Myocardial Scarring and Sudden Cardiac Death in Young Patients With Hypertrophic Cardiomyopathy: A Multicenter Cohort Study.

Importance: The ability to predict sudden cardiac death (SCD) in children and adolescents with hypertrophic cardiomyopathy (HCM) is currently inadequate. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging is associated with SCD events in adults with HCM. Objective: To examine the prognostic significance of LGE in patients with HCM who are younger than 21 years. Design, Setting, and Participants: This multicenter, retrospective cohort study was conducted from April 8, 2015, to September 12, 2022, in patients with HCM who were younger than 21 years and had undergone CMR imaging across multiple sites in the US, Europe, and South America. Observers of CMR studies were masked toward outcomes and demographic characteristics. Exposure: Natural history of HCM. Main Outcome and Measures: The primary outcome was SCD and surrogate events, including resuscitated cardiac arrest and appropriate discharges from an implantable defibrillator. Continuous and categorical data are expressed as mean (SD), median (IQR), or number (percentage), respectively. Survivor curves comparing patients with and without LGE were constructed by the Kaplan-Meier method, and likelihood of subsequent clinical events was further evaluated using univariate and multivariable Cox proportional hazards models. Results: Among 700 patients from 37 international centers, median (IQR) age was 14.8 (11.9-17.4) years, and 518 participants (74.0%) were male. During a median (IQR) [range] follow-up period of 1.9 (0.5-4.1) [0.1-14.8] years, 35 patients (5.0%) experienced SCD or equivalent events. LGE was present in 230 patients (32.9%), which constituted an mean (SD) burden of 5.9% (7.3%) of left ventricular myocardium. The LGE amount was higher in older patients and those with greater left ventricular mass and maximal wall thickness; patients with LGE had lower left ventricular ejection fractions and larger left atrial diameters. The presence and burden of LGE was associated with SCD, even after correcting for existing risk stratification tools. Patients with 10% or more LGE, relative to total myocardium, had a higher risk of SCD (unadjusted hazard ratio [HR], 2.19; 95% CI, 1.59-3.02; P < .001). Furthermore, the addition of LGE burden improved the performance of the HCM Risk-Kids score (before LGE addition: 0.66; 95% CI, 0.58-0.75; after LGE addition: 0.73; 95% CI, 0.66-0.81) and Precision Medicine in Cardiomyopathy score (before LGE addition: 0.68; 95% CI, 0.49-0.77; after LGE addition: 0.73; 95% CI, 0.64-0.82) SCD predictive models. Conclusions and Relevance: In this retrospective cohort study, quantitative LGE was a risk factor for SCD in patients younger than 21 years with HCM and improved risk stratification.

Noninvasive Pressure-Volume Loops Predict Major Adverse Cardiac Events in Heart Failure With Reduced Ejection Fraction.

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by ventricular remodeling and impaired myocardial energetics. Left ventricular pressure-volume (PV) loop analysis can be performed noninvasively using cardiovascular magnetic resonance (CMR) imaging to assess cardiac thermodynamic efficiency. Objectives: The aim of the study was to investigate whether noninvasive PV loop parameters, derived from CMR, could predict major adverse cardiac events (MACE) in HFrEF patients. Methods: PV loop parameters (stroke work, ventricular efficiency, external power, contractility, and energy per ejected volume) were computed from CMR cine images and brachial blood pressure. The primary end point was MACE (cardiovascular death, heart failure (HF) hospitalization, myocardial infarction, revascularization, ventricular tachycardia/fibrillation, heart transplantation, or left ventricular assist device implantation within 5 years). Associations between PV loop parameters and MACE were evaluated using multivariable Cox regression. Results: One hundred and sixty-four HFrEF patients (left ventricular ejection fraction ≤40%, age 63 [IQR: 55-70] years, 79% male) who underwent clinical CMR examination between 2004 and 2014 were included. Eighty-eight patients (54%) experienced at least one MACE after an average of 2.8 years. Unadjusted models demonstrated a significant association between MACE and all PV loop parameters (P < 0.05 for all), HF etiology (P < 0.001), left ventricular ejection fraction (P = 0.003), global longitudinal strain (P < 0.001), and N-terminal prohormone of brain natriuretic peptide level (P = 0.001). In the multivariable Cox regression analysis adjusted for age, sex, hypertension, diabetes, and HF etiology, ventricular efficiency was associated with MACE (HR: 1.04 (95% CI: 1.01-1.08) per-% decrease, P = 0.01). Conclusions: Ventricular efficiency, derived from noninvasive PV loop analysis from standard CMR scans, is associated with MACE in patients with HFrEF.

