Cardiac dysfunction during exercise in young adults with bronchopulmonary dysplasia.

Background: Worldwide, 1-2% of children are born premature and at risk for developing bronchopulmonary dysplasia (BPD). Preterm-born adults are at risk for early cardiovascular disease. The role of BPD is unclear. This study aims to examine cardiorespiratory function during submaximal exercise in young adult survivors of extreme prematurity, with or without BPD. Methods: 40 preterm-born young adults, 20 with BPD (median gestational age 27 weeks, interquartile range (IQR) 26-28 weeks) and 20 without BPD (median gestational age 28 weeks, IQR 27-29 weeks) were prospectively compared to age-matched at term-born adults (median gestational age 39 weeks, IQR 38-40 weeks). Participants underwent exercise testing and cardiovascular magnetic resonance with submaximal exercise. Results: Resting heart rate in BPD subjects was higher than in at term-born subjects (69±10 mL versus 61±7 mL, p=0.01). Peak oxygen uptake during maximal cardiopulmonary exercise testing was decreased in BPD subjects (91±18% versus 106±17% of predicted, p=0.01). In BPD subjects, cardiac stroke volume change with exercise was impaired compared to at term-born subjects (11±13% versus 25±10%; p<0.001). With exercise, left ventricular end-diastolic volume decreased more in preterm-born subjects with versus without BPD (-10±8% versus -3±8%; p=0.01) and compared to at term-born subjects (0±5%; p<0.001). Exploratory data analysis revealed that exercise stroke volume and end-diastolic volume change were inversely correlated with oxygen dependency in those born prematurely. Conclusions: In preterm-born young adults, particularly those with BPD, resting cardiac function, exercise performance and cardiac response to exercise is impaired compared to controls. Exercise cardiovascular magnetic resonance may reveal an important predisposition for heart disease later in life.

Comprehensive Cardiovascular Magnetic Resonance-Derived Myocardial Strain Analysis Provides Independent Prognostic Value in Acute Myocarditis.

Background Late gadolinium enhancement and left ventricular (LV) ejection fraction on cardiovascular magnetic resonance (CMR) are prognostic markers, but their predictive value for incident heart failure or life-threatening arrhythmias in acute myocarditis patients is limited. CMR-derived feature tracking provides a more sensitive analysis of myocardial function and may improve risk stratification in myocarditis. In this study, the prognostic value of LV, right ventricular, and left atrial strain in acute myocarditis patients is evaluated. Methods and Results In this multicenter retrospective study, patients with CMR-proven acute myocarditis were included. The primary end point was occurrence of major adverse cardiovascular events: all-cause mortality, heart transplantation, heart failure hospitalizations, and life threatening arrhythmias. LV global longitudinal strain, global circumferential strain and global radial strain, right ventricular-global longitudinal strain and left atrial strain were measured. Unadjusted and adjusted cox proportional hazard regression analysis were performed. In total, 162 CMR-proven myocarditis patients were included (41 ± 17 years, 75% men). Mean LV ejection fraction was 51 ± 12%, and 144 (89%) patients had presence of late gadolinium enhancement. Major adverse cardiovascular events occurred in 29 (18%) patients during a follow-up of 5.5 (2.2-8.3) years. All LV strain parameters were independent predictors of outcome beyond clinical features, LV ejection fraction and late gadolinium enhancement (LV-global longitudinal strain: hazard ratio [HR] 1.07, P=0.02; LV-global circumferential strain: HR 1.15, P=0.02; LV-global radial strain: HR 0.98, P=0.03), but right ventricular or left atrial strain did not predict outcome. Conclusions CMR-derived LV strain analysis provides independent prognostic value on top of clinical parameters, LV ejection fraction and late gadolinium enhancement in acute myocarditis patients, while left atrial and right ventricular strain seem to be of less importance.

Contemporary family screening in hypertrophic cardiomyopathy: the role of cardiovascular magnetic resonance.

