Multiparametric exercise stress cardiovascular magnetic resonance in the diagnosis of coronary artery disease: the EMPIRE trial.

BACKGROUND: Stress cardiovascular magnetic resonance (CMR) offers assessment of ventricular function, myocardial perfusion and viability in a single examination to detect coronary artery disease (CAD). We developed an in-scanner exercise stress CMR (ExCMR) protocol using supine cycle ergometer and aimed to examine the diagnostic value of a multiparametric approach in patients with suspected CAD, compared with invasive fractional flow reserve (FFR) as the reference gold standard. METHODS: In this single-centre prospective study, patients who had symptoms of angina and at least one cardiovascular disease risk factor underwent both ExCMR and invasive angiography with FFR. Rest-based left ventricular function (ejection fraction, regional wall motion abnormalities), tissue characteristics and exercise stress-derived (perfusion defects, inducible regional wall motion abnormalities and peak exercise cardiac index percentile-rank) CMR parameters were evaluated in the study. RESULTS: In the 60 recruited patients with intermediate CAD risk, 50% had haemodynamically significant CAD based on FFR. Of all the CMR parameters assessed, the late gadolinium enhancement, stress-inducible regional wall motion abnormalities, perfusion defects and peak exercise cardiac index percentile-rank were independently associated with FFR-positive CAD. Indeed, this multiparametric approach offered the highest incremental diagnostic value compared to a clinical risk model (χ2 for the diagnosis of FFR-positive increased from 7.6 to 55.9; P < 0.001) and excellent performance [c-statistic area under the curve 0.97 (95% CI: 0.94-1.00)] in discriminating between FFR-normal and FFR-positive patients. CONCLUSION: The study demonstrates the clinical potential of using in-scanner multiparametric ExCMR to accurately diagnose CAD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03217227, Registered 11 July 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03217227?id=NCT03217227&draw=2&rank=1&load=cart.

The application of exercise stress cardiovascular magnetic resonance in patients with suspected dilated cardiomyopathy.

OBJECTIVES: The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM. METHODS: Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; PeakCI). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events. RESULTS: No patients with confirmed G+P+ DCM had PeakCI exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with PeakCI below 35th percentile had characteristics similar to confirmed DCM while patients with higher PeakCI were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004). CONCLUSIONS: In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.

Relationship of Quantitative Retinal Capillary Network and Myocardial Remodeling in Systemic Hypertension.

Background This study examined the associations between quantitative optical coherence tomography angiography (OCTA) parameters and myocardial abnormalities as documented on cardiovascular magnetic resonance imaging in patients with systemic hypertension. Methods and Results We conducted a cross-sectional study of 118 adults with hypertension (197 eyes). Patients underwent cardiovascular magnetic resonance imaging and OCTA (PLEX Elite 9000, Carl Zeiss Meditec). Associations between OCTA parameters (superficial and deep retinal capillary density) and adverse cardiac remodeling (left ventricular mass, remodeling index, interstitial fibrosis, global longitudinal strain, and presence of left ventricular hypertrophy) were studied using multivariable linear regression analysis with generalized estimating equations. Of the 118 patients with hypertension enrolled (65% men; median [interquartile range] age, 59 [13] years), 29% had left ventricular hypertrophy. After adjusting for age, sex, systolic blood pressure, diabetes, and signal strength of OCTA scans, patients with lower superficial capillary density had significantly higher left ventricular mass (ß=-0.150; 95% CI, -0.290 to -0.010), higher interstitial volume (ß=-0.270; 95% CI, -0.535 to -0.0015), and worse global longitudinal strain (ß=-0.109; 95% CI, -0.187 to -0.032). Lower superficial capillary density was found in patients with hypertension with replacement fibrosis versus no replacement fibrosis (16.53±0.64 mm-1 versus 16.96±0.64 mm-1; P=0.003). Conclusions We showed significant correlations between retinal capillary density and adverse cardiac remodeling markers in patients with hypertension, supporting the notion that the OCTA could provide a non-invasive index of microcirculation alteration for vascular risk stratification in people with hypertension.

Markers of Focal and Diffuse Nonischemic Myocardial Fibrosis Are Associated With Adverse Cardiac Remodeling and Prognosis in Patients With Hypertension: The REMODEL Study.