Evaluating the effect of rapamycin treatment in Alzheimer's disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol.

BACKGROUND: Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer's disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The "Evaluating Rapamycin Treatment in Alzheimer's Disease using Positron Emission Tomography" (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer's disease. METHODS: ERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer's disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function. DISCUSSION: The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer's disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06022068, date of registration 2023-08-30.

Non-invasive pressure-volume loops using the elastance model and CMR: a porcine validation at transient pre-loads.

Aims: Pressure-volume (PV) loops have utility in the evaluation of cardiac pathophysiology but require invasive measurements. Recently, a time-varying elastance model to derive PV loops non-invasively was proposed, using left ventricular (LV) volume by cardiovascular magnetic resonance (CMR) and brachial cuff pressure as inputs. Validation was performed using CMR and pressure measurements acquired on the same day, but not simultaneously, and without varying pre-loads. This study validates the non-invasive elastance model used to estimate PV loops at varying pre-loads, compared with simultaneous measurements of invasive pressure and volume from real-time CMR, acquired concurrent to an inferior vena cava (IVC) occlusion. Methods and results: We performed dynamic PV loop experiments under CMR guidance in 15 pigs (n = 7 naïve, n = 8 with ischaemic cardiomyopathy). Pre-load was altered by IVC occlusion, while simultaneously acquiring invasive LV pressures and volumes from real-time CMR. Pairing pressure and volume signals yielded invasive PV loops, and model-based PV loops were derived using real-time LV volumes. Haemodynamic parameters derived from invasive and model-based PV loops were compared. Across 15 pigs, 297 PV loops were recorded. Intra-class correlation coefficient (ICC) agreement was excellent between model-based and invasive parameters: stroke work (bias = 0.007 ± 0.03 J, ICC = 0.98), potential energy (bias = 0.02 ± 0.03 J, ICC = 0.99), ventricular energy efficiency (bias = -0.7 ± 2.7%, ICC = 0.98), contractility (bias = 0.04 ± 0.1 mmHg/mL, ICC = 0.97), and ventriculoarterial coupling (bias = 0.07 ± 0.15, ICC = 0.99). All haemodynamic parameters differed between naïve and cardiomyopathy animals (P < 0.05). The invasive vs. model-based PV loop dice similarity coefficient was 0.88 ± 0.04. Conclusion: An elastance model-based estimation of PV loops and associated haemodynamic parameters provided accurate measurements at transient loading conditions compared with invasive PV loops.

Diagnostic confidence with quantitative cardiovascular magnetic resonance perfusion mapping increases with increased coverage of the left ventricle.