AIMS: Genetic testing in relatives of hypertrophic cardiomyopathy (HCM) patients leads to early identification of pathogenic DNA variant carriers (G+), before the onset of left ventricular hypertrophy. Routine phenotyping consists of electrocardiography (ECG) and transthoracic echocardiography (TTE). Cardiovascular magnetic resonance (CMR) has become valuable in the work-up of HCM. In this study, we investigated the value of CMR in phenotyping of G+ family members. METHODS AND RESULTS: This study included 91 G+ subjects who underwent ECG, TTE and CMR, with a maximal wall thickness (MWT) <15 mm on TTE. The relative performance of TTE and CMR regarding wall thickness measurements and HCM diagnoses was assessed. HCM was defined as MWT of ≥13 mm. Logistic regression was performed to assess whether ECG and TTE parameters can predict CMR results. Most subjects (75%) had an MWT <13 mm on TTE, of which 23 (34%) were diagnosed with HCM based on CMR. MWT differences (range 1-10 mm) were often caused by an anterobasal hook-shaped thickening of the myocardium not visible on TTE. Two of 23 (9%) subjects with HCM on TTE were reclassified as no HCM on CMR. Normal ECG and TTE results almost excluded reclassifications by CMR. The prevalence of other HCM-related abnormalities on CMR was low. CONCLUSION: CMR reclassified 27% of subjects. Subjects with normal ECG/TTE results were reclassified in a low number of cases, justifying screening with ECG and TTE in G+ relatives. In subjects with abnormal ECGs and/or poor TTE image quality, CMR is indicated.

Evaluation of intraventricular flow by multimodality imaging: a review and meta-analysis.

BACKGROUND: The aim of this systematic review was to evaluate current inter-modality agreement of noninvasive clinical intraventricular flow (IVF) assessment with 3 emerging imaging modalities: echocardiographic particle image velocimetry (EPIV), vector flow mapping (VFM), and 4-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR). METHODS: We performed a systematic literature review in the databases EMBASE, Medline OVID and Cochrane Central for identification of studies evaluating left ventricular (LV) flow patterns using one of these flow visualization modalities. Of the 2224 initially retrieved records, 10 EPIV, 23 VFM, and 25 4D flow CMR studies were included in the final analysis. RESULTS: Vortex parameters were more extensively studied with EPIV, while LV energetics and LV transport mechanics were mainly studied with 4D flow CMR, and LV energy loss and vortex circulation were implemented by VFM studies. Pooled normative values are provided for these parameters. The meta- analysis for the values of two vortex morphology parameters, vortex length and vortex depth, failed to reveal a significant change between heart failure patients and healthy controls. CONCLUSION: Agreement between the different modalities studying intraventricular flow is low and different methods of measurement and reporting were used among studies. A multimodality framework with a standardized set of flow parameters is necessary for implementation of noninvasive flow visualization in daily clinical practice. The full potential of noninvasive flow visualization in addition to diagnostics could also include guiding medical or interventional treatment.

Novel Morphological Features on CMR for the Prediction of Pathogenic Sarcomere Gene Variants in Subjects Without Hypertrophic Cardiomyopathy.

Background: Carriers of pathogenic DNA variants (G+) causing hypertrophic cardiomyopathy (HCM) can be identified by genetic testing. Several abnormalities have been brought forth as pre-clinical expressions of HCM, some of which can be identified by cardiovascular magnetic resonance (CMR). In this study, we assessed morphological differences between G+/left ventricular hypertrophy-negative (LVH-) subjects and healthy controls and examined whether CMR-derived variables are useful for the prediction of sarcomere gene variants. Methods: We studied 57 G+ subjects with a maximal wall thickness (MWT) < 13 mm, and compared them to 40 healthy controls matched for age and sex on a group level. Subjects underwent CMR including morphological, volumetric and function assessment. Logistic regression analysis was performed for the determination of predictive CMR characteristics, by which a scoring system for G+ status was constructed. Results: G+/LVH- subjects were subject to alterations in the myocardial architecture, resulting in a thinner posterior wall thickness (PWT), higher interventricular septal wall/PWT ratio and MWT/PWT ratio. Prominent hook-shaped configurations of the anterobasal segment were only observed in this group. A model consisting of the anterobasal hook, multiple myocardial crypts, right ventricular/left ventricular ratio, MWT/PWT ratio, and MWT/left ventricular mass ratio predicted G+ status with an area under the curve of 0.92 [0.87-0.97]. A score of ≥3 was present only in G+ subjects, identifying 56% of the G+/LVH- population. Conclusion: A score system incorporating CMR-derived variables correctly identified 56% of G+ subjects. Our results provide further insights into the wide phenotypic spectrum of G+/LVH- subjects and demonstrate the utility of several novel morphological features. If genetic testing for some reason cannot be performed, CMR and our purposed score system can be used to detect possible G+ carriers and to aid planning of the control intervals.

Improvement of late gadolinium enhancement image quality using a deep learning-based reconstruction algorithm and its influence on myocardial scar quantification.

