Machine Learning-Driven Phenogrouping and Cardiorespiratory Fitness Response in Metastatic Breast Cancer.

PURPOSE: The magnitude of cardiorespiratory fitness (CRF) impairment during anticancer treatment and CRF response to aerobic exercise training (AT) are highly variable. The aim of this ancillary analysis was to leverage machine learning approaches to identify patients at high risk of impaired CRF and poor CRF response to AT. METHODS: We evaluated heterogeneity in CRF among 64 women with metastatic breast cancer randomly assigned to 12 weeks of highly structured AT (n = 33) or control (n = 31). Unsupervised hierarchical cluster analyses were used to identify representative variables from multidimensional prerandomization (baseline) data, and to categorize patients into mutually exclusive subgroups (ie, phenogroups). Logistic and linear regression evaluated the association between phenogroups and impaired CRF (ie, ≤16 mL O2·kg-1·min-1) and CRF response. RESULTS: Baseline CRF ranged from 10.2 to 38.8 mL O2·kg-1·min-1; CRF response ranged from -15.7 to 4.1 mL O2·kg-1·min-1. Of the n = 120 candidate baseline variables, n = 32 representative variables were identified. Patients were categorized into two phenogroups. Compared with phenogroup 1 (n = 27), phenogroup 2 (n = 37) contained a higher number of patients with none or >three lines of previous anticancer therapy for metastatic disease and had lower resting left ventricular systolic and diastolic function, cardiac output reserve, hematocrit, lymphocyte count, patient-reported outcomes, and CRF (P < .05) at baseline. Among patients allocated to AT (phenogroup 1, n = 12; 44%; phenogroup 2, n = 21; 57%), CRF response (-1.94 ± 3.80 mL O2·kg-1·min-1 v 0.70 ± 2.22 mL O2·kg-1·min-1) was blunted in phenogroup 2 compared with phenogroup 1. CONCLUSION: Phenotypic clustering identified two subgroups with unique baseline characteristics and CRF outcomes. The identification of CRF phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions among patients with cancer.

Optimized quantitative mapping of cardiopulmonary oscillations using hyperpolarized 129 Xe gas exchange MRI: Digital phantoms and clinical evaluation in CTEPH.

PURPOSE: The interaction between 129 Xe atoms and pulmonary capillary red blood cells provides cardiogenic signal oscillations that display sensitivity to precapillary and postcapillary pulmonary hypertension. Recently, such oscillations have been spatially mapped, but little is known about optimal reconstruction or sensitivity to artifacts. In this study, we use digital phantom simulations to specifically optimize keyhole reconstruction for oscillation imaging. We then use this optimized method to re-establish healthy reference values and quantitatively evaluate microvascular flow changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary thromboendarterectomy (PTE). METHODS: A six-zone digital lung phantom was designed to investigate the effects of radial views, key radius, and SNR. One-point Dixon 129 Xe gas exchange MRI images were acquired in a healthy cohort (n = 17) to generate a reference distribution and thresholds for mapping red blood cell oscillations. These thresholds were applied to 10 CTEPH participants, with 6 rescanned following PTE. RESULTS: For undersampled acquisitions, a key radius of 0.14 k max $$ 0.14{k}_{\mathrm{max}} $$ was found to optimally resolve oscillation defects while minimizing excessive heterogeneity. CTEPH participants at baseline showed higher oscillation defect + low (32 ± 14%) compared with healthy volunteers (18 ± 12%, p < 0.001). For those scanned both before and after PTE, oscillation defect + low decreased from 37 ± 13% to 23 ± 14% (p = 0.03). CONCLUSIONS: Digital phantom simulations have informed an optimized keyhole reconstruction technique for gas exchange images acquired with standard 1-point Dixon parameters. Our proposed methodology enables more robust quantitative mapping of cardiogenic oscillations, potentially facilitating effective regional quantification of microvascular flow impairment in patients with pulmonary vascular diseases such as CTEPH.

Association of leadless pacing with ventricular and valvular function.

