Multimodality Cardiac Imaging, Cardiac Symptoms, and Clinical Outcomes in Patients Who Recovered from Mild COVID-19.

Background Many patients have persistent cardiac symptoms after mild COVID-19. However, studies assessing the relationship between symptoms and cardiac imaging are limited. Purpose To assess the relationship between multi-modality cardiac imaging parameters, symptoms, and clinical outcomes in patients recovered from mild COVID-19 compared to COVID-19 negative controls. Materials and Methods Patients who underwent PCR testing for SARS-CoV-2 between August 2020 and January 2022 were invited to participate in this prospective, single-center study. Participants underwent cardiac MRI, echocardiography, and assessment of cardiac symptoms at 3-6 months after SARS-CoV-2 testing. Cardiac symptoms and outcomes were also evaluated at 12-18 months. Statistical analysis included Fisher's exact test and logistic regression. Results This study included 122 participants who recovered from COVID-19 ([COVID+] mean age, 42 years ± 13 [SD]; 73 females) and 22 COVID-19 negative controls (mean age, 46 years ± 16 [SD]; 13 females). At 3-6 months, 20% (24/122) and 44% (54/122) of COVID+ participants had at least one abnormality on echocardiography and cardiac MRI, respectively, which did not differ compared to controls (23% [5/22]; P = .77 and 41% [9/22]; P = .82, respectively). However, COVID+ participants more frequently reported cardiac symptoms at 3-6 months compared to controls (48% [58/122] vs. 23% [4/22]; P = .04). An increase in native T1 (10 ms) was associated with increased odds of cardiac symptoms at 3-6 months (OR, 1.09 [95% CI: 1.00, 1.19]; P = .046) and 12-18 months (OR, 1.14 [95% CI: 1.01, 1.28]; P = .028). No major adverse cardiac events occurred during follow-up. Conclusion Patients recovered from mild COVID-19 reported increased cardiac symptoms 3-6 months after diagnosis compared to controls, but the prevalence of abnormalities on echocardiography and cardiac MRI did not differ between groups. Elevated native T1 was associated with cardiac symptoms 3-6 months and 12-18 months after mild COVID-19.

Dusp6 is a genetic modifier of growth through enhanced ERK activity.

Like other single-gene disorders, muscular dystrophy displays a range of phenotypic heterogeneity even with the same primary mutation. Identifying genetic modifiers capable of altering the course of muscular dystrophy is one approach to deciphering gene-gene interactions that can be exploited for therapy development. To this end, we used an intercross strategy in mice to map modifiers of muscular dystrophy. We interrogated genes of interest in an interval on mouse chromosome 10 associated with body mass in muscular dystrophy as skeletal muscle contributes significantly to total body mass. Using whole-genome sequencing of the two parental mouse strains combined with deep RNA sequencing, we identified the Met62Ile substitution in the dual-specificity phosphatase 6 (Dusp6) gene from the DBA/2 J (D2) mouse strain. DUSP6 is a broadly expressed dual-specificity phosphatase protein, which binds and dephosphorylates extracellular-signal-regulated kinase (ERK), leading to decreased ERK activity. We found that the Met62Ile substitution reduced the interaction between DUSP6 and ERK resulting in increased ERK phosphorylation and ERK activity. In dystrophic muscle, DUSP6 Met62Ile is strongly upregulated to counteract its reduced activity. We found that myoblasts from the D2 background were insensitive to a specific small molecule inhibitor of DUSP6, while myoblasts expressing the canonical DUSP6 displayed enhanced proliferation after exposure to DUSP6 inhibition. These data identify DUSP6 as an important regulator of ERK activity in the setting of muscle growth and muscular dystrophy.

Cux1 promotes cell proliferation and polycystic kidney disease progression in an ADPKD mouse model.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1CD;Cux1tm2Ejn). While kidneys isolated from newborn Pkd1CD mice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1CD;Cux1tm2Ejn-/- mice did not show any cysts. Because Cux1tm2Ejn-/- are perinatal lethal, we evaluated Pkd1CD mice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1CD;Cux1tm2Ejn-/- mice, newborn Pkd1CD;Cux1tm2Ejn+/- mice did not show any cysts. Comparison of Pkd1CD and Pkd1CD;Cux1tm2Ejn+/- mice at later stages of development showed a reduction in the severity of PKD in the Pkd1CD;Cux1tm2Ejn+/- mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.