OBJECTIVES: The aim of this study was to assess the effect of a deep learning (DL)-based reconstruction algorithm on late gadolinium enhancement (LGE) image quality and to evaluate its influence on scar quantification. METHODS: Sixty patients (46 ± 17 years, 50% male) with suspected or known cardiomyopathy underwent CMR. Short-axis LGE images were reconstructed using the conventional reconstruction and a DL network (DLRecon) with tunable noise reduction (NR) levels from 0 to 100%. Image quality of standard LGE images and DLRecon images with 75% NR was scored using a 5-point scale (poor to excellent). In 30 patients with LGE, scar size was quantified using thresholding techniques with different standard deviations (SD) above remote myocardium, and using full width at half maximum (FWHM) technique in images with varying NR levels. RESULTS: DLRecon images were of higher quality than standard LGE images (subjective quality score 3.3 ± 0.5 vs. 3.6 ± 0.7, p < 0.001). Scar size increased with increasing NR levels using the SD methods. With 100% NR level, scar size increased 36%, 87%, and 138% using 2SD, 4SD, and 6SD quantification method, respectively, compared to standard LGE images (all p values < 0.001). However, with the FWHM method, no differences in scar size were found (p = 0.06). CONCLUSIONS: LGE image quality improved significantly using a DL-based reconstruction algorithm. However, this algorithm has an important impact on scar quantification depending on which quantification technique is used. The FWHM method is preferred because of its independency of NR. Clinicians should be aware of this impact on scar quantification, as DL-based reconstruction algorithms are being used. KEY POINTS: • The image quality based on (subjective) visual assessment and image sharpness of late gadolinium enhancement images improved significantly using a deep learning-based reconstruction algorithm that aims to reconstruct high signal-to-noise images using a denoising technique. • Special care should be taken when scar size is quantified using thresholding techniques with different standard deviations above remote myocardium because of the large impact of these advanced image enhancement algorithms. • The full width at half maximum method is recommended to quantify scar size when deep learning algorithms based on noise reduction are used, as this method is the least sensitive to the level of noise and showed the best agreement with visual late gadolinium enhancement assessment.

Diagnostic Cardiovascular Magnetic Resonance Imaging Criteria in Noncompaction Cardiomyopathy and the Yield of Genetic Testing.

BACKGROUND: Noncompaction cardiomyopathy (NCCM) is characterized by a thickened myocardial wall with excessive trabeculations of the left ventricle, and ∼30% is explained by a (likely) pathogenic variant [(L)PV] in a cardiomyopathy gene. Diagnosing an (L)PV is important because it allows accurate identification of which relatives are at risk and helps predicting prognosis. The goal of this study was to assess which specific clinical and morphologic characteristics of the myocardium may predict an (L)PV and which of the cardiovascular magnetic resonance (CMR) diagnostic criteria for NCCM can best be used for that purpose. METHODS: Sixty-two patients with NCCM, diagnosed by means of echocardiographic Jenni criteria, underwent CMR imaging that was evaluated according the Petersen, Stacey, Jacquier, Captur, and Choi diagnostic CMR criteria for NCCM. Patients also underwent DNA testing and were stratified according to having an (L)PV. RESULTS: Thirty-three patients (53%) with NCCM had an (L)PV. The apical and mid-lateral segments were the dominant locations for meeting Petersen and/or Stacey criteria. Correlation between different CMR criteria varied from moderate to very strong. In multivariate binary logistic regression analysis with CMR and non-CMR parameters, independent positive predictors for an (L)PV were familial cardiomyopathy, trabecular mass, and meeting Petersen criteria in ≥ 2 out of 3 long-axis views, whereas left bundle branch block and hypertension were negative predictors. The receiver operating characteristic curve of this multivariate model had an area under the curve of 0.89 (95% confidence interval 0.82-0.97). CONCLUSIONS: CMR criteria together with family history help to distinguish those patients in whom an (L)PV can be identified, consequently leading to referral for genetic diagnostics and cascade screening.

Detection of Subclinical Cardiovascular Disease by Cardiovascular Magnetic Resonance in Lymphoma Survivors.

BACKGROUND: Long-term survivors of Hodgkin lymphoma (HL) and mediastinal non-Hodgkin lymphoma experience late adverse effects of radiotherapy and/or anthracycline-containing chemotherapy, leading to premature cardiovascular morbidity and mortality. OBJECTIVES: The aim of this study was to identify markers for subclinical cardiovascular disease using cardiovascular magnetic resonance (CMR) in survivors of HL and non-Hodgkin lymphoma. METHODS: CMR was performed in 80 lymphoma survivors treated with mediastinal radiotherapy with or without anthracyclines, and results were compared with those among 40 healthy control subjects matched for age and sex. RESULTS: Of the 80 lymphoma survivors, 98% had histories of HL, the mean age was 47 ± 11 years, and 54% were male. Median radiotherapy dose was 36 Gy (interquartile range: 36-40 Gy), and radiotherapy was combined with anthracyclines in 70 lymphoma survivors (88%). Mean time between diagnosis and CMR was 20 ± 8 years. Significantly lower left ventricular (LV) ejection fraction (53% ± 5% vs 60% ± 5%; P < 0.001) and LV mass (47 ± 10 g/m2 vs 56 ± 8 g/m2; P < 0.001) and higher LV end-systolic volume (37 ± 8 mL/m2 vs 33 ± 7 mL/m2; P = 0.013) were found in lymphoma survivors. LV global strain parameters were also significantly worse in lymphoma survivors (P < 0.02 for all). Native myocardial T1 was significantly higher in lymphoma survivors compared with healthy control subjects (980 ± 33 ms vs 964 ± 25 ms; P = 0.007), and late gadolinium enhancement was present in 11% of the survivors. CONCLUSIONS: Long-term lymphoma survivors have detectable changes in LV function and native myocardial T1 on CMR. Further longitudinal studies are needed to assess the implication of these changes in relation to treatment and clinical outcome.

The clinical impact of phase offset errors and different correction methods in cardiovascular magnetic resonance phase contrast imaging: a multi-scanner study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) phase contrast (PC) flow measurements suffer from phase offset errors. Background subtraction based on stationary phantom measurements can most reliably be used to overcome this inaccuracy. Stationary tissue correction is an alternative and does not require additional phantom scanning. The aim of this study was 1) to compare measurements with and without stationary tissue correction to phantom corrected measurements on different GE Healthcare CMR scanners using different software packages and 2) to evaluate the clinical implications of these methods. METHODS: CMR PC imaging of both the aortic and pulmonary artery flow was performed in patients on three different 1.5 T CMR scanners (GE Healthcare) using identical scan parameters. Uncorrected, first, second and third order stationary tissue corrected flow measurement were compared to phantom corrected flow measurements, our reference method, using Medis QFlow, Circle cvi42 and MASS software. The optimal (optimized) stationary tissue order was determined per scanner and software program. Velocity offsets, net flow, clinically significant difference (deviation > 10% net flow), and regurgitation severity were assessed. RESULTS: Data from 175 patients (28 (17-38) years) were included, of which 84% had congenital heart disease. First, second and third order and optimized stationary tissue correction did not improve the velocity offsets and net flow measurements. Uncorrected measurements resulted in the least clinically significant differences in net flow compared to phantom corrected data. Optimized stationary tissue correction per scanner and software program resulted in net flow differences (> 10%) in 19% (MASS) and 30% (Circle cvi42) of all measurements compared to 18% (MASS) and 23% (Circle cvi42) with no correction. Compared to phantom correction, regurgitation reclassification was the least common using uncorrected data. One CMR scanner performed worse and significant net flow differences of > 10% were present both with and without stationary tissue correction in more than 30% of all measurements. CONCLUSION: Phase offset errors had a significant impact on net flow quantification, regurgitation assessment and varied greatly between CMR scanners. Background phase correction using stationary tissue correction worsened accuracy compared to no correction on three GE Healthcare CMR scanners. Therefore, careful assessment of phase offset errors at each individual scanner is essential to determine whether routine use of phantom correction is necessary. TRIAL REGISTRATION: Observational Study.

Frequency and Significance of Coronary Artery Disease and Myocardial Bridging in Patients With Hypertrophic Cardiomyopathy.

The etiology of chest pain in hypertrophic cardiomyopathy (HC) is diverse and includes coronary artery disease (CAD) as well as HC-specific causes. Myocardial bridging (MB) has been associated with HC, chest pain, and accelerated atherosclerosis. We compared HC patients with age-, gender- and CAD pre-test probability-matched outpatients presenting with chest pain to investigate differences in the presence of MB and CAD using coronary computed tomography angiography (CCTA). We studied 84 HC patients who underwent CCTA and compared these with 168 matched controls (age 54 ± 11 years, 70% men, pre-test probability 12% [5% to 32%]). MB, calcium score, plaque morphology and presence and extent of CAD were assessed for each patient. Linear mixed models were used to assess differences between cases and controls. MB was more often seen in HC patients (50% vs 25%, p <0.001). Calcium score and the presence of obstructive CAD were similar in both groups (9 [0 to 225] vs 4 [0 to 82] and 18% vs 19%; p = 0.22 and p = 0.82). In the HC group, MB was associated with pathogenic DNA variants (p = 0.04), but not with the presence of chest pain (74% vs 76%, p = 0.8), nor with worse outcome (log-rank p = 0.30). In conclusion, the prevalence and extent of CAD was equal among patients with and without HC, demonstrating that pre-test risk prediction using the CAD Consortium clinical risk score performs well in HC patients. MB was twice as prevalent in the HC group compared with matched controls, but was not associated with chest pain or decreased event-free survival in these patients.

Cardiac remodelling in a swine model of chronic thromboembolic pulmonary hypertension: comparison of right vs. left ventricle.

KEY POINTS: Right ventricle (RV) function is the most important determinant of survival and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The changes in right and left ventricle gene expression that contribute to ventricular remodelling are incompletely investigated. RV remodelling in our CTEPH swine model is associated with increased expression of the genes involved in inflammation (TGFß), oxidative stress (ROCK2, NOX1 and NOX4), and apoptosis (BCL2 and caspase-3). Alterations in ROCK2 expression correlated inversely with RV contractile reserve during exercise. Since ROCK2 has been shown to be involved in hypertrophy, oxidative stress, fibrosis and endothelial dysfunction, ROCK2 inhibition may present a viable therapeutic target in CTEPH. ABSTRACT: Right ventricle (RV) function is the most important determinant of survival and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The present study investigated whether the increased cardiac afterload is associated with (i) cardiac remodelling and hypertrophic signalling; (ii) changes in angiogenic factors and capillary density; and (iii) inflammatory changes associated with oxidative stress and interstitial fibrosis. CTEPH was induced in eight chronically instrumented swine by chronic nitric oxide synthase inhibition and up to five weekly pulmonary embolizations. Nine healthy swine served as a control. After 9 weeks, RV function was assessed by single beat analysis of RV-pulmonary artery (PA) coupling at rest and during exercise, as well as by cardiac magnetic resonance imaging. Subsequently, the heart was excised and RV and left ventricle (LV) tissues were processed for molecular and histological analyses. Swine with CTEPH exhibited significant RV hypertrophy in response to the elevated PA pressure. RV-PA coupling was significantly reduced, correlated inversely with pulmonary vascular resistance and did not increase during exercise in CTEPH swine. Expression of genes associated with hypertrophy (BNP), inflammation (TGFß), oxidative stress (ROCK2, NOX1 and NOX4), apoptosis (BCL2 and caspase-3) and angiogenesis (VEGFA) were increased in the RV of CTEPH swine and correlated inversely with RV-PA coupling during exercise. In the LV, only significant changes in ROCK2 gene-expression occurred. In conclusion, RV remodelling in our CTEPH swine model is associated with increased expression of genes involved in inflammation and oxidative stress, suggesting that these processes contribute to RV remodelling and dysfunction in CTEPH and hence represent potential therapeutic targets.

Validation of 4D flow CMR against simultaneous invasive hemodynamic measurements: a swine study.

The purpose of this study was to compare invasively measured aorta flow with 2D phase contrast flow and 4D flow measurements by cardiovascular magnetic resonance (CMR) imaging in a large animal model. Nine swine (mean weight 63 ± 4 kg) were included in the study. 4D flow CMR exams were performed on a 1.5T MRI scanner. Flow measurements were performed on 4D flow images at the aortic valve level, in the ascending aorta, and main pulmonary artery. Simultaneously, flow was measured using an invasive flow probe, placed around the ascending aorta. Additionally, standard 2D phase contrast flow and 2D left ventricular (LV) volumetric data were used for comparison. The correlations of cardiac output (CO) between the invasive flow probe, and CMR modalities were strong to very strong. CO measured by 4D flow CMR correlated better with the CO measured by the invasive flow probe than 2D flow CMR flow and volumetric LV data (4D flow CMR: Spearman's rho = 0.86 at the aortic valve level and 0.90 at the ascending aorta level; 2D flow CMR: 0.67 at aortic valve level; LV measurements: 0.77). In addition, there tended to be a correlation between mean pulmonary artery flow and aorta flow with 4D flow (Spearman's rho = 0.65, P = 0.07), which was absent in measurements obtained with 2D flow CMR (Spearman's rho = 0.40, P = 0.33). This study shows that aorta flow can be accurately measured by 4D flow CMR compared to simultaneously measured invasive flow. This helps to further validate the quantitative reliability of this technique.