BACKGROUND: The prognostic significance of focal and diffuse myocardial fibrosis in patients with cardiovascular risk factors is unclear. METHODS: REMODEL (Response of the Myocardium to Hypertrophic Conditions in the Adult Population) is an observational cohort of asymptomatic patients with essential hypertension. All participants underwent cardiovascular magnetic resonance to assess for myocardial fibrosis: nonischemic late gadolinium enhancement (LGE), native myocardial T1, postcontrast myocardial T1, extracellular volume fraction including/excluding LGE regions, interstitial volume (extracellular volume×myocardial volume), and interstitial/myocyte ratio. Primary outcome was a composite of first occurrence acute coronary syndrome, heart failure hospitalization, strokes, and cardiovascular mortality. Patients were recruited from February 2016 and followed until June 2021. RESULTS: Of the 786 patients with hypertension (58±11 years; 39% women; systolic blood pressure, 130±14 mm Hg), 145 (18%) had nonischemic LGE. Patients with nonischemic LGE were more likely to be men, have diabetes, be current smokers, and have higher blood pressure (P<0.05 for all). Compared with those without LGE, patients with nonischemic LGE had greater left ventricular mass (66±22 versus 49±9 g/m2; P<0.001), worse multidirectional strain (P<0.001 for all measures), and elevated circulating markers of myocardial wall stress and myocardial injury, adjusted for potential confounders. Twenty-four patients had primary outcome over 39 (30-50) months of follow-up. Of all the cardiovascular magnetic resonance markers of myocardial fibrosis assessed, only nonischemic LGE (hazard ratio, 6.69 [95% CI, 2.54-17.60]; P<0.001) and indexed interstitial volume (hazard ratio, 1.11 [95% CI, 1.04-1.19]; P=0.002) demonstrated independent association with primary outcome. CONCLUSIONS: In patients with hypertension, myocardial fibrosis on cardiovascular magnetic resonance is associated with adverse cardiac remodeling and outcomes.

The remodelling index risk stratifies patients with hypertensive left ventricular hypertrophy.

AIMS: Hypertensive left ventricular hypertrophy (LVH) is associated with increased cardiovascular events. We previously developed the remodelling index (RI) that incorporated left ventricular (LV) volume and wall-thickness in a single measure of advanced hypertrophy in hypertensive patients. This study examined the prognostic potential of the RI in reference to contemporary LVH classifications. METHODS AND RESULTS: Cardiovascular magnetic resonance was performed in 400 asymptomatic hypertensive patients. The newly derived RI (EDV3t, where EDV is LV end-diastolic volume and t is the maximal wall thickness across 16 myocardial segments) stratified hypertensive patients: no LVH, LVH with normal RI (LVHNormal-RI), and LVH with low RI (LVHLow-RI). The primary outcome was a composite of all-cause mortality, acute coronary syndromes, strokes, and decompensated heart failure. LVHLow-RI was associated with increased LV mass index, fibrosis burden, impaired myocardial function and elevated biochemical markers of myocardial injury (high-sensitive cardiac troponin I), and wall stress. Over 18.3 ± 7.0 months (601.3 patient-years), 14 adverse events occurred (2.2 events/100 patient-years). Patients with LVHLow-RI had more than a five-fold increase in adverse events compared to those with LVHNormal-RI (11.6 events/100 patient-years vs. 2.0 events/100 patient-years, respectively; log-rank P < 0.001). The RI provided incremental prognostic value over and above a model consisting of clinical variables, LVH and concentricity; and predicted adverse events independent of clinical variables, LVH, and other prognostic markers. Concentric and eccentric LVH were associated with adverse prognosis (log-rank P = 0.62) that was similar to the natural history of hypertensive LVH (5.1 events/100 patient-years). CONCLUSION: The RI provides prognostic value that improves risk stratification of hypertensive LVH.

A Systematic Quality Scoring Analysis to Assess Automated Cardiovascular Magnetic Resonance Segmentation Algorithms.

