One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction

Background: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. Methods: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V–V 0 )}–1], where “P” is transmural pressure (pulmonary capillary wedge pressure – right atrial pressure), “S” is the pressure asymptote of the curve, “V” is the LV end-diastolic volume index, “V 0 ” is equilibrium volume, and “a” is the constant that characterizes LV myocardial stiffness. Results: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min –1 ·kg –1 , P <0.0001, interaction P =0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min –1 ·kg –1 , P =0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P =0.001). Conclusions: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03476785.

A correction to van Wyk’s model of the compressibility of fibrous materials

van Wyk put forward a compression model of fibrous materials utilizing a library of analytical approaches, including the continuum mechanics, stereological, geometrical probability, least square method, and excluded area concept. In this letter, we wish to point out a key error noted in van Wyk’s work with the objective of correcting misconceptions that are held by the majority of us. Through this contribution, we question the “inverse cube” pressure-volume relationship of random fibrous materials. The pressure-volume relationship has been revisited by modifying the formulation of the mean length of a fiber element between consecutive contacts projected on the compression direction.

Medical Events on Board Aircraft: Reducing Confusion and Misinterpretation in the Scientific Literature

INTRODUCTION: A topic in aviation medicine that attracts much attention from the scientific community as well as from the media concerns medical incidents on board commercial airline flights. It was noticed that many papers on the subject were written by authors whose specialization was outside that of aviation medicine and that they sometimes made basic errors concerning the application of scientific principles of the subject. A review was undertaken to determine if there were any patterns to the observed errors and, if so, to consider whether recommendations might be provided that could reduce their frequency.METHOD: A literature search was undertaken of MEDLINE using PubMed for English-only articles published between January 1, 1974, and February 1, 2019, employing the following search terms: air emergency, air emergencies, air passenger, air travel, aircraft, airline, aviation, commercial air, flight, and fitness to fly. In addition, other relevant papers held in the personal collection of the authors were reviewed.RESULTS: Many cases of misinterpretation or misunderstanding of aviation medicine were found, which could be classified into eight main categories: references; cabin altitude; pressure/volume relationship; other technical aspects of aircraft operations; regulations; medical events; in-flight deaths; and automated external defibrillator.CONCLUSION: Papers were identified as having questionable statements of fact or of emphasis. Such instances often appeared to result from authors being unfamiliar with the subject of aviation medicine and/or the commercial aviation environment. Simple steps could be taken by authors to reduce the future rate of such instances and recommendations are provided.Thibeault C, Evans AD. Medical events on board aircraft: reducing confusion and misinterpretation in the scientific literature. Aerosp Med Hum Perform. 2021; 92(4):265273.

A Framework for Evaluating Myocardial Stiffness Using 3D-Printed Hearts

MRI-driven computational modeling is increasingly used to simulate in vivo cardiac mechanical behavior and estimate subject-specific myocardial stiffness. However, in vivo validation of these estimates is exceedingly difficult due to the lack of a known ground-truth in vivo myocardial stiffness. We have developed 3D-printed heart phantoms of known myocardium-mimicking stiffness and MRI relaxation properties and incorporated the heart phantoms within a highly controlled MRI-compatible setup to simulate in vivo diastolic filling. The setup enables the acquisition of experimental data needed to evaluate myocardial stiffness using computational constitutive modeling: phantom geometry, loading pressures, boundary conditions, and filling strains. The pressure-volume relationship obtained from the phantom setup was used to calibrate an in silico model of the heart phantom undergoing simulated diastolic filling. The model estimated stiffness was compared with ground-truth stiffness obtained from uniaxial tensile testing. Ultimately, the setup is designed to enable extensive validation of MRI and FEM-based myocardial stiffness estimation frameworks.

Non-linearity of end-systolic pressure–volume relation in afterload increases is caused by an overlay of shortening deactivation and the Frank–Starling mechanism