BACKGROUND: Traditional transvenous pacemakers are associated with worsening tricuspid valve function due to lead-related leaflet impingement, as well as ventricular dysfunction related to electromechanical dyssynchrony from chronic right ventricular (RV) pacing. The association of leadless pacing with ventricular and valvular function has not been well established. We aimed to assess the association of leadless pacemaker placement with changes in valvular regurgitation and ventricular function. METHODS AND RESULTS: Echocardiographic features before and after leadless pacemaker implant were analyzed in consecutive patients who received a leadless pacemaker with pre- and postprocedure echocardiography at Duke University Hospital between November 2014 and November 2019. Valvular regurgitation was graded ordinally from 0 (none) to 3 (severe). Among 54 patients, the mean age was mean age was 70.1 ± 14.3 years, 24 (44%) were women, and the most frequent primary pacing indication was complete heart block in 24 (44%). The median RV pacing burden was 45.4 (interquartile range [IQR] 3.5-97.0). On echocardiogram performed 8.9 months (IQR 4.5-14.5) after implant, there was no change in the average severity of tricuspid regurgitation (mean change 0.07 ± 1.15, p = .64) from pre-procedure echocardiogram. We observed a decrease in the average left ventricular ejection fraction (LVEF) (52.3 ± 9.3 to 47.9 ± 12.1, p = .0019) and tricuspid annular plane systolic excursion (TAPSE) (1.8 ± 0.6 to 1.6 ± 0.4, p = .0437). Thirteen patients (24%) had absolute drop in LVEF of ≥10%. CONCLUSION: We did not observe short term worsening valvular function in patients with leadless pacemakers. However, consistent with the pathophysiologic impact of RV pacing, leadless pacing was associated with a reduction in biventricular function.

Prognostic Value of Cardiac Magnetic Resonance Imaging in Patients With a Working Diagnosis of MINOCA-An Outcome Study With up to 10 Years of Follow-Up.

BACKGROUND: Patients with a working diagnosis of myocardial infarction with unobstructed coronary arteries (MINOCA) represent a heterogeneous cohort. The prognosis could vary substantially depending on the underlying cause. Although cardiac magnetic resonance (CMR) is considered a key diagnostic tool in these patients, there are limited data linking the CMR diagnosis with the outcome. METHODS: This study is a prospective outcomes registry of consecutive patients presenting with a working diagnosis of MINOCA who were clinically referred for CMR at an academic hospital from October 2003 to February 2020. We assessed the relationships between the prespecified CMR diagnoses of acute myocardial infarction (AMI), myocarditis, nonischemic cardiomyopathy (NICM), normal CMR study, and major adverse cardiac events (MACEs). RESULTS: Of 252 patients, the CMR diagnosis was AMI in 63 (25%), myocarditis in 33 (13%), NICM in 111 (44%), normal CMR in 37 (15%), and other diagnoses in 8 (3%). A specific nonischemic cause was diagnosed allowing true MINOCA to be ruled-out in 57% of the cohort. During up to 10 years of follow-up (1595 patient-years), MACE occurred in 84 patients (33%), which included 64 deaths (25%). The unadjusted cumulative 10-year rate of MACE was 47% in AMI, 24% in myocarditis, 50% in NICM, and 3.5% in patients with a normal CMR (Log-rank P<0.001). The CMR diagnosis provided incremental prognostic value over clinical factors including age, gender, coronary artery disease risk factors, presentation with ST-elevation, and peak troponin (incremental χ² 17.9, P<0.001); and patients with diagnoses of AMI, myocarditis, and NICM had worse MACE-free survival than patients with a normal CMR. CONCLUSIONS: In patients with a working diagnosis of MINOCA, CMR allows ruling-out true MINOCA in over half of the patients. CMR diagnoses of AMI, myocarditis, and NICM are associated with worse MACE-free survival, whereas a normal CMR study portends a benign prognosis.

The association with organ procurement techniques and early cardiac transplant outcomes using cardiac MRI.