BACKGROUND: Quantitative cardiovascular magnetic resonance (CMR) first pass perfusion maps are conventionally acquired with 3 short-axis (SAX) views (basal, mid, and apical) in every heartbeat (3SAX/1RR). Thus, a significant part of the left ventricle (LV) myocardium, including the apex, is not covered. The aims of this study were 1) to investigate if perfusion maps acquired with 3 short-axis views sampled every other RR-interval (2RR) yield comparable quantitative measures of myocardial perfusion (MP) as 1RR and 2) to assess if acquiring 3 additional perfusion views (i.e., total of 6) every other RR-interval (2RR) increases diagnostic confidence. METHODS: In 287 patients with suspected ischemic heart disease stress and rest MP were performed on clinical indication on a 1.5T MR scanner. Eighty-three patients were examined by acquiring 3 short-axis perfusion maps with 1RR sampling (3SAX/1RR); for which also 2RR maps were reconstructed. Additionally, in 103 patients 3 short-axis and 3 long-axis (LAX; 2-, 3, and 4-chamber view) perfusion maps were acquired using 2RR sampling (3SAX + 3LAX/2RR) and in 101 patients 6 short-axis perfusion maps using 2RR sampling (6SAX/2RR) were acquired. The diagnostic confidence for ruling in or out stress-induced ischemia was scored according to a Likert scale (certain ischemia [2 points], probably ischemia [1 point], uncertain [0 points], probably no ischemia [1 point], certain no ischemia [2 points]). RESULTS: There was a strong correlation (R = 0.99) between 3SAX/1RR and 3SAX/2RR for global MP (mL/min/g). The diagnostic confidence score increased significantly when the number of perfusion views was increased from 3 to 6 (1.24 ± 0.68 vs 1.54 ± 0.64, p < 0.001 with similar increase for 3SAX+3LAX/2RR (1.29 ± 0.68 vs 1.55 ± 0.65, p < 0.001) and for 6SAX/2RR (1.19 ± 0.69 vs 1.53 ± 0.63, p < 0.001). CONCLUSION: Quantitative perfusion mapping with 2RR sampling of data yields comparable perfusion values as 1RR sampling, allowing for the acquisition of additional views within the same perfusion scan. The diagnostic confidence for stress-induced ischemia increases when adding 3 additional views, short- or long axes, to the conventional 3 short-axis views. Thus, future development and clinical implementation of quantitative CMR perfusion should aim at increasing the LV coverage from the current standard using 3 short-axis views.

Timing of Regadenoson-induced Peak Hyperemia and the Effects on Coronary Flow Reserve.

Background: Regadenoson is used to induce hyperemia in cardiac imaging, facilitating diagnosis of ischemia and assessment of coronary flow reserve (CFR). While the regadenoson package insert recommends administration of radionuclide tracer 10-20 seconds after injection, peak hyperemia has been observed at approximately 100 seconds after injection in healthy volunteers undergoing cardiovascular magnetic resonance imaging (CMR). It is unclear when peak hyperemia occurs in a patient population. Objectives: The goal of this study was to determine time to peak hyperemia after regadenoson injection in healthy volunteers and patients, and whether the recommended image timing in the package insert underestimates CFR. Methods: Healthy volunteers (n=15) and patients (n=25) underwent stress CMR, including phase-contrast imaging of the coronary sinus at rest and multiple timepoints after 0.4 mg regadenoson injection. Coronary sinus flow (ml/min) was divided by resting values to yield CFR. Smoothed, time-resolved curves for CFR were generated with pointwise 95% confidence intervals. Results: CFR between 60 and 120 seconds was significantly higher than CFR at 30 seconds after regadenoson injection (p < 0.05) as shown by non-overlapping 95% confidence intervals for both healthy volunteers (30 s, [2.8, 3.4]; 60 s, [3.8, 4.4]; 90 s, [4.1, 4.7]; 120 s, [3.6, 4.3]) and patients (30 s, [2.1, 2.5]; 60 s, [2.6, 3.1]; 90 s, [2.7, 3.2]; 120 s, [2.5, 3.1]). Conclusion: Imaging at 90 seconds following regadenoson injection is the optimal approach to capture peak hyperemia. Imaging at 30 seconds, which is more aligned with the package insert recommendation, would yield an underestimate of CFR and confound assessment of microvascular dysfunction.

Influenza-A mediated pre-existing immunity levels to SARS-CoV-2 could predict early COVID-19 outbreak dynamics.

Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is highly variable and could be mediated by a cross-protective pre-immunity. We identified 14 cross-reactive peptides between SARS-CoV-2 and influenza A H1N1, H3N2, and human herpesvirus (HHV)-6A/B with potential relevance. The H1N1 peptide NGVEGF was identical to a peptide in the most critical receptor binding motif in SARS-CoV-2 spike protein that interacts with the angiotensin converting enzyme 2 receptor. About 62%-73% of COVID-19-negative blood donors in Stockholm had antibodies to this peptide in the early pre-vaccination phase of the pandemic. Seasonal flu vaccination enhanced neutralizing capacity to SARS-CoV-2 and T cell immunity to this peptide. Mathematical modeling taking the estimated pre-immunity levels to flu into account could fully predict pre-Omicron SARS-CoV-2 outbreaks in Stockholm and India. This cross-immunity provides mechanistic explanations to the epidemiological observation that influenza vaccination protected people against early SARS-CoV-2 infections and implies that flu-mediated cross-protective immunity significantly dampened the first SARS-CoV-2 outbreaks.

Prognostic utility and characterization of left ventricular hypertrophy using global thickness.

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, and several measures related to LV wall thickness exist. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy. Subjects having undergone CMR were studied (cardiac patients, n = 2543; healthy volunteers, n = 100). A new measure, global wall thickness (GT, GTI if indexed to body surface area) was accurately calculated from LV mass and end-diastolic volume. Among patients with follow-up (n = 1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12-1.20], p < 0.001), followed by GTI (HR 1.14[1.09-1.19], p < 0.001). Among patients with normal findings (n = 326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35-1.94], p < 0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p < 0.05 for all). LV mass is highly prognostic when mass is elevated, but GT is easily and accurately calculated, and adds value and discrimination amongst those with normal LV mass (early disease).

Patients with volume-loaded right ventricle - quantification of left ventricular hemodynamic response to intervention measured by noninvasive pressure-volume loops.

Volume loading of the right ventricle (RV) in patients with atrial septal defect (ASD) and patients with repaired Tetralogy of Fallot (rToF) affects the pumping mechanics of the left ventricle (LV). Intervention of the lesion will relieve the RV volume load however quantifiable impact on exercise capacity, arrhytmias or death are limited. A possible explanation could be remaining effects on the function of the LV. The aim of this study was therefore to investigate if hemodynamics of the LV differs between patients with RV volume load due to ASD or rToF and healthy controls and if they change after intervention. Eighteen patients with ASD, 17 patients with rToF and 16 healthy controls underwent cardiac magnetic resonance imaging (CMR) and maximal exercise test with continuous gas analysis. Reexamination was performed 13 ± 2 months after closure of the ASD in 13 of the patients and 10 ± 4 months after pulmonary valve replacement (PVR) in 9 of the patients with rToF. Non-invasive PV-loops from CMR and brachial pressures were analyzed. Stroke work (SW) and potential energy (PE) increased after ASD closure but not in ToF patients after valve repair. Patients with ASD or rToF had higher contractility and arterial elastance than controls. No major effects were seen in LV energetics or in peak VO2 after ASD closure or PVR. Peak VO2 correlated positively with SW and PE in patients with ASD (r = 0.54, p < 0.05; r = 0.61, p < 0.01) and controls (r = 0.72, p < 0.01; r = 0.53, p < 0.05) to approximately the same degree as peak VO2 and end-diastolic volume (EDV) or end-systolic volume (ESV). In ToF patients there was no correlation between PV loop parameters and peak VO2 even if correlation was found between peak VO2 and EDV or ESV. In conclusion, the LV seems to adapt its pumping according to anatomic circumstances without losing efficiency, however there are indications of persistent vascular dysfunction, expressed as high arterial elastance, which might have impact on exercise performance and prognosis. Future studies might elucidate if the duration of RV volume load and decreased LV filling have any impact on the ability of the vascular function to normalize after ASD closure or PVR.

In vivo hepatic flow distribution by computational fluid dynamics can predict pulmonary flow distribution in patients with Fontan circulation.