The linearity and load insensitivity of the end-systolic pressure–volume-relationship (ESPVR), a parameter that describes the ventricular contractile state, are controversial. We hypothesize that linearity is influenced by a variable overlay of the intrinsic mechanism of autoregulation to afterload (shortening deactivation) and preload (Frank-Starling mechanism). To study the effect of different short-term loading alterations on the shape of the ESPVR, experiments on twenty-four healthy pigs were executed. Preload reductions, afterload increases and preload reductions while the afterload level was increased were performed. The ESPVR was described either by a linear or a bilinear regression through the end-systolic pressure volume (ES-PV) points. Increases in afterload caused a biphasic course of the ES-PV points, which led to a better fit of the bilinear ESPVRs (r2 0.929 linear ESPVR vs. r2 0.96 and 0.943 bilinear ESPVR). ES-PV points of a preload reduction on a normal and augmented afterload level could be well described by a linear regression (r2 0.974 linear ESPVR vs. r2 0.976 and 0.975 bilinear ESPVR). The intercept of the second ESPVR (V0) but not the slope demonstrated a significant linear correlation with the reached afterload level (effective arterial elastance Ea). Thus, the early response to load could be described by the fixed slope of the ESPVR and variable V0, which was determined by the actual afterload. The ESPVR is only apparently nonlinear, as its course over several heartbeats was affected by an overlay of SDA and FSM. These findings could be easily transferred to cardiovascular simulation models to improve their accuracy.

Ocular Pressure-Volume Relationship and Ganglion Cell Death in Glaucoma

We studied how GC death in glaucoma related to the intraocular pressure (IOP), eyeball volume (VS) and elasticity (volumetric KS and tensile ES), and eyeball volume-pressure relation. Glaucomatous GC loss was studied in DBA/2J (D2) mice with wild-type mice as controls. GCs were retrogradely identified and observed with a confocal microscope. The elasticity calculation was also done on published data from patients treated by a gas bubble injection in the vitreous cavity. The GC population in D2 mice (1.5- to 14-month-old) was negatively correlated with following factors: VS (p = 0.0003), age (p = 0.0026) and IOP (but p = 0.0966). As indicated by average values, adult D2 mice (³6 months) suffered significant GC loss, low KS and ES, and universal expansion of VS with normal IOP. KS and ES in the patients were also lower upon prolonged eyeball expansion compared to acute expansion. Based on the results and presumptions of a closed and continuous eyeball space (thereby ΔVS » ΔVW, ΔVW-the change in the aqueous humor amount), we deduced equations on the ocular volume-pressure relationship: ΔIOP = KS*ΔVW/VS or ΔIOP = (2/3)*[1/(1-n)]*(H/R)*ES*ΔVW/VS (n, Poisson’s ratio taken as 0.5; R, the curvature radius; and H, the shell thickness). Under normal atmospheric pressure, IOP of 10~50 mmHg contributed only 1.2~6.6% of the pressure opposing the retina and eyeball shell. We conclude: 1) A disturbance of ocular volume-pressure homeostasis, mediated primarily by low KS and ES, expanded VS, and large ΔVW, is correlated with GC death in glaucoma and 2) D2 mice with GC loss and normal IOP may serve as animal models for human normal-tension glaucoma.

Abstract 16333: Racial Differences in Pressure-volume Relationships in Val122Ile Associated Cardiac Amyloidosis

Background: Transthyretin cardiac amyloidosis (ATTR-CA) is the leading cause of restrictive cardiomyopathy in older adults. The valine-to-isoleucine substitution (Val122Ile) is the most common inherited variant in the U.S., primarily affecting patients of Afro-Caribbean descent. This variant has also been identified in white individuals in Northern Italy who present with a similar disease phenotype. It is unknown whether there are between-race differences in cardiac chamber function at diagnosis of Val122Ile associated ATTR-CA. Methods: In this retrospective study of 70 patients from two amyloid centers with Val122Ile associated ATTR-CA diagnosed over two decades, clinical and echocardiographic features at diagnosis were compared between races. Cardiac chamber performance was compared using noninvasive, single beat pressure-volume analysis. Results: Average age at diagnosis was 72 years. Compared to white patients (n=17), black individuals (n=53) had lower systolic blood pressure (110 vs. 131 mmHg , p<0.001), reduced pulse pressure (41 vs. 58 mmHg, p<0.001), and impaired renal function (eGFR 46 vs. 67 mL/min/1.73m 2 , p<0.001) at the time of diagnosis. End-systolic pressure-volume relationship (2.3 vs. 1.9 mmHg/mL, p = 0.88), and arterial elastance (3.0 vs. 3.0 mmHg/mL, p = 1.0) were similar between groups (Panel A). Black patients had an end-diastolic pressure-volume relationship shifted upward and leftward relative to white patients, indicating reduced left ventricular capacity. Accordingly, pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in black compared to white individuals (8,415 vs. 11,538 mmHg*mL, p = 0.012, Panel B). Conclusion: Despite presenting at a similar age to white patients, black individuals with Val122Ile associated ATTR-CA have a greater degree of cardiac remodeling which drives reduced overall chamber function. These findings suggest a more aggressive disease phenotype.