BACKGROUND: Heart transplantation (HT) has historically been limited by organ availability. Use of donation after circulatory death (DCD) donors addresses this limitation by utilizing previously unused hearts through use of the Organ Care System (OCS). OBJECTIVES: This study aimed to determine the impact of procurement and transportation method on allograft structure and function using early post-transplant cardiac magnetic resonance imaging (MRI). METHODS: Patients who underwent HT at our institution from February 1, 2020, through April 30, 2021 who underwent cardiac MRI imaging <60 days from transplant were included. Recipient and donor characteristics, clinical outcomes, and MRI findings were compared between those who underwent DCD transplantation using the OCS device (DCD-OCS), brain dead donation (DBD) using the OCS device (DBD-OCS), and DBD transported via cold storage (DBD-cold storage) using one-way analysis of variance. RESULTS: A total of 85 patients underwent HT with a cardiac MRI during the study period. Thirty-one (36%) patients received a DCD organ, 16 (19%) received a DBD-OCS organ and 38 (45%) received a DBD-cold storage organ. Rates of primary graft dysfunction (PGD) were significantly higher in DCD transplants (19.5% DCD vs. .0% DBD-OCS and 5.3% DBD-cold storage; p < .050 across three groups), but with no differences in mortality or rejection. There were no differences in cardiac MRI findings between the three transplant types, including presence of gadolinium hyperenhancement after transplant (all p > .050). CONCLUSIONS: We observed no differences in early cardiac MRI findings between patients that received DCD and DBD-OCS heart transplants compared with those receiving DBD-cold storage transplants.

Imaging the right atrium in pulmonary hypertension: A systematic review and meta-analysis.

BACKGROUND: Right atrial (RA) imaging has emerged as a promising tool for the evaluation of patients with pulmonary hypertension (PH), albeit without systematic validation. METHODS: PubMed, Web of Science and the Cochrane library were searched for studies investigating the prognostic value of RA imaging assessment in patients with PH from 2000 to June 2021 (PROSPERO Identifier: CRD42020212850). An inverse variance-weighted meta-analysis of univariable hazard ratios (HRs) was performed using a random effects model. RESULTS: Thirty-five studies were included (3,476 patients with PH; 74% female, 86% pulmonary arterial hypertension). Risk of bias was low/moderate (Quality of Prognosis Studies checklist). RA area (HR 1.06; 95% confidence interval [CI] 1.04-1.08), RA indexed area (HR 1.09; 95% CI 1.04-1.14), RA peak longitudinal strain (PLS; HR 0.94; 95% CI 0.91-0.97) and RA total emptying fraction (HR 0.96; 95% CI 0.94-0.98) were significantly associated with combined end-points including death, clinical worsening and/or lung transplantation; RA volume and volume index showed marginal significant associations. RA area (HR 1.06; 95% CI 1.04-1.07), RA indexed area (HR 1.12; 95% CI 1.07-1.17) and RA PLS (HR 0.98; 95% CI 0.97-0.99) showed significant associations with mortality; RA total emptying fraction showed a marginal association. CONCLUSIONS: Imaging-based RA assessment qualifies as a relevant prognostic marker in PH. RA area reliably predicts composite end-points and mortality, which underscores its clinical utility. RA PLS emerged as a promising imaging measure, but is currently limited by the number of studies and different acquisition methods.

Role of cardiac magnetic resonance (CMR) in planning ventricular septal myomectomy in patients with hypertrophic obstructive cardiomyopathy (HOCM).

Septal myectomy is currently the gold standard treatment for symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). The procedure needs to be tailored and performed in a personalized fashion, taking into consideration the anatomic and physiologic heterogeneity of this disease. The extent and location of surgical myectomy will depend on the location of the hypertrophy, with the goal of widening the outflow tract and improve the function of the mitral valve. CMR helps to identify hypertrophy not well visualized by TTE, providing more accurate wall thickness measurements and differentiating HOCM from other causes of LV hypertrophy. CMR also helps identify an abnormal attachment of papillary muscle to the MV or to the septal myocardium and mitral valve pathology. A collaborative approach with cardiac surgeons, radiologists and cardiologists will optimize preoperative planning to improve the success for surgical myectomy.

Polypharmacy and Cardiovascular Diseases: Consideration for Older Adults and Women.

PURPOSE OF REVIEW: The intent of this review is to provide an update in polypharmacy in older adults and women with a focus on common determinants and strategies to mitigate polypharmacy. RECENT FINDINGS: Polypharmacy is becoming a critical focus in the management of cardiovascular diseases. It may emerge unintentionally while managing multimorbidity in older adults or in the vulnerable subgroup of patients, such as pregnant and lactating females. Clinicians should utilize several approaches such as deprescribing, sex-specific risk assessment, and encouraging healthy lifestyle to minimize inappropriate and unnecessary use of medications. A shared decision-making model along with coordination and collaboration among healthcare providers should be utilized in the selection and management of pharmacotherapies.