Rapid Device-Detected Nonsustained Ventricular Tachycardia in the Risk Stratification of Hypertrophic Cardiomyopathy.

BACKGROUND: Nonsustained ventricular tachycardia (NSVT) detected by ambulatory Holter (Holter NSVT) is a major risk factor for sudden cardiac death in hypertrophic cardiomyopathy (HCM). We hypothesized that the prognostic utility of Holter NSVT in HCM would improve with prolonged monitoring and a higher heart rate cut-off for detection. METHODS: We enrolled 60 patients (44 ± 14 years) with HCM, who had a prophylactic implantable cardioverter defibrillator (ICD). Positive Holter NSVT (prior to implant) was defined as ≥3 beats at ≥120 beats per minute (bpm). We assessed the prevalence of rapid NSVT (RNSVT) detected by their ICD within 12 months of its implant, defined as 4-16 beats at ≥150-200 bpm. The primary outcome was appropriate ICD therapy (antitachycardia pacing and shocks) for sustained ventricular arrhythmia (VA). RESULTS: Holter NSVT was detected in 34 patients. RNSVT occurred in 21 (35%) patients of whom five did not have Holter NSVT. Over a median follow-up of 61 (interquartile range 29, 129) months after ICD implant, nine patients had VA. RNSVT, but not Holter NSVT, was significantly associated with VA (hazard ratio 6.2, 95% confidence interval [1.3-30], P = 0.01) by multivariable Cox regression analysis that included conventional risk factors. Receiver operating characteristic analysis for RNSVT (area under curve 0.80, P = 0.005) showed that the occurrence of ≥2 episodes of RNSVT discriminated patients for VA optimally (sensitivity 78%, specificity 84%, positive predictive value 47%, negative predictive value 96%). CONCLUSIONS: In this pilot study, RNSVT detected by continuous monitoring independently predicted VA in HCM and offered superior discrimination of VA risk compared to conventional risk factors, including Holter NSVT. Future studies are needed to validate these findings in a larger, unselected HCM cohort.

Two-dimensional transthoracic measure of mitral annulus in mitral valve prolapse and moderate to severe regurgitation: a method comparison analysis with three-dimensional transesophageal echocardiography.

BACKGROUND: Mitral annulus (MA) area is derived during transthoracic echocardiography (TTE) assuming of a circular shape using the MA diameter from the apical 4 chamber (A4c) view. Since the MA is not a circular structure, we hypothesized that an elliptical model using parasternal long-axis (PLAX) and apical 2 chamber (A2c) view measured MA diameters would have better agreement with 3-dimensional transesophageal echocardiography (3D TEE) measured MA in degenerative mitral valve disease (DMVD). METHODS: Seventy-six patients with moderate-to-severe DMVD had 2D TTE and 3D TEE performed. MA area was measured retrospectively using semi-automatic modeling of 3D data (3D TEEsa) and considered as the reference method. MA diameters were measured using different 2D TTE views. MA area was calculated using assumptions of a circular or an elliptical shape. 2D TTE derived and 3D TEEsa. MA areas were compared using linear regression and Bland-Altman analysis. RESULTS: The median MA area measured at 3D TEEsa was 1,386 (1,293-1,673) mm2. With 2D TTE, the circular model using A4c view diameter resulted in a small systematic underestimation of MA area (6%), while the elliptical model using PLAX and A2c diameters resulted in 25% systematic underestimation. The standard deviations of the distributions of inter-method differences were wide for all 2D TTE methods (265-289 mm2) when compared to 3D TEEsa, indicating imprecision. CONCLUSIONS: When compared with 3D TEEsa modeling of the MA as the reference, the assumption of a circular shape using A4c TTE view diameter was the method with the least systematic error to assess MA area in DMVD and moderate to severe regurgitation.

Interpretable machine learning for automated left ventricular scar quantification in hypertrophic cardiomyopathy patients.