In Fontan patients, a lung deprived of hepatic blood may develop pulmonary arterio-venous malformations (PAVMs) resulting in shunting, reduced pulmonary vascular resistance (PVR) and decreased oxygenation. To provide guidance for corrective invasive interventions, we aimed to non-invasively determine how the hepatic to pulmonary blood flow balance correlates with pulmonary flow, PVR, and with oxygen saturation. Magnetic resonance imaging (MRI) data from eighteen Fontan patients (eight females, age 3-14 years) was used to construct patient-specific computational fluid dynamics (CFD) models to calculate the hepatic to pulmonary blood flow. This was correlated with pulmonary vein flow, simulated PVR and oxygen saturation. Clinical applicability of the findings was demonstrated with an interventional patient case. The hepatic to pulmonary blood flow balance correlated with right/left pulmonary vein flow (R2 = 0.50), left/right simulated PVR (R2 = 0.47), and oxygen saturation at rest (R2 = 0.56). In the interventional patient, CFD predictions agreed with post-interventional MRI measurements and with regressions in the cohort. The balance of hepatic blood to the lungs has a continuous effect on PVR and oxygen saturation, even without PAVM diagnosis. MRI combined with CFD may help in planning of surgical and interventional designs affecting the hepatic to pulmonary blood flow balance in Fontan patients.

Hemodynamic forces from 4D flow magnetic resonance imaging predict left ventricular remodeling following cardiac resynchronization therapy.

BACKGROUND: Patients with heart failure and left bundle branch block (LBBB) may receive cardiac resynchronization therapy (CRT), but current selection criteria are imprecise, and many patients have limited treatment response. Hemodynamic forces (HDF) have been suggested as a marker for CRT response. The aim of this study was therefore to investigate left ventricular (LV) HDF as a predictive marker for LV remodeling after CRT. METHODS: Patients with heart failure, EF < 35% and LBBB (n = 22) underwent CMR with 4D flow prior to CRT. LV HDF were computed in three directions using the Navier-Stokes equations, reported in median N [interquartile range], and the ratio of transverse/longitudinal HDF was calculated for systole and diastole. Transthoracic echocardiography was performed before and 6 months after CRT. Patients with end-systolic volume reduction ≥ 15% were defined as responders. RESULTS: Non-responders had smaller HDF than responders in the inferior-anterior direction in systole (0.06 [0.03] vs. 0.07 [0.03], p = 0.04), and in the apex-base direction in diastole (0.09 [0.02] vs. 0.1 [0.05], p = 0.047). Non-responders had larger diastolic HDF ratio compared to responders (0.89 vs. 0.67, p = 0.004). ROC analysis of diastolic HDF ratio for identifying CRT non-responders had AUC of 0.88 (p = 0.005) with sensitivity 57% and specificity 100% for ratio > 0.87. Intragroup comparison found higher HDF ratio in systole compared to diastole for responders (p = 0.003), but not for non-responders (p = 0.8). CONCLUSION: Hemodynamic force ratio is a potential marker for identifying patients with heart failure and LBBB who are unlikely to benefit from CRT. Larger-scale studies are required before implementation of HDF analysis into clinical practice.

Incremental Value of Exercise ECG to Myocardial Perfusion Single-Photon Emission Computed Tomography for Prediction of Cardiac Events.

Background Both myocardial perfusion single-photon emission computed tomography (MPS) and exercise ECG (Ex-ECG) carry prognostic information in patients with stable chest pain. However, it is not fully understood if combining the findings of MPS and Ex-ECG improves risk prediction. Current guidelines no longer recommend Ex-ECG for diagnostic evaluation of chronic coronary syndrome, but Ex-ECG could still be of incremental prognostic importance. Methods and Results This study comprised 908 consecutive patients (age 63.3±9.4 years, 49% male) who performed MPS with Ex-ECG. Subjects were followed for 5 years. The end point was a composite of cardiovascular death, acute myocardial infarction, unstable angina, and unplanned percutaneous coronary intervention. National registry data and medical charts were used for end point allocation. Combining the findings of MPS and Ex-ECG resulted in concordant evidence of ischemia in 72 patients or absence of ischemia in 634 patients. Discordant results were found in 202 patients (MPS-/Ex-ECG+, n=126 and MPS+/Ex-ECG-, n=76). During follow-up, 95 events occurred. Annualized event rates significantly increased across groups (MPS-/Ex-ECG- =1.3%, MPS-/Ex-ECG+ =3.0%, MPS+/Ex-ECG- =5.1% and MPS+/Ex-ECG+ =8.0%). In multivariable analyses MPS was the strongest predictor regardless of Ex-ECG findings (MPS+/Ex-ECG-, hazard ratio [HR], 3.0, P=0.001 or MPS+/Ex-ECG+, HR,4.0, P<0.001). However, an abnormal Ex-ECG almost doubled the risk in subjects with normal MPS (MPS-/Ex-ECG+, HR, 1.9, P=0.04). Conclusions In patients with chronic coronary syndrome, combining the results from MPS and Ex-ECG led to improved risk prediction. Even though MPS is the stronger predictor, there is an incremental value of adding data from Ex-ECG to MPS, especially in patients with normal MPS.

Diagnostic accuracy for CZT gamma camera compared to conventional gamma camera technique with myocardial perfusion single-photon emission computed tomography: Assessment of myocardial infarction and function.

BACKGROUND: The solid-state cadmium-zinc-telluride (CZT) gamma camera for myocardial perfusion single-photon emission computed tomography (MPS) has theoretical advantages compared to the conventional gamma camera technique. This includes more sensitive detectors and better energy resolution. We aimed to explore the diagnostic performance of gated MPS with a CZT gamma camera compared to a conventional gamma camera for detection of myocardial infarct (MI) and assessment of left ventricular (LV) volumes and ejection fraction (LVEF), using cardiac magnetic resonance (CMR) as the reference method. METHODS: Seventy-three patients (26% female) with known or suspected chronic coronary syndrome were examined with gated MPS using both a CZT gamma camera and a conventional gamma camera as well as with CMR. Presence and extent of MI on MPS and late gadolinium enhancement (LGE) CMR was evaluated. For LV volumes, LVEF and LV mass, gated MPS images and cine CMR images were evaluated. RESULTS: MI was found in 42 patients on CMR. The overall sensitivity, specificity, positive and negative predictive values for the CZT and the conventional gamma camera were the same (67%, 100%, 100% and 69%). For infarct size > 3% on CMR, the sensitivity was 82% for the CZT and 73% for the conventional gamma camera, respectively. LV volumes were significantly underestimated by MPS compared to CMR (P ≤ .002 for all measures). The underestimation was slightly less pronounced for the CZT compared to the conventional gamma camera (2-10 mL, P ≤ .03 for all measures). For LVEF, however, accuracy was high for both gamma cameras. CONCLUSION: Differences between a CZT and a conventional gamma camera for detection of MI and assessment of LV volumes and LVEF are small and do not appear to be clinically significant.

Mild hypothermia attenuates ischaemia/reperfusion injury: insights from serial non-invasive pressure-volume loops.