Assessment of Papillary Muscle Infarction with Dark-Blood Delayed Enhancement Cardiac MRI in Canines and Humans.

Background The relationship between papillary muscle infarction (papMI) and the culprit coronary lesion has not been fully investigated. Delayed enhancement cardiac MRI may detect papMI, yet its accuracy is unknown. Flow-independent dark-blood delayed enhancement (FIDDLE) cardiac MRI has been shown to improve the detection of myocardial infarction adjacent to blood pool. Purpose To assess the diagnostic performance of delayed enhancement and FIDDLE cardiac MRI for the detection of papMI, and to investigate the prevalence of papMI and its relationship to the location of the culprit coronary lesion. Materials and Methods A prospective canine study was used to determine the accuracy of conventional delayed enhancement imaging and FIDDLE imaging for detection of papMI, with pathology-based findings as the reference standard. Participants with first-time myocardial infarction with a clear culprit lesion at coronary angiography were prospectively enrolled at a single hospital from 2015 to 2018 and compared against control participants with low Framingham risk scores. In canines, diagnostic accuracy was calculated for delayed enhancement and FIDDLE imaging. Results In canines (n = 27), FIDDLE imaging was more sensitive (100% [23 of 23] vs 57% [13 of 23], P < .001) and accurate (100% [54 of 54] vs 80% [43 of 54], P = .01) than delayed enhancement imaging for detection of papMI. In 43 participants with myocardial infarction (mean age, 56 years ± 16 [SD]; 28 men), the infarct-related artery was the left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX), and right coronary artery in 47% (20 of 43), 26% (11 of 43), and 28% (12 of 43), respectively. The prevalence of anterior papMI was lower than posterior papMI (37% [16 of 43 participants] vs 44% [19 of 43 participants]) despite more LAD culprit lesions. Culprits leading to papMI were restricted to a smaller "at-risk" portion of the coronary tree for anterior papMI (subtended first diagonal branch of the LAD or first marginal branch of the LCX) compared with posterior (subtended posterior descending artery or third obtuse marginal branch of the LCX). Culprits within these at-risk portions were predictive of papMI at a similar rate (anterior, 83% [15 of 18 participants] vs posterior, 86% [18 of 21 participants]). Conclusion Flow-independent dark-blood delayed enhancement cardiac MRI, unlike conventional delayed enhancement cardiac MRI, was highly accurate in the detection of papillary muscle infarction (papMI). Anterior papMI was less prevalent than posterior papMI, most likely due to culprit lesions being restricted to a smaller portion of the coronary tree rather than because of redundant, dual vascular supply. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kawel-Boehm and Bremerich in this issue.

Noninvasive diagnosis of pulmonary hypertension with hyperpolarised 129Xe magnetic resonance imaging and spectroscopy.

Background: The diagnosis of pulmonary hypertension (PH) remains challenging. Pre- and post-capillary PH have different signatures on noninvasive 129Xe gas-exchange magnetic resonance imaging (MRI) and dynamic MR spectroscopy (MRS). We tested the accuracy of 129Xe MRI/MRS to diagnose PH status compared to right heart catheterisation (RHC). Methods: 129Xe MRI/MRS from 93 subjects was used to develop a diagnostic algorithm, which was tested in 32 patients undergoing RHC on the same day (n=20) or within 5 months (42±40 days) (n=12). Three expert readers, blinded to RHC, used 129Xe MRI/MRS to classify subjects as pre-capillary PH, post-capillary PH, no PH and no interstitial lung disease (ILD), or ILD. Results: For pre-capillary PH, 129Xe MRI/MRS diagnostic accuracy was 75% (95% CI 66-84) with a sensitivity of 67% (95% CI 54-79) and a specificity of 86% (95% CI 75-96); for post-capillary PH accuracy was 69% (95% CI 59-78) with sensitivity of 54% (95% CI 34-74) and specificity of 74% (95% CI 63-84). The model performed well in straightforward cases of pre-capillary PH but was less accurate in its diagnosis in the presence of mixed disease, particularly in the presence of ILD or combined post- and pre-capillary PH. Conclusion: This study demonstrates the potential to develop 129Xe MRI/MRS into a modality with good accuracy in detecting pre- and post-capillary PH. Furthermore, the combination of 129Xe dynamic MRS and gas-exchange MRI uniquely provide concurrent, noninvasive assessment of both haemodynamics and gas-exchange impairment that may aid in the detection of PH.