Scar quantification on cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) images is important in risk stratifying patients with hypertrophic cardiomyopathy (HCM) due to the importance of scar burden in predicting clinical outcomes. We aimed to develop a machine learning (ML) model that contours left ventricular (LV) endo- and epicardial borders and quantifies CMR LGE images from HCM patients.We retrospectively studied 2557 unprocessed images from 307 HCM patients followed at the University Health Network (Canada) and Tufts Medical Center (USA). LGE images were manually segmented by two experts using two different software packages. Using 6SD LGE intensity cutoff as the gold standard, a 2-dimensional convolutional neural network (CNN) was trained on 80% and tested on the remaining 20% of the data. Model performance was evaluated using the Dice Similarity Coefficient (DSC), Bland-Altman, and Pearson's correlation. The 6SD model DSC scores were good to excellent at 0.91 ± 0.04, 0.83 ± 0.03, and 0.64 ± 0.09 for the LV endocardium, epicardium, and scar segmentation, respectively. The bias and limits of agreement for the percentage of LGE to LV mass were low (-0.53 ± 2.71%), and correlation high (r = 0.92). This fully automated interpretable ML algorithm allows rapid and accurate scar quantification from CMR LGE images. This program does not require manual image pre-processing, and was trained with multiple experts and software, increasing its generalizability.

A Practical Approach to Echocardiographic Imaging in Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is frequently unrecognized or misdiagnosed. The recently published consensus recommendations from the American Society of Echocardiography provided recommendations for the utilization of multimodality imaging in the care of patients with HCM. This document provides an additional practical framework for optimal image and measurement acquisition and guidance on how to tailor the echocardiography examination for individuals with HCM. It also provides resources for physicians and sonographers to use to develop HCM imaging protocols.

Evaluation of left ventricular relaxation and filling pressures in obstructive hypertrophic cardiomyopathy: comparison between invasive hemodynamics and two-dimensional speckle tracking.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is usually associated with marked diastolic dysfunction, characterized by impaired myocardial relaxation and increased myocardial stiffness. The noninvasive evaluation of diastolic function in these patients remains a challenge since usual methods have shown a modest correlation with invasive measurements of left ventricular (LV) relaxation and filling pressures. METHODS AND RESULTS: We retrospectively analyzed 44 patients with obstructive HCM who underwent cardiac catheterization and echocardiography performed within 48 hours. Standard echocardiographic diastolic parameters and systolic and diastolic myocardial mechanics (including longitudinal and circumferential strain [S] and strain rate [Sr]), LV rotation, and early reverse rotation rate (fraction of early apical reverse rotation [FEARR]) were correlated with diastolic hemodynamic indices. Estimated LA pressure by echo and the LV end-diastolic pressure (LVEDP) or the LV pre-A pressure did not correlate. Longitudinal strain was low and circumferential strain was abnormally higher than normal. FEARR and negative dp/dt inversely correlated (R =-0.57, P = 0.0001), and early diastolic Sr to systolic Sr ratio (SrE/SrS) correlated with the LVEDP (r = 0.61, P < 0.0001). Furthermore, a SrE to SrS ratio ≥ 0.79 had a sensitivity of 87% and a specificity of 75% for predicting elevated LVEDP (≥ 15 mmHg). Average circumferential strain rate during atrial contraction and LV pre-A pressure (r =-0.62, P < 0.001) inversely correlated. CONCLUSIONS: FEARR is decreased in HCM and appears to be a good measure of diastolic dysfunction. Myocardial mechanics can be used to assess LV relaxation and filling pressures in patients with obstructive HCM.

A Diagnostic Dilemma from a Presentation of Shortness of Breath and Chest Pain.

INTRODUCTION: A patient presented to hospital with chest pain and shortness of breath on 2 occasions 4 weeks apart. Clinical examination revealed an elevated jugular venous pressure consistent with heart failure or elevated filling pressures. METHODS: The patient was investigated through various modalities including electrocardiogram (ECG), transthoracic echocardiogram, coronary angiography, MRI, cardiac catheterization, positron emission tomography, and an extensive laboratory workup. RESULTS: Serial hs TnI measurements consistently revealed grossly elevated troponin I (>10 000 ng/L). In-lab investigation of increased high sensitivity troponin I (hsTnI) showed evidence of falsely increased troponin due to the presence of heterophilic antibodies. DISCUSSION: This case demonstrates a complex patient presentation and the value of involving the laboratory medicine team when dealing with potentially discrepant results. This is a rare report of grossly elevated troponin due to heterophilic antibodies for high-sensitivity troponin Abbott assay.

Recommendations for Multimodality Cardiovascular Imaging of Patients with Hypertrophic Cardiomyopathy: An Update from the American Society of Echocardiography, in Collaboration with the American Society of Nuclear Cardiology, the Society for Cardiovascular Magnetic Resonance, and the Society of Cardiovascular Computed Tomography.