AIMS: Mild hypothermia, 32-35°C, reduces infarct size in experimental studies, potentially mediating reperfusion injuries, but human trials have been ambiguous. To elucidate the cardioprotective mechanisms of mild hypothermia, we analysed cardiac performance in a porcine model of ischaemia/reperfusion, with serial cardiovascular magnetic resonance (CMR) imaging throughout 1 week using non-invasive pressure-volume (PV) loops. METHODS AND RESULTS: Normothermia and Hypothermia group sessions (n = 7 + 7 pigs, non-random allocation) were imaged with Cardiovascular magnetic resonance (CMR) at baseline and subjected to 40 min of normothermic ischaemia by catheter intervention. Thereafter, the Hypothermia group was rapidly cooled (mean 34.5°C) for 5 min before reperfusion. Additional CMR sessions at 2 h, 24 h, and 7 days acquired ventricular volumes and ischaemic injuries (unblinded analysis). Stroke volume (SV: -24%; P = 0.029; Friedmans test) and ejection fraction (EF: -20%; P = 0.068) were notably reduced at 24 h in the Normothermia group compared with baseline. In contrast, the decreases were ameliorated in the Hypothermia group (SV: -6%; P = 0.77; EF: -6%; P = 0.13). Mean arterial pressure remained stable in Normothermic animals (-3%, P = 0.77) but dropped 2 h post-reperfusion in hypothermic animals (-18%, P = 0.007). Both groups experienced a decrease and partial recovery pattern for PV loop-derived variables over 1 week, but the adverse effects tended to attenuate in the Hypothermia group. Infarct sizes were 10 ± 8% in Hypothermic and 15 ± 8% in Normothermic animals (P = 0.32). Analysis of covariance at 24 h indicated that hypothermia has cardioprotective properties incremental to reducing infarct size, such as higher external power (P = 0.061) and lower arterial elastance (P = 0.015). CONCLUSION: Using non-invasive PV loops by CMR, we observed that mild hypothermia at reperfusion alleviates the heart's work after ischaemia/reperfusion injuries during the first week and preserves short-term cardiac performance. This hypothesis-generating study suggests hypothermia to have cardioprotective properties, incremental to reducing infarct size. The primary cardioprotective mechanism was likely an afterload reduction acutely unloading the left ventricle.

A note on variable susceptibility, the herd-immunity threshold and modeling of infectious diseases.

The unfolding of the COVID-19 pandemic has been very difficult to predict using mathematical models for infectious diseases. While it has been demonstrated that variations in susceptibility have a damping effect on key quantities such as the incidence peak, the herd-immunity threshold and the final size of the pandemic, this complex phenomenon is almost impossible to measure or quantify, and it remains unclear how to incorporate it for modeling and prediction. In this work we show that, from a modeling perspective, variability in susceptibility on an individual level is equivalent with a fraction θ of the population having an "artificial" sterilizing immunity. We also derive novel formulas for the herd-immunity threshold and the final size of the pandemic, and show that these values are substantially lower than predicted by the classical formulas, in the presence of variable susceptibility. In the particular case of SARS-CoV-2, there is by now undoubtedly variable susceptibility due to waning immunity from both vaccines and previous infections, and our findings may be used to greatly simplify models. If such variations were also present prior to the first wave, as indicated by a number of studies, these findings can help explain why the magnitude of the initial waves of SARS-CoV-2 was relatively low, compared to what one may have expected based on standard models.

Deep learning can yield clinically useful right ventricular segmentations faster than fully manual analysis.

Right ventricular (RV) volumes are commonly obtained through time-consuming manual delineations of cardiac magnetic resonance (CMR) images. Deep learning-based methods can generate RV delineations, but few studies have assessed their ability to accelerate clinical practice. Therefore, we aimed to develop a clinical pipeline for deep learning-based RV delineations and validate its ability to reduce the manual delineation time. Quality-controlled delineations in short-axis CMR scans from 1114 subjects were used for development. Time reduction was assessed by two observers using 50 additional clinical scans. Automated delineations were subjectively rated as (A) sufficient for clinical use, or as needing (B) minor or (C) major corrections. Times were measured for manual corrections of delineations rated as B or C, and for fully manual delineations on all 50 scans. Fifty-eight % of automated delineations were rated as A, 42% as B, and none as C. The average time was 6 min for a fully manual delineation, 2 s for an automated delineation, and 2 min for a minor correction, yielding a time reduction of 87%. The deep learning-based pipeline could substantially reduce the time needed to manually obtain clinically applicable delineations, indicating ability to yield right ventricular assessments faster than fully manual analysis in clinical practice. However, these results may not generalize to clinics using other RV delineation guidelines.

Right ventricular longitudinal function is linked to left ventricular filling pressure in patients with repaired tetralogy of fallot.