Assessment of myocardial lipomatous metaplasia using an optimized out-of-phase cine steady-state free-precession sequence: Validation and clinical implementation.

Myocardial lipomatous metaplasia, which can serve as substrate for ventricular arrhythmias, is usually composed of regions in which there is an admixture of fat and nonfat tissue. Although dedicated sequences for the detection of fat are available, it would be time-consuming and burdensome to routinely use these techniques to image the entire heart of all patients as part of a typical cardiac MRI exam. Conventional steady-state free-precession (SSFP) cine imaging is insensitive to detecting myocardial regions with partial fatty infiltration. We developed an optimization process for SSFP imaging to set fat signal consistently "out-of-phase" with water throughout the heart, so that intramyocardial regions with partial volume fat would be detected as paradoxically dark regions. The optimized SSFP sequence was evaluated using a fat phantom, through simulations, and in 50 consecutive patients undergoing clinical cardiac MRI. Findings were validated using standard Dixon gradient-recalled-echo (GRE) imaging as the reference. Phantom studies of test tubes with diverse fat concentrations demonstrated good agreement between measured signal intensity and simulated values calculated using Bloch equations. In patients, a line of signal cancellation at the interface between myocardium and epicardial fat was noted in all cases, confirming that SSFP images were consistently out-of-phase throughout the entire heart. Intramyocardial dark regions identified on out-of-phase SSFP images were entirely dark throughout in 33 patients (66%) and displayed an India-ink pattern in 17 (34%). In all cases, dark intramyocardial regions were also seen in the same locations on out-of-phase GRE and were absent on in-phase GRE, confirming that these regions represent areas with partial fat. In conclusion, if appropriately optimized, SSFP cine imaging allows for consistent detection of myocardial fatty metaplasia in patients undergoing routine clinical cardiac MRI without the need for additional image acquisitions using dedicated fat-specific sequences.

Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart.

There is an increased appreciation for the importance of the right heart and pulmonary circulation in several disease states across the spectrum of pulmonary hypertension and left heart failure. However, assessment of the structure and function of the right heart and pulmonary circulation can be challenging, due to the complex geometry of the right ventricle, comorbid pulmonary airways and parenchymal disease, and the overlap of hemodynamic abnormalities with left heart failure. Several new and evolving imaging modalities interrogate the right heart and pulmonary circulation with greater diagnostic precision. Echocardiographic approaches such as speckle-tracking and 3-dimensional imaging provide detailed assessments of regional systolic and diastolic function and volumetric assessments. Magnetic resonance approaches can provide high-resolution views of cardiac structure/function, tissue characterization, and perfusion through the pulmonary vasculature. Molecular imaging with positron emission tomography allows an assessment of specific pathobiologically relevant targets in the right heart and pulmonary circulation. Machine learning analysis of high-resolution computed tomographic lung scans permits quantitative morphometry of the lung circulation without intravenous contrast. Inhaled magnetic resonance imaging probes, such as hyperpolarized 129Xe magnetic resonance imaging, report on pulmonary gas exchange and pulmonary capillary hemodynamics. These approaches provide important information on right ventricular structure and function along with perfusion through the pulmonary circulation. At this time, the majority of these developing technologies have yet to be clinically validated, with few studies demonstrating the utility of these imaging biomarkers for diagnosis or monitoring disease. These technologies hold promise for earlier diagnosis and noninvasive monitoring of right heart failure and pulmonary hypertension that will aid in preclinical studies, enhance patient selection and provide surrogate end points in clinical trials, and ultimately improve bedside care.

Acute echocardiographic and hemodynamic response to his-bundle pacing in patients with first-degree atrioventricular block.