Hypertrophic cardiomyopathy (HCM) is defined by the presence of left ventricular hypertrophy in the absence of other potentially causative cardiac, systemic, syndromic, or metabolic diseases. Symptoms can be related to a range of pathophysiologic mechanisms including left ventricular outflow tract obstruction with or without significant mitral regurgitation, diastolic dysfunction with heart failure with preserved and heart failure with reduced ejection fraction, autonomic dysfunction, ischemia, and arrhythmias. Appropriate understanding and utilization of multimodality imaging is fundamental to accurate diagnosis as well as longitudinal care of patients with HCM. Resting and stress imaging provide comprehensive and complementary information to help clarify mechanism(s) responsible for symptoms such that appropriate and timely treatment strategies may be implemented. Advanced imaging is relied upon to guide certain treatment options including septal reduction therapy and mitral valve repair. Using both clinical and imaging parameters, enhanced algorithms for sudden cardiac death risk stratification facilitate selection of HCM patients most likely to benefit from implantable cardioverter-defibrillators.

Diagnostic and Prognostic Value of Myocardial Work Indices for Identification of Cancer Therapy-Related Cardiotoxicity.

BACKGROUND: Echocardiographic global longitudinal strain (GLS) is a useful measure for detection of cancer treatment-related cardiac dysfunction (CTRCD) but is influenced by blood pressure changes. This limitation may be overcome by assessment of myocardial work (MW), which incorporates blood pressure into the calculation. OBJECTIVES: This work aims to determine whether myocardial work indices (MWIs) can help diagnose or prognosticate CTRCD. METHODS: In this prospective cohort study, 136 women undergoing anthracycline and trastuzumab treatment for HER2+ breast cancer, underwent serial echocardiograms and cardiac magnetic resonance pre- and post-anthracycline and every 3 months during trastuzumab. GLS, global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency were measured. CTRCD was defined with cardiac magnetic resonance. Generalized estimating equations quantified the association between changes in GLS and MWIs and CTRCD at the current (diagnosis) and subsequent visit (prognosis). Regression tree analysis was used to explore the combined use of GLS and MW for the diagnostic/prognostic assessment of CTRCD. RESULTS: Baseline left ventricular ejection fraction (LVEF) was 63.2 ± 4.0%. Thirty-seven (27.2%) patients developed CTRCD. An absolute change in GLS (standardized odds ratio [sOR]: 1.97 [95% CI: 1.07-3.66]; P = 0.031) and GWI (sOR: 1.73 [95% CI: 1.04-2.85]; P = 0.033) were associated with concurrent CTRCD. An absolute change in GLS (sOR: 1.79 [95% CI: 1.22-2.62]; P = 0.003), GWI (sOR: 1.67 [95% CI: 1.20-2.32]; P = 0.003), and GCW (sOR: 1.65 [95% CI: 1.17-2.34]; P = 0.005) were associated with subsequent CTRCD. Change in GWI and GCW demonstrated incremental value over GLS and clinical factors for the diagnosis of concurrent CTRCD. In a small group with a GLS change <3.3% (absolute), and a >21 mm Hg reduction in systolic blood pressure, worsening of GWI identified patients with higher probability of concurrent CTRCD (24.0% vs 5.2%). MWIs did not improve identification of subsequent CTRCD beyond knowledge of GLS change. CONCLUSIONS: GLS can be used to diagnose and prognosticate cardiac magnetic resonance (CMR) defined CTRCD, with additional value from MWIs in selected cases. (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI [EMBRACE-MRI]; NCT02306538).

Automated Quantification of Abnormal QRS Peaks From High-Resolution ECGs Predicts Late Ventricular Arrhythmias in Hypertrophic Cardiomyopathy: A 5-Year Prospective Multicenter Study.