Experimental data on pulmonary regurgitation has linked right ventricular longitudinal function to left ventricular filling pressure in animals with induced and treated pulmonary regurgitation but this relationship has not been investigated in patients with repaired Tetralogy of Fallot (rToF). The aim of this study was to determine if right ventricular longitudinal function assessed using cardiovascular magnetic resonance (CMR) is associated with left ventricular filling pressure in patients with rToF. A second objective of this study was to determine if direction of septal movement is related to right ventricular pressure load in rToF. Eighteen patients with rToF undergoing CMR and heart catheterization prior to pulmonary valve replacement were retrospectively included and catheter-based pressure measurements were compared with CMR-derived RV regional function. Left ventricular filling pressure was measured as precapillary wedge pressure (PCWP). Longitudinal contribution to RV stroke volume correlated with PCWP (r = 0.48; p = 0.046) but not with RV EF or pulmonary regurgitation. Neither RV longitudinal strain nor TAPSE showed correlation with PCWP. Longitudinal contribution to stroke volume was lower for the RV compared to the LV (49 vs 54%; p = 0.039). Direction of septal movement did not show a correlation with RV end-systolic pressure. Right ventricular longitudinal pumping is associated with left ventricular filling pressure in rToF-patients and this inter-ventricular coupling may explain LV underfilling in patients with pulmonary regurgitation and rToF and may be of value to determine right ventricular dysfunction. RV systolic pressure, however, cannot be assessed from the direction of septal movement, in these patients.

Comparison of 2D and 4D Flow MRI in Neonates Without General Anesthesia.

BACKGROUND: Neonates with critical congenital heart disease require early intervention. Four-dimensional (4D) flow may facilitate surgical planning and improve outcome, but accuracy and precision in neonates are unknown. PURPOSE: To 1) validate two-dimensional (2D) and 4D flow MRI in a phantom and investigate the effect of spatial and temporal resolution; 2) investigate accuracy and precision of 4D flow and internal consistency of 2D and 4D flow in neonates; and 3) compare scan time of 4D flow to multiple 2D flows. STUDY TYPE: Phantom and prospective patients. POPULATION: A total of 17 neonates with surgically corrected aortic coarctation (age 18 days [IQR 11-20]) and a three-dimensional printed neonatal aorta phantom. FIELD STRENGTH/SEQUENCE: 1.5T, 2D flow and 4D flow. ASSESSMENT: In the phantom, 2D and 4D flow volumes (ascending and descending aorta, and aortic arch vessels) with different resolutions were compared to high-resolution reference 2D flow. In neonates, 4D flow was compared to 2D flow volumes at each vessel. Internal consistency was computed as the flow volume in the ascending aorta minus the sum of flow volumes in the aortic arch vessels and descending aorta, divided by ascending aortic flow. STATISTICAL TESTS: Bland-Altman plots, Pearson correlation coefficient (r), and Student's t-tests. RESULTS: In the phantom, 2D flow differed by 0.01 ± 0.02 liter/min with 1.5 mm spatial resolution and -0.01 ± 0.02 liter/min with 0.8 mm resolution; 4D flow differed by -0.05 ± 0.02 liter/min with 2.4 mm spatial and 42 msec temporal resolution, -0.01 ± 0.02 liter/min with 1.5 mm, 42 msec resolution and -0.01 ± 0.02 liter/min with 1.5 mm, 21 msec resolution. In patients, 4D flow and 2D flow differed by -0.06 ± 0.08 liter/min. Internal consistency in patients was -11% ± 17% for 2D flow and 5% ± 13% for 4D flow. Scan time was 17.1 minutes [IQR 15.5-18.5] for 2D flow and 6.2 minutes [IQR 5.3-6.9] for 4D flow, P < 0.0001. DATA CONCLUSION: Neonatal 4D flow MRI is time efficient and can be acquired with good internal consistency without contrast agents or general anesthesia, thus potentially expanding 4D flow use to the youngest and smallest patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.