noninfarcted myocardium in CAD patients has not yet been determined. OBJECTIVES: This study sought to examine prognostic significance of native T1 mapping of noninfarcted myocardium in patients with CAD. METHODS: A prospective, observational, multicenter longitudinal study of consecutive patients undergoing routine cardiac magnetic resonance imaging with T1 mapping and LGE. The primary endpoint was all-cause mortality. Major adverse cardiocerebrovascular events (MACCE) (cardiac mortality, nonfatal acute coronary syndrome, stroke, and appropriate device discharge) are also reported. RESULTS: A total of 34 deaths and 71 MACCE (n = 665, males n = 424, median age [interquartile range] 57 [22] years; 64%; median follow-up period of 17 [11] months) were observed. Native T1 and extracellular volume were univariate predictors of outcome. Native T1 and LGE were stronger predictors of survival and MACCE compared with extracellular volume, LVEF, cardiac volumes, and clinical scores (p < 0.001). Native T1 of noninfarcted myocardium was the sole independent predictor of all-cause mortality (chi-square = 21.7; p < 0.001), which was accentuated in the absence of LGE or LVEF ≤35%. For MACCE, native T1 and LGE extent were joint independent predictors (chi-square = 25.6; p < 0.001). CONCLUSIONS: Characterization of noninfarcted myocardium by native T1 is an important predictor of outcome in CAD patients, over and above the traditional risk stratifiers. The current study's results provide a basis for a novel risk stratification model in CAD based on a complementary assessment of noninfarcted myocardium and post-infarction scar, by native T1 mapping and LGE, respectively.

Comprehensive use of cardiac computed tomography to guide left ventricular lead placement in cardiac resynchronization therapy.

BACKGROUND: Optimal lead positioning is an important determinant of cardiac resynchronization therapy (CRT) response. OBJECTIVE: The purpose of this study was to evaluate cardiac computed tomography (CT) selection of the optimal epicardial vein for left ventricular (LV) lead placement by targeting regions of late mechanical activation and avoiding myocardial scar. METHODS: Eighteen patients undergoing CRT upgrade with existing pacing systems underwent preimplant electrocardiogram-gated cardiac CT to assess wall thickness, hypoperfusion, late mechanical activation, and regions of myocardial scar by the derivation of the stretch quantifier for endocardial engraved zones (SQUEEZ) algorithm. Cardiac venous anatomy was mapped to individualized American Heart Association (AHA) bull's-eye plots to identify the optimal venous target and compared with acute hemodynamic response (AHR) in each coronary venous target using an LV pressure wire. RESULTS: Fifteen data sets were evaluable. CT-SQUEEZ-derived targets produced a similar mean AHR compared with the best achievable AHR (20.4% ± 13.7% vs 24.9% ± 11.1%; P = .36). SQUEEZ-derived guidance produced a positive AHR in 92% of target segments, and pacing in a CT-SQUEEZ target vein produced a greater clinical response rate vs nontarget segments (90% vs 60%). CONCLUSION: Preprocedural CT-SQUEEZ-derived target selection may be a valuable tool to predict the optimal venous site for LV lead placement in patients undergoing CRT upgrade.

Native T1 and T2 mapping by CMR in lupus myocarditis: Disease recognition and response to treatment.

BACKGROUND: Lupus myocarditis is likely more common than recognized clinically due to non-specific symptoms and lack of reliable non-invasive diagnostic tests. We investigated the role of native T1 and T2 in recognition of active myocardial inflammatory involvement in patients with systemic lupus erythematous (SLE). METHODS: 76 patients with clinically suspected lupus myocarditis (14 males, age: 44±16years) underwent quantitative tissue characterization with native T1 and T2 mapping. Normotensive healthy subjects taking no medication served as controls (n=46). Follow-up CMR studies were performed in a total of 35 subjects of which 14 patients received intensified anti-inflammatory treatment, as guided by SLE disease activity. RESULTS: Compared to controls SLE patients had higher inflammatory markers, LV mass, native T1 and T2 values, and reduced longitudinal strain (p<0.01). In patients with a positive troponin test (n=36; 46%), native T1 and T2 were significantly higher (p<0.01) with otherwise similar proportions of diffuse perimyocardial LGE (33%) and pericardial effusion (32%). Sixty-nine patients (83%) had an abnormal native T1, whereas 51 (71%) met diagnostic criteria for acute myocarditis. Follow-up CMRs revealed significantly greater reduction in native T1 and T2 values in patients with intensified anti-inflammatory treatment (p<0.001) with the greatest change observed within the first follow-up period and plateauing thereafter. Native T1 and T2 were significant predictors of treatment response. CONCLUSIONS: Native T1 and T2 mapping support recognition of lupus myocarditis and reflect the response to anti-inflammatory treatment. Native T1 and T2 mapping may support an effective, noninvasive, radiation- and gadolinium contrast-free screening method for lupus myocarditis.

T1-Mapping and Outcome in Nonischemic Cardiomyopathy: All-Cause Mortality and Heart Failure.

OBJECTIVES: The study sought to examine prognostic relevance of T1 mapping parameters (based on a T1 mapping method) in nonischemic dilated cardiomyopathy (NIDCM) and compare them with conventional markers of adverse outcome. BACKGROUND: NIDCM is a recognized cause of poor clinical outcome. NIDCM is characterized by intrinsic myocardial remodeling due to complex pathophysiological processes affecting myocardium diffusely. Lack of accurate and noninvasive characterization of diffuse myocardial disease limits recognition of early cardiomyopathy and effective clinical management in NIDCM. Cardiac magnetic resonance (CMR) supports detection of diffuse myocardial disease by T1 mapping. METHODS: This is a prospective observational multicenter longitudinal study in 637 consecutive patients with dilated NIDCM (mean age 50 years [interquartile range: 37 to 76 years]; 395 males [62%]) undergoing CMR with T1 mapping and late gadolinium enhancement (LGE) at 1.5-T and 3.0-T. The primary endpoint was all-cause mortality. A composite of heart failure (HF) mortality and hospitalization was a secondary endpoint. RESULTS: During a median follow-up period of 22 months (interquartile range: 19 to 25 months), we observed a total of 28 deaths (22 cardiac) and 68 composite HF events. T1 mapping indices (native T1 and extracellular volume fraction), as well as the presence and extent of LGE, were predictive of all-cause mortality and HF endpoint (p < 0.001 for all). In multivariable analyses, native T1 was the sole independent predictor of all-cause and HF composite endpoints (hazard ratio: 1.1; 95% confidence interval: 1.06 to 1.15; hazard ratio: 1.1; 95% confidence interval: 1.05 to 1.1; p < 0.001 for both), followed by the models including the extent of LGE and right ventricular ejection fraction, respectively. CONCLUSIONS: Noninvasive measures of diffuse myocardial disease by T1 mapping are significantly predictive of all-cause mortality and HF events in NIDCM. We provide a basis for a novel algorithm of risk stratification in NIDCM using a complementary assessment of diffuse and regional disease by T1 mapping and LGE, respectively.