BACKGROUND: The quantitative measures used to assess the performance of automated methods often do not reflect the clinical acceptability of contouring. A quality-based assessment of automated cardiac magnetic resonance (CMR) segmentation more relevant to clinical practice is therefore needed. OBJECTIVE: We propose a new method for assessing the quality of machine learning (ML) outputs. We evaluate the clinical utility of the proposed method as it is employed to systematically analyse the quality of an automated contouring algorithm. METHODS: A dataset of short-axis (SAX) cine CMR images from a clinically heterogeneous population (n = 217) were manually contoured by a team of experienced investigators. On the same images we derived automated contours using a ML algorithm. A contour quality scoring application randomly presented manual and automated contours to four blinded clinicians, who were asked to assign a quality score from a predefined rubric. Firstly, we analyzed the distribution of quality scores between the two contouring methods across all clinicians. Secondly, we analyzed the interobserver reliability between the raters. Finally, we examined whether there was a variation in scores based on the type of contour, SAX slice level, and underlying disease. RESULTS: The overall distribution of scores between the two methods was significantly different, with automated contours scoring better than the manual (OR (95% CI) = 1.17 (1.07-1.28), p = 0.001; n = 9401). There was substantial scoring agreement between raters for each contouring method independently, albeit it was significantly better for automated segmentation (automated: AC2 = 0.940, 95% CI, 0.937-0.943 vs manual: AC2 = 0.934, 95% CI, 0.931-0.937; p = 0.006). Next, the analysis of quality scores based on different factors was performed. Our approach helped identify trends patterns of lower segmentation quality as observed for left ventricle epicardial and basal contours with both methods. Similarly, significant differences in quality between the two methods were also found in dilated cardiomyopathy and hypertension. CONCLUSIONS: Our results confirm the ability of our systematic scoring analysis to determine the clinical acceptability of automated contours. This approach focused on the contours' clinical utility could ultimately improve clinicians' confidence in artificial intelligence and its acceptability in the clinical workflow.

Lowering the Recommended Maximal Wall Thickness Threshold Improves Diagnostic Sensitivity in Asians With Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is defined as left ventricular end-diastolic maximal wall thickness (WTMax) ≥15.0 mm, without accounting for ethnicity, sex, and body size. It is well-established that Asians have smaller hearts than do Caucasians. Objectives: This study aims to examine the implications of this single absolute WTMax threshold on the diagnosis of HCM in Asians. Methods: The study consisted of 360 healthy volunteers (male: n = 174; age: 50 ± 12 years) and 114 genetically characterized patients with HCM (male: n = 83; age: 52 ± 13 years; genotype-positive, n = 39). All participants underwent cardiovascular magnetic resonance. WTMax was measured semiautomatically at end-diastole according to the standard 16 myocardial segments. Results: Healthy male volunteers had increased WTMax compared with that of female volunteers (8.4 ± 1.2 mm vs 6.6 ± 1.1 mm, respectively; P < 0.001). Conversely, WTMax was similar between male and female patients with HCM (15.2 ± 3.4 mm vs 14.7 ± 3.0 mm, respectively; P = 0.484) and between those with and without a pathogenic gene variant (P = 0.828). Using the recommended diagnostic threshold of 15.0 mm, 56 patients with HCM had WTMax <15.0 mm and no healthy volunteers had WTMax >15.0 mm (specificity of 100% and sensitivity of 51%). Lowering WTMax thresholds to 10.0 mm in female patients and 12.0 mm in male patients did not affect specificity (100%) but significantly improved sensitivity (84%). Despite lower left ventricular mass, female patients with HCM demonstrated more features of adverse cardiac remodeling than did male patients: increased myocardial fibrosis, higher asymmetric ratio, and disproportionately worse myocardial strain. Conclusions: The study highlights cautious application of guideline-recommended WTMax to diagnose HCM in Asians. Lowering WTMax to account for ethnicity and sex improves diagnostic sensitivity without compromising specificity.

Echocardiographic Global Longitudinal Strain Is Associated With Myocardial Fibrosis and Predicts Outcomes in Aortic Stenosis.

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF.

Paradoxical Higher Myocardial Wall Stress and Increased Cardiac Remodeling Despite Lower Mass in Females.

Background Increased left ventricular (LV) mass is characterized by increased myocardial wall thickness and/or ventricular dilatation that is associated with worse outcomes. We aim to comprehensively compare sex-stratified associations between measures of LV remodeling and increasing LV mass in the general population. Methods and Results Participants were prospectively recruited in the National Heart Center Singapore Biobank to examine health and cardiovascular risk factors in the general population. Cardiovascular magnetic resonance was performed in all individuals. Participants with established cardiovascular diseases and abnormal cardiovascular magnetic resonance scan results were excluded. Global and regional measures of LV remodeling (geometry, function, interstitial volumes, and wall stress) were performed using conventional image analysis and novel 3-dimensional machine learning phenotyping. Sex-stratified analyses were performed in 1005 participants (57% males; 53±13 years). Age and prevalence of cardiovascular risk factors were well-matched in both sexes (P>0.05 for all). Progressive increase in LV mass was associated with increased concentricity in either sex, but to a greater extent in females. Compared with males, females had higher wall stress (mean difference: 170 mm Hg, P<0.0001) despite smaller LV mass (42.4±8.2 versus 55.6±14.2 g/m2, P<0.0001), lower blood pressures (P<0.0001), and higher LV ejection fraction (61.9±5.9% versus 58.6±6.4%, P<0.0001). The regions of increased concentric remodeling corresponded to regions of increased wall stress. Compared with males, females had increased extracellular volume fraction (27.1±2.4% versus 25.1±2.9%, P<0.0001). Conclusions Compared with males, females have lower LV mass, increased wall stress, and concentric remodeling. These findings provide mechanistic insights that females are susceptible to particular cardiovascular complications.