BACKGROUND: Atrial pacing and right ventricular (RV) pacing are both associated with adverse outcomes among patients with first-degree atrioventricular block (1°AVB). His-bundle pacing (HBP) provides physiological activation of the ventricle and may be able to improve both atrioventricular (AV) and inter-ventricular synchrony in 1°AVB patients. This study evaluates the acute echocardiographic and hemodynamic effects of atrial, atrial-His-bundle sequential (AH), and atrial-ventricular (AV) sequential pacing in 1°AVB patients. METHODS: Patients with 1°AVB undergoing atrial fibrillation ablation were included. Following left atrial (LA) catheterization, patients underwent atrial, AH- and AV-sequential pacing. LA/left ventricular (LV) pressure and echocardiographic measurements during the pacing protocols were compared. RESULTS: Thirteen patients with 1°AVB (mean PR 221 ± 26 ms) were included. The PR interval was prolonged with atrial pacing compared to baseline (275 ± 73 ms, p = .005). LV ejection fraction (LVEF) was highest during atrial pacing (62 ± 11%), intermediate with AH-sequential pacing (59 ± 7%), and lowest with AV-sequential pacing (57 ± 12%) though these differences were not statistically significant. No significant differences were found in LA or LV mean pressures or LV dP/dT. LA and LV volumes, isovolumetric times, electromechanical delays, and global longitudinal strains were similar across pacing protocols. CONCLUSION: Despite pronounced PR prolongation, the acute effects of atrial pacing were not significantly different than AH- or AV-sequential pacing. Normalizing atrioventricular and/or inter-ventricular dyssynchrony did not result in acute improvements in cardiac output or loading conditions.

Progression of cardiac structure and function in people with human immunodeficiency virus.

OBJECTIVE: People living with HIV (PLWH) are at increased risk for cardiac dysfunction. It is unknown how their global longitudinal cardiac function, cardiac structure, and other indices of function progress over time. We aimed to characterize the longitudinal trend in cardiac structure and function in PLWH. DESIGN: Retrospective study of PLWH with clinically obtained echocardiograms at an academic medical center. METHODS: We reviewed archived transthoracic echocardiograms (TTEs) performed between 2001 and 2012 on PLWH. The primary outcome measures were progression of global longitudinal strain (GLS, left and right ventricles), LV mass, E/e' ratio, LV end-systolic, and -diastolic volumes using hierarchical mixed model analysis as a function of CD4+ T cell count and HIV RNA suppression. Models were adjusted for clinical and demographic characteristics. RESULTS: We analyzed 469 TTEs from 150 individuals (median age 46 years, 58% male). Median CD4+ T cell counts at nadir and proximal to first echocardiogram were 85 and 222 cells/mm3 , respectively. Over a median of 5 years, LV mass index increased regardless of nadir or proximal CD4+ T cell count or viral suppression status. PLWH with viral suppression at baseline had more normal GLS throughout the follow-up period. There were no significant trends in LV end-systolic volume index or E/e'. CONCLUSIONS: In PLWH, HIV viral suppression is associated with early gains in echocardiographic indices of cardiac function that persist for up to >5 years. HIV disease control impacts routine echocardiographic measures with known impacts on long-term prognosis.

Cardiovascular magnetic resonance-derived left ventricular intraventricular pressure gradients among patients with precapillary pulmonary hypertension.

AIMS: Precapillary pulmonary hypertension (pPH) affects left ventricular (LV) function by ventricular interdependence. Since LV ejection fraction (EF) is commonly preserved, LV dysfunction should be assessed with more sensitive techniques. Left atrial (LA) strain and estimation of LV intraventricular pressure gradients (IVPG) may be valuable in detecting subtle changes in LV mechanics; however, the value of these techniques in pPH is unknown. Therefore, the aim of our study is to evaluate LA strain and LV-IVPGs from cardiovascular magnetic resonance (CMR) cines in pPH patients. METHODS AND RESULTS: In this cross-sectional study, 31 pPH patients and 22 healthy volunteers underwent CMR imaging. Feature-tracking LA strain was measured on four- and two-chamber cines. LV-IVPGs (from apex-base) are computed from a formulation using the myocardial movement and velocity of the reconstructed 3D-LV (derived from long-axis cines using feature-tracking). Systolic function, both LV EF and systolic ejection IVPG, was preserved in pPH patients. Compared to healthy volunteers, diastolic function was impaired in pPH patients, depicted by (i) lower LA reservoir (36 ± 7% vs. 26 ± 9%, P < 0.001) and conduit strain (26 ± 6% vs. 15 ± 8%, P < 0.001) and (ii) impaired diastolic suction (-9.1 ± 3.0 vs. ‒6.4 ± 4.4, P = 0.02) and E-wave decelerative IVPG (8.9 ± 2.6 vs. 5.7 ± 3.1, P < 0.001). Additionally, 11 pPH patients (35%) showed reversal of IVPG at systolic-diastolic transition compared to none of the healthy volunteers (P = 0.002). CONCLUSIONS: pPH impacts LV function by altering diastolic function, demonstrated by an impairment of LA phasic function and LV-IVPG analysis. These parameters could therefore potentially be used as early markers for LV functional decline in pPH patients.