Background Patients with hypertrophic cardiomyopathy (HCM) are at risk of ventricular arrhythmia (VA) attributed to abnormal electrical activation arising from myocardial fibrosis and myocyte disarray. We sought to quantify intra-QRS peaks (QRSp) in high-resolution ECGs as a measure of abnormal activation to predict late VA in patients with HCM. Methods and Results Prospectively enrolled patients with HCM (n=143, age 53±14 years) with prophylactic implantable cardioverter-defibrillators had 3-minute, high-resolution (1024 Hz), digital 12-lead ECGs recorded during intrinsic rhythm. For each precordial lead, QRSp was defined as the total number of peaks detected in the QRS complex that deviated from a smoothing filtered version of the QRS. The VA end point was appropriate implantable cardioverter-defibrillator therapy during 5-year prospective follow-up. After 5 years, 21 (16%) patients had VA. Patients who were VA positive had greater QRSp (6.0 [4.0-7.0] versus 4.0 [2.0-5.0]; P<0.01) and lower left ventricular ejection fraction (57±11 versus 62±9; P=0.038) compared with patients who were VA negative, but had similar established HCM risk metrics. Receiver operating characteristic analysis revealed that QRSp discriminated VA (area under the curve=0.76; P<0.001), with a QRSp ≥4 achieving 91% sensitivity and 39% specificity. The annual VA rate was greater in patients with QRSp ≥4 versus QRSp <4 (4.4% versus 0.98%; P=0.012). In multivariable Cox regression, age <50 years (hazard ratio [HR], 2.53; P=0.009) and QRSp (HR per QRS peak, 1.41; P=0.009) predicted VA after adjusting for established HCM risk metrics. In patients aged <50 years, the annual VA rate was 0.0% for QRSp <4 compared with 6.9% for QRSp ≥4 (P=0.012). Conclusions QRSp predicted VA in patients with HCM who were eligible for an implantable cardioverter-defibrillator after adjusting for established HCM risk metrics, such that each additional QRS peak increases VA risk by 40%. QRSp <4 was associated with a <1% annual VA risk in all patients, and no VA risk among those aged <50 years. This novel ECG metric may improve patient selection for prophylactic implantable cardioverter-defibrillator therapy by identifying those with low VA risk. These findings require further validation in a lower risk HCM cohort. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02560844.

A Combined Echocardiography Approach for the Diagnosis of Cancer Therapy-Related Cardiac Dysfunction in Women With Early-Stage Breast Cancer.

IMPORTANCE: Diagnosis of cancer therapy-related cardiac dysfunction (CTRCD) remains a challenge. Cardiovascular magnetic resonance (CMR) provides accurate measurement of left ventricular ejection fraction (LVEF), but access to repeated scans is limited. OBJECTIVE: To develop a diagnostic model for CTRCD using echocardiographic LVEF and strain and biomarkers, with CMR as the reference standard. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, patients were recruited from University of Toronto-affiliated hospitals from November 2013 to January 2019 with all cardiac imaging performed at a single tertiary care center. Women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were included. The main exclusion criterion was contraindication to CMR. A total of 160 patients were recruited, 136 of whom completed the study. EXPOSURES: Sequential therapy with anthracyclines and trastuzumab. MAIN OUTCOMES AND MEASURES: Patients underwent echocardiography, high-sensitivity troponin I (hsTnI), B-type natriuretic peptide (BNP), and CMR studies preanthracycline and postanthracycline every 3 months during and after trastuzumab therapy. Echocardiographic measures included 2-dimensional (2-D) LVEF, 3-D LVEF, peak systolic global longitudinal strain (GLS), and global circumferential strain (GCS). LVEF CTRCD was defined using the Cardiac Review and Evaluation Committee Criteria, GLS or GCS CTRCD as a greater than 15% relative change, and abnormal hsTnI and BNP as greater than 26 pg/mL and ≥ 35 pg/mL, respectively, at any follow-up point. Combinations of echocardiographic measures and biomarkers were examined to diagnose CMR CTRCD using conditional inference tree models. RESULTS: Among 136 women (mean [SD] age, 51.1 [9.2] years), CMR-identified CTRCD occurred in 37 (27%), and among those with analyzable images, in 30 of 131 (23%) by 2-D LVEF, 27 of 124 (22%) by 3-D LVEF, 53 of 126 (42%) by GLS, 61 of 123 (50%) by GCS, 32 of 136 (24%) by BNP, and 14 of 136 (10%) by hsTnI. In isolation, 3-D LVEF had greater sensitivity and specificity than 2-D LVEF for CMR CTRCD while GLS had greater sensitivity than 2-D or 3-D LVEF. Regression tree analysis identified a sequential algorithm using 3-D LVEF, GLS, and GCS for the optimal diagnosis of CTRCD (area under the receiver operating characteristic curve, 89.3%). The probability of CTRCD when results for all 3 tests were negative was 1.0%. When 3-D LVEF was replaced by 2-D LVEF in the model, the algorithm still performed well; however, its primary value was to rule out CTRCD. Biomarkers did not improve the ability to diagnose CTRCD. CONCLUSIONS AND RELEVANCE: Using CMR CTRCD as the reference standard, these data suggest that a sequential approach combining echocardiographic 3-D LVEF with 2-D GLS and 2-D GCS may provide a timely diagnosis of CTRCD during routine CTRCD surveillance with greater accuracy than using these measures individually. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02306538.

Comparison of two different speckle tracking software systems: does the method matter?

BACKGROUND: Echocardiographic speckle tracking strain has gained clinical importance. However, the comparability of measurements between different software systems is not well defined. METHODS: In 47 healthy subjects left ventricular (LV) two-dimensional (2D) peak strain and time to peak strain (TTP) generated by EchoPAC (2DS) and velocity vector imaging (VVI) were compared. For each type of strain (longitudinal [LS], circumferential [CS], and radial strain [RS]) we compared global, anatomical level and segmental values. RESULTS: When comparing 2DS to VVI, Pearson correlation coefficients (r) of global LS, CS, and RS were 0.68, 0.44, and 0.59, respectively (all P < 0.05). Correlation of global TTP was higher: 0.81(LS), 0.80 (CS), and 0.68 (RS), all P < 0.01. Segmental peak strain differed significantly between 2DS and VVI in 8/18 (LS), 17/18 (CS), and 15/18 (RS) LV segments (P < 0.05). However, segmental TTP significantly differed only in 5/18 (LS), 7/18 (CS), and 4/18 (RS) of LV segments. Similar strain gradients were found for both systems: apical strain was higher than basal and midventricular strain in LS and CS, with a reversed pattern for RS (P < 0.05). CONCLUSION: TTP strain as well as strain gradients were comparable between VVI and 2DS, but most peak strain values were not. The software-dependency of peak strain values must be considered in clinical application. Further studies comparing the diagnostic and prognostic accuracy of strain values generated by different software systems are mandatory.

Microvolt QRS Alternans in Hypertrophic Cardiomyopathy: A Novel Risk Marker of Late Ventricular Arrhythmias.

Background Unlike T-wave alternans (TWA), the relation between QRS alternans (QRSA) and ventricular arrhythmia (VA) risk has not been evaluated in hypertrophic cardiomyopathy (HCM). We assessed microvolt QRSA/TWA in relation to HCM risk factors and late VA outcomes in HCM. Methods and Results Prospectively enrolled patients with HCM (n=130) with prophylactic implantable cardioverter-defibrillators underwent digital 12-lead ECG recordings during ventricular pacing (100-120 beats/min). QRSA/TWA was quantified using the spectral method. Patients were categorized as QRSA+ and/or TWA+ if sustained alternans was present in ≥2 precordial leads. The VA end point was appropriate implantable cardioverter-defibrillator therapy over 5 years of follow-up. QRSA+ and TWA+ occurred together in 28% of patients and alone in 7% and 7% of patients, respectively. QRSA magnitude increased with pacing rate (1.9±0.6 versus 6.2±2.0 µV; P=0.006). Left ventricular thickness was greater in QRSA+ than in QRSA- patients (22±7 versus 20±6 mm; P=0.035). Over 5 years follow-up, 17% of patients had VA. The annual VA rate was greater in QRSA+ versus QRSA- patients (5.8% versus 2.0%; P=0.006), with the QRSA+/TWA- subgroup having the greatest rate (13.3% versus 2.6%; P<0.001). In those with <2 risk factors, QRSA- patients had a low annual VA rate compared QRSA+ patients (0.58% versus 7.1%; P=0.001). Separate Cox models revealed QRSA+ (hazard ratio [HR], 2.9 [95% CI, 1.2-7.0]; P=0.019) and QRSA+/TWA- (HR, 7.9 [95% CI, 2.9-21.7]; P<0.001) as the most significant VA predictors. TWA and HCM risk factors did not predict VA. Conclusions In HCM, microvolt QRSA is a novel, rate-dependent phenomenon that can exist without TWA and is associated with greater left ventricular thickness. QRSA increases VA risk 3-fold in all patients, whereas the absence of QRSA confers low VA risk in patients with <2 risk factors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02560844.

Clinical, Echocardiographic, and Biomarker Associations With Impaired Cardiorespiratory Fitness Early After HER2-Targeted Breast Cancer Therapy.

BACKGROUND: Cardiorespiratory fitness (CRF) is reduced in cancer survivors and predicts cardiovascular disease (CVD)-related and all-cause mortality. However, routine measurement of CRF is not always feasible. OBJECTIVES: The purpose of this study was to identify clinical, cardiac biomarker, and imaging measures associated with reduced peak oxygen consumption (VO2peak) (measure of CRF) early post-breast cancer therapy to help inform CVD risk. METHODS: Consecutive women with early-stage HER2+ breast cancer receiving anthracyclines and trastuzumab were recruited prospectively. Within 6 ± 2 weeks of trastuzumab completion, we collected clinical information, systolic/diastolic echocardiographic measures, high-sensitivity troponin I, B-type natriuretic peptide, and VO2peak using a cycle ergometer. Regression models were used to examine the association between VO2peak and clinical, imaging, and cardiac biomarkers individually and in combination. RESULTS: Among 147 patients (age 52.2 ± 9.3 years), the mean VO2peak was 19.1 ± 5.0 mL O2·kg-1·min-1 (84.2% ± 18.7% of predicted); 44% had a VO2peak below threshold for functional independence (<18 mL O2·kg-1·min-1). In multivariable analysis, absolute global longitudinal strain (GLS) (ß = 0.58; P = 0.007), age per 10 years (ß: -1.61; P = 0.001), and E/e' (measure of diastolic filling pressures) (ß = -0.45; P = 0.038) were associated with VO2peak. GLS added incremental value in explaining the variability in VO2peak. The combination of age ≥50 years, E/e' ≥7.8, and GLS <18% identified a high probability (85.7%) of compromised functional independence, whereas age <50 years, E/e' <7.8, and GLS ≥18% identified a low probability (0%). High-sensitivity troponin I and B-type natriuretic peptide were not associated with VO2peak. CONCLUSIONS: Readily available clinical measures were associated with VO2peak early post-breast cancer therapy. A combination of these parameters had good discrimination to identify patients with compromised functional independence and potentially increased future CVD risk.

Lung Ultrasound for Cardiologists in the Time of COVID-19.

Lung ultrasound (LUS) is a point-of-care ultrasound technique used for its portability, widespread availability, and ability to provide real-time diagnostic information and procedural guidance. LUS outperforms lung auscultation and chest X-ray, and it is an alternative to chest computed tomography in selected cases. Cardiologists may enhance their physical and echocardiographic examination with the addition of LUS. We present a practical guide to LUS, including device selection, scanning, findings, and interpretation. We outline a 3-point scanning protocol using 2-dimensional and M-mode imaging to evaluate the pleural line, pleural space, and parenchyma. We describe LUS findings and interpretation for common causes of respiratory failure. We provide guidance specific of COVID-19, which at the time of writing is a global pandemic. In this context, LUS emerges as a particularly useful tool for the diagnosis and management of patients with cardiopulmonary disease.

Left Ventricular Mass and Wall Thickness Measurements Using Echocardiography and Cardiac MRI in Patients with Fabry Disease: Clinical Significance of Discrepant Findings.

PURPOSE: To compare transthoracic echocardiography (TTE) and cardiac MRI measurements of left ventricular mass (LVM) and maximum wall thickness (MWT) in patients with Fabry disease and evaluate the clinical significance of discrepancies between modalities. MATERIALS AND METHODS: Seventy-eight patients with Fabry disease (mean age, 46 years ± 14 [standard deviation]; 63% female) who underwent TTE and cardiac MRI within a 6-month interval between 2008 and 2018 were included in this retrospective cohort study. The clinical significance of measurement discrepancies was evaluated with respect to diagnosis of left ventricular hypertrophy (LVH), eligibility for disease-specific therapy, and prognosis. Statistical analysis included paired-sample t test, Cox proportional hazard models, Akaike information criterion (AIC), and intraclass correlation coefficients. RESULTS: LVM indexed to body surface area (LVMI) and MWT were significantly higher at TTE compared with MRI (105 g/m2 ± 48 vs 78 g/m2 ± 36, P < .001 and 14 mm ± 4 vs 13 mm ± 5, P = .008, respectively). LVH classification was discordant between modalities in 23 patients (29%) (P < .001). Eligibility for disease-specific therapy based on MWT was discordant between modalities in 20 patients (26%) (P < .001). LVMI assessed with MRI was a better predictor of the combined endpoint compared with LVMI assessed with TTE (AIC, 127 vs 131). Interobserver agreement for LVMI and MWT was higher for MRI (intraclass correlation coefficient, 0.951 and 0.912, respectively) compared with TTE (intraclass correlation coefficient, 0.940 and 0.871; respectively). CONCLUSION: TTE overestimates LVM and MWT and has lower reproducibility compared with cardiac MRI in Fabry disease. Measurement discrepancies between modalities are clinically significant with respect to diagnosis of LVH, prognosis, and treatment decisions.© RSNA, 2020.

Association of Left Ventricular Ejection Fraction with Mortality and Hospitalizations.

BACKGROUND: Although echocardiography is widely used to measure left ventricular ejection fraction (LVEF), its prognostic value has not been demonstrated in a broad range of patients including those acutely hospitalized for cardiac or noncardiac causes. We determined whether greater degrees of left ventricular systolic dysfunction were associated with progressively increasing risks of death or cardiovascular hospitalizations among patients in hospital or outpatient settings. METHODS: A total of 27,323 patients with LVEF measured and 19,445 matched controls were followed for 223,034 person-years. Outcomes of total mortality, cardiovascular death, cardiovascular hospitalizations, and heart failure hospitalizations were examined using cause-specific hazard competing-risks analysis. RESULTS: In the study cohort (median age, 68 [interquartile range, 58-77], 14,828 women [31.7%]), the hazard ratios (95% CI) for all-cause death were 1.67 (1.57-1.77), 1.30 (1.24-1.36), and 1.17 (1.11-1.23) when LVEF was <25%, 25%-35%, or 36%-45% compared with LVEF 46%-55% (all P < .001). Rates of cardiovascular death were similarly higher with lower LVEF. The hazard ratios for cardiovascular hospitalization were 1.35 (1.27-1.42), 1.21 (1.16-1.27), and 1.13 (1.07-1.18) for LVEFs <25%, 25%-35%, and 36%-45%, respectively (all P < .001). The rate of heart failure hospitalizations was amplified, with hazard ratios of 1.71 (1.59-1.85), 1.39 (1.31-1.48), and 1.21 (1.13-1.29) for LVEFs <25%, 25%-35%, or 36%-45% (all P < .001). The rate of mortality and hospitalizations increased comparably with greater reductions in LVEF during both inpatient cardiac or noncardiac admissions (P < .001). CONCLUSIONS: Quantitative echocardiographic LVEF stratified the risk of death and hospitalization in a wide range of clinical settings, including during noncardiac admissions.

Atrial cardiopathy in patients with embolic strokes of unknown source and other stroke etiologies.

OBJECTIVE: To investigate the prevalence and clinical determinants of atrial cardiopathy in patients with embolic stroke of unknown source (ESUS) and compare with other established stroke etiologies. METHODS: In a cross-sectional study of 846 consecutive patients with ischemic stroke, we compared the prevalence of atrial cardiopathy (defined by p-wave terminal force in V1 >5,000 µV·ms or severe left atrial enlargement) between ESUS patients and patients with large artery atherosclerosis (LAA) and small vessel disease (SVD) strokes. Baseline characteristics were also compared between ESUS and cardioembolic (CE) patients. RESULTS: Of all, 158 (19%) patients met ESUS diagnostic criteria, while others were classified into LAA (n = 224, 26%), SVD (n = 154, 18%), and CE (n = 310, 37%). The prevalence of atrial cardiopathy was higher in ESUS patients compared to noncardioembolic stroke patients (26.6% vs 12.1% in LAA vs 16.9% in SVD; p = 0.001). ESUS patients were younger, were less hypertensive, and had higher cholesterol and low-density lipoprotein levels, but also had less left ventricular or atrial abnormalities when compared to CE patients. CONCLUSION: The prevalence of atrial cardiopathy was high in ESUS patients compared with patients with nonembolic strokes. Interestingly, ESUS patients were also clinically different from CE patients. While the presence of atrial cardiopathy may reflect a unique mechanism of thromboembolism in ESUS patients, it is still unclear if they may benefit from anticoagulation, or if the presence of atrial cardiopathy in this population could serve as a risk-stratifying marker for stroke recurrence. Further efforts are necessary to provide better characterization of the ESUS population in order to develop better stroke preventive strategies.