Author Correction: High-Sensitivity cardiac Troponins in Cardio-Healthy Subjects: A Cardiovascular Magnetic Resonance Imaging Study.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

High-Sensitivitycardiac Troponinsin Cardio-Healthy Subjects: A Cardiovascular Magnetic Resonance Imaging Study.

The 99th percentile upper reference limits (URL) of high-sensitivity cardiac troponin (hs-cTn) in healthy subjects are essential for diagnosis and management of cardiovascular diseases. Unless screened stringently, subclinical disease affects the derived URL. In 779 healthy subjects(49% males; 17-88 years) screened by cardiovascular magnetic resonance (CMR), the gold standard for assessing cardiac volumes and myocardial mass; and estimated glomerular filtration rate (eGFR), the 99th percentile URL of hsTnT (Roche) and hs-cTnI (Abbott) were similar to the published URL. The overall 99th percentile URL of hsTnT and hsTnI were 15.2 and 21.2 ng/L, respectively; males had higher values than females (hsTnT: 16.8 versus 11.9 ng/L and hsTnI: 38.8 versus 14.4 ng/L). Correlation between hsTnT and hsTnI was modest (r = 0.45; p < 0.001). A larger proportion of healthy volunteers <60 years had detectable hsTnI compared to hsTnT (n = 534; 30.0% versus 18.3%, p < 0.001). Lower eGFR was an independent clinical determinant of hsTnT, but not hsTnI. Both hs-cTn concentrations were independently associated with myocardial mass and cardiac volumes (p < 0.01 for all), but only hsTnI was independently associated with CMR multi-directional strain measures and extent of LV trabeculations (p < 0.05 for all). Differences exist between hs-cTn assays and may influence their selection depending on cardiac conditions, patient population and local factors.

Novel Index of Maladaptive Myocardial Remodeling in Hypertension.

BACKGROUND: Hypertensive left ventricular hypertrophy (HTN-LVH) is a leading cause of heart failure. Conventional patterns of cardiac geometry do not adequately risk-stratify patients with HTN-LVH. Using cardiovascular magnetic resonance, we developed a novel Remodeling Index (RI) that was designed to detect an exaggerated hypertrophic response to hypertension and tested its potential to risk-stratify hypertensive patients. METHODS AND RESULTS: The RI was derived using LaPlace's Law (), and normal RI ranges were established in 180 healthy volunteers. The utility of the RI was examined in 256 asymptomatic hypertensive patients and 10 patients with heart failure with preserved ejection fraction. Hypertensive patients underwent multimodal cardiac assessment: contrast-enhanced cardiovascular magnetic resonance, echocardiograms, 24-hour blood pressure monitoring, and cardiac biomarkers (high-sensitivity cardiac troponins, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and galectin-3). Blood pressure accounted for only 20% of the variance observed in LV mass. Although there was no association between blood pressure and myocardial fibrosis, LV mass was independently associated with fibrosis. Compared with hypertensive patients without LVH (n=191; 74.6%) and those with HTN-LVH and normal RI (n=50; 19.5%), patients with HTN-LVH and low RI (HTN-LVH/low RI; n=15, 5.9%) had an amplified myocardial response: elevated indexed LV masses (83±24 g/m2), more fibrosis (73%), and higher biomarkers of myocardial injury and dysfunction (P<0.05 for all). RI was similar in HTN-LVH/low RI and heart failure with preserved ejection fraction (4.1 [3.4-4.5] versus 3.7 [3.4-4.0], respectively; P=0.15). CONCLUSIONS: We suggest that RI provides an approach for stratifying hypertensive patients and is suitable for testing in other disease cohorts to assess its clinical utility. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02670031.