Benefit/risk Ratio of Low-dose Methotrexate in Cutaneous Lesions of Mycosis Fungoides and Sézary Syndrome.

Low-dose methotrexate is widely used in mycosis fungoides and Sézary syndrome, but few studies have evaluated this treatment. The aim of this study was to evaluate the benefit/risk ratio of this regimen on skin lesions. A retrospective survey of a series of patients treated for mycosis fungoides or Sézary syndrome with low-dose methotrexate and followed for at least one year in a tertiary referral centre was performed. From a total of 48 patients, complete response and partial response were achieved in 10 (21%) and 25 (52%) patients, respectively, with no significant difference in response rates between mycosis fungoides and Sézary syndrome. Of the responders, 20 out of 35 (57%) relapsed after a median time of 11 months. Forty-four of the total of 48 patients discontinued methotrexate, mainly due to primary or secondary failure and/or limiting toxicity (9 patients). Overall, the benefit/risk ratio of low-dose methotrexate in mycosis fungoides and Sézary syndrome appears favorable and this treat-ment remains a valid option in mycosis fungoides/Sézary syndrome. However, its activity is limited in duration and significant toxicity may occur in some patients.

Early impairment of myocardial deformation assessed by regional speckle-tracking echocardiography in the indeterminate form of Chagas disease without fibrosis detected by cardiac magnetic resonance.

Chagas disease (CD) will account for 200,000 cardiovascular deaths worldwide over the next 5 years. Early detection of chronic Chagas cardiomyopathy (CCC) is a challenge. We aimed to test if speckle-tracking echocardiography (STE) can detect incipient myocardial damage in CD. METHODS: Among 325 individuals with positive serological tests, 25 (age 55±12yrs) were selected to compose the group with indeterminate form of Chagas disease (IFCD), based on stringent criteria of being asymptomatic and with normal EKG/X-ray studies. This group was compared with a group of 20 patients with CCC (55±11yrs) and a group of 20 non-infected matched control (NC) subjects (48±10yrs). CD patients and NC were submitted to STE and CD patients were submitted to cardiac magnetic resonance (CMR) with late gadolinium administration to detect cardiac fibrosis by the late enhancement technique. Global longitudinal strain (GLS), circumferential (GCS) and radial strain (GRS) were defined as the average of segments measured from three apical view (GLS) and short axis views (GRS and GCS). Regional left ventricular (LV) longitudinal strain (Reg LS) was measured from each of the 17 segments. Twist was measured as systolic peak difference between basal and apical rotation and indexed to LV length to express torsion. RESULTS: STE global indices (GLS, GCS, twist and torsion) were reduced in CCC vs NC (GLS: -14±6.3% vs -19.3±1.6%, p = 0.001; GCS: -13.6±5.2% vs -17.3 ±2.8%; p = 0.008; twist: 8±7° vs 14±7°, p = 0.01 and torsion: 0.96±1°/cm vs 1.9±1°/cm, p = 0.005), but showed no differences in IFCD vs NC. RegLS was reduced in IFCD vs NC in four LV segments: basal-inferior (-16.3±3.3% vs -18.6±2.2%, p = 0.013), basal inferoseptal (-13.1±3.4 vs -15.2±2.7, p = 0.019), mid-inferoseptal (-17.7±3.2 vs -19.4±2, p = 0.032) and mid-inferolateral (-15.2±3.5 vs -17.8±2.8, p = 0.014). These abnormalities in RegLS occurred in the absence of myocardial fibrosis detectable with CMR in nearly 92% of subjects with IFCD, while myocardial fibrosis was present in 65% with CCC. CONCLUSION: RegLS detects early regional impairment of myocardial strain that is independent from fibrosis in IFCD subjects.

Identification of Undetected Monogenic Cardiovascular Disorders.

BACKGROUND: Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed. OBJECTIVES: The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort. METHODS: Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease. RESULTS: In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals. CONCLUSIONS: Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists.