Flow inefficiencies in non-obstructive HCM revealed by kinetic energy and hemodynamic forces on 4D-flow CMR.

Aims: Patients with non-obstructive hypertrophic cardiomyopathy (HCM) exhibit myocardial changes which may cause flow inefficiencies not detectable on echocardiogram. We investigated whether left ventricular (LV) kinetic energy (KE) and hemodynamic forces (HDF) on 4D-flow cardiovascular magnetic resonance (CMR) can provide more sensitive measures of flow in non-obstructive HCM. Methods and results: Ninety participants (70 with non-obstructive HCM and 20 healthy controls) underwent 4D-flow CMR. Patients were categorized as phenotype positive (P+) based on maximum wall thickness (MWT) ≥ 15 mm or ≥13 mm for familial HCM, or pre-hypertrophic sarcomeric variant carriers (P-). LV KE and HDF were computed from 4D-flow CMR. Stroke work was computed using a previously validated non-invasive method. P+ and P- patients and controls had comparable diastolic velocities and LV outflow gradients on echocardiography, LV ejection fraction, and stroke volume on CMR. P+ patients had greater stroke work than P- patients, higher systolic KE compared with controls (5.8 vs. 4.1 mJ, P = 0.0009), and higher late diastolic KE relative to P- patients and controls (2.6 vs. 1.4 vs. 1.9 mJ, P < 0.0001, respectively). MWT was associated with systolic KE (r = 0.5, P < 0.0001) and diastolic KE (r = 0.4, P = 0.005), which also correlated with stroke work. Systolic HDF ratio was increased in P+ patients compared with controls (1.0 vs. 0.8, P = 0.03) and correlated with MWT (r = 0.3, P = 0.004). Diastolic HDF was similar between groups. Sarcomeric variant status was not associated with KE or HDF. Conclusion: Despite normal flow velocities on echocardiography, patients with non-obstructive HCM exhibited greater stroke work, systolic KE and HDF ratio, and late diastolic KE relative to controls. 4D-flow CMR provides more sensitive measures of haemodynamic inefficiencies in HCM, holding promise for clinical trials of novel therapies and clinical surveillance of non-obstructive HCM.

Local carotid stiffness, hemodynamic forces and blood viscosity in patients with cerebral lacunar infarctions.

OBJECTIVE: The carotid stiffness is an important factor in the pathogenesis of cerebrovascular small vessel disease. Our study aimed to evaluate the relation of the local arterial stiffness of the common carotid artery (CCA) to the hemodynamic forces and blood viscosity in patients with cerebral lacunar infarctions (LI). METHODS: Twenty-two patients with chronic LI and 15 age-matched controls were examined. An ultrasound examination of the CCA intima-media thickness (IMT), the parameters of local CCA stiffness: distensibility (DC) and compliance coefficients (CC), α and ß stiffness indices and pulse wave velocity (PWV) was performed. The local hemodynamic forces were calculated: circumferential wall tension (CWT) and wall shear stress (WSS). Whole blood viscosity (WBV) and shear stresses at shear rates of 0.277 s - 1 to 94.5 s - 1 were measured in patients and controls. RESULTS: Higher values of IMT, a significant decrease of DC and CC and an increase of α and ß stiffness indices and PWV in the LI patients compared to the controls were obtained. A parallel significant increase in CWT and a decrease in WSS was found. An increase in WBV and a significant increase in shear stresses were detected. In the LI patients, the increased stiffness indices were associated with an increase in age, cholesterol and WBV at higher shear rates in the left CCA. In the controls, the IMT and stiffness indices correlated significantly with the hemodynamic factors and WBV in both CCAs, while the stiffness indices correlated with the hemodynamic forces in the left CCA. CONCLUSION: The results of the present study demonstrate different associations of the local carotid stiffness indices with the hemodynamic forces and WBV in patients with LI and controls.

Echocardiography-Derived Hemodynamic Forces Are Associated with Clinical Outcomes in Patients with Non-Ischemic Dilated Cardiomyopathy.

Introduction: Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by a reduced left ventricular (LV) ejection fraction (LVEF, <50%) and a high risk for heart failure (HF) and death. Echocardiography-derived hemodynamic forces (HDFs) may provide important information on LV mechanics, but their prognostic value is unknown. Aim: To explore the features of echocardiography-derived HDFs in NIDCM and their association with clinical endpoints. Methods: Asymptomatic, non-hospitalized NIDCM patients free from coronary artery disease and moderate or severe valvular heart disease were included in this single-center observational retrospective longitudinal study. Those with atrial fibrillation and a follow-up <12 months were excluded. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause death, HF hospitalization, and ambulatory intravenous diuretics administration. LV HDFs were analyzed with a prototype software. Apex-base (HDFs-ab), lateral-septal (HDFs-ls), and HDFs-angle were computed. Results: Ninety-seven patients were included, sixty-seven (69%) were males, mean age was 62 ± 14 years, and mean LVEF was 39.2 ± 8.6%. During a median follow-up of 4.2 (3.1-5.1) years, 19 (20%) patients experienced MACE. These patients had a higher HDFs-angle (71.0 (67.0-75.0) vs. 68.0 (63.0-71.0)°, p = 0.005), lower HDFs-ls (1.36 (1.01-1.85) vs. 1.66 ([1.28-2.04])%, p = 0.015), but similar HDFs-ab (5.02 (4.39-6.34) vs. 5.66 (4.53-6.78)%, p = 0.375) compared to those without MACE. in a Cox regression analysis, HDFs-angle (HR 1.16 (95%-CI 1.04-1.30), p = 0.007) was associated with MACE, while other conventional echocardiography parameters, including LVEF and LV longitudinal strain, were not. Conclusions: HDFs-angle is associated with clinical endpoints in NIDCM. A higher HDFs-angle may be a marker of impaired myocardial performance in patients with reduced LVEF.

Impact of left ventricular hemodynamic forces in adult patients with treated aortic coarctation and preserved left ventricular systolic function.

BACKGROUND: The LV myocardial strain and hemodynamic forces (HDFs) are innovative markers of LV function. Aortic coarctation is safely repaired in infancy; however, mortality and morbidity remain increased in later life. The study investigated the role of left ventricular myocardial deformation and HDFs in asymptomatic patients who underwent successful aortic coarctation repair. METHODS: Clinical and echocardiographic data were analyzed from 42 repaired CoA, 32 ± 20 years after surgery, 2D echocardiographic global longitudinal strain (GLS), circumferential strain (GCS) and HDFs were determined. CoA patients were compared with 42 patients affected by blood hypertension and 84 healthy controls; all matched for age and gender. RESULTS: All groups had normal LV ejection fraction (LVEF), dimensions, and volumes. CoA patients showed a significantly higher rate of LV mass indexed (p < .001) and left atrial volumes indexed (p < .001). LV myocardial and endocardial global longitudinal and circumferential strain were decreased in CoA patients (p < .001, p < .001; p = .032 and p < .001, respectively). HDF parameters such as LV longitudinal force, LV systolic longitudinal force and LV impulse (LVim) were uniformly reduced (p = .006, p = .001, and p = .001, respectively). LV myocardial strain and HDF parameter values were independently associated with hospitalization for heart failure on univariable Cox regression analysis. CONCLUSION: Despite preserved LVEF, patients with CoA had lower LV myocardial strain and HDF parameters values, independently associated with hospitalization for heart failure.

Left ventricular remodeling in twin pregnancy, noninvasively assessed using hemodynamic forces and pressure-volume relation analysis: prospective, cohort study.

This study was designed to prospectively investigate the pattern of intraventricular hemodynamic forces (HDFs) associated with left ventricular (LV) function and remodeling in women with uncomplicated twin pregnancy. Transthoracic echocardiography was performed on 35 women (aged 35.9 ± 4.7-yr old) during gestation (T1, <14 wk; T2, 14-27 wk; T3, >28 wk) and 6-7 mo after delivery (T0). LV HDFs were computed from echocardiography long-axis data sets using a novel technique based on endocardial boundary tracking, both in apex-base (A-B) and latero-septal (L-S) directions. HDF distribution was evaluated by L-S over A-B HDF ratio (L-S:A-B HDF ratio). At T1, L-S:A-B HDF ratio was higher than in T0 (P < 0.05) indicating HDF misalignment. At T2, a slight impairment of cardiac function was then recorded with a reduction of global longitudinal strain (GLS) and left ventricular end-systolic elastance (Ees) at pressure-volume relationship analysis versus T1 (both P < 0.05). Finally, at T3, when HDF misalignment and LV contractility reduction (GLS and Ees) were all restored, a rightward shift of the end-diastolic pressure-volume relationship (EDPVR) with an increase of ventricular capacitance was documented. In twin pregnancy, HDF misalignment in the first trimester precedes the slight temporary decrease in left ventricular systolic function in the second trimester; at the third trimester, a rightward shift of the EDPVR was associated with a realignment of HDF and normalization of ventricular contractility indexes. These coordinated changes that occur in the maternal heart during twin pregnancy suggest the role of HDFs in cardiac remodeling.NEW & NOTEWORTHY These changes indicate that 1) the misalignment of hemodynamic forces (HDFs) precedes a mild reduction in systolic function in twin pregnancy and 2) the positive left ventricular (LV) response to hemodynamic stress is mainly due to an improved diastolic function with enhanced LV cavity compliance.

Cardiac imaging in athlete's heart: current status and future prospects.

BACKGROUND: Physical activity contributes to changes in cardiac morphology, which are known as "athlete's heart". Therefore, these modifications can be characterized using different imaging modalities such as echocardiography, including Doppler (flow Doppler and Doppler myocardial imaging) and speckle-tracking, along with cardiac magnetic resonance, and cardiac computed tomography. MAIN TEXT: Echocardiography is the most common method for assessing cardiac structure and function in athletes due to its availability, repeatability, versatility, and low cost. It allows the measurement of parameters like left ventricular wall thickness, cavity dimensions, and mass. Left ventricular myocardial strain can be measured by tissue Doppler (using the pulse wave Doppler principle) or speckle tracking echocardiography (using the two-dimensional grayscale B-mode images), which provide information on the deformation of the myocardium. Cardiac magnetic resonance provides a comprehensive evaluation of cardiac morphology and function with superior accuracy compared to echocardiography. With the addition of contrast agents, myocardial state can be characterized. Thus, it is particularly effective in differentiating an athlete's heart from pathological conditions, however, is less accessible and more expensive compared to other techniques. Coronary computed tomography is used to assess coronary artery anatomy and identify anomalies or diseases, but its use is limited due to radiation exposure and cost, making it less suitable for young athletes. A novel approach, hemodynamic forces analysis, uses feature tracking to quantify intraventricular pressure gradients responsible for blood flow. Hemodynamic forces analysis has the potential for studying blood flow within the heart and assessing cardiac function. CONCLUSIONS: In conclusion, each diagnostic technique has its own advantages and limitations for assessing cardiac adaptations in athletes. Examining and comparing the cardiac adaptations resulting from physical activity with the structural cardiac changes identified through different diagnostic modalities is a pivotal focus in the field of sports medicine.

Evolution of Echocardiography-Derived Hemodynamic Force Parameters After Cardiac Resynchronization Therapy.

Echocardiography-derived hemodynamic forces (HDF) allow calculation of intraventricular pressure gradients from routine transthoracic echocardiographic images. The evolution of HDF after cardiac resynchronization therapy (CRT) has not been investigated in large cohorts. The aim was to assess HDF in patients with heart failure implanted with CRT versus healthy controls. HDF were assessed before and 6 months after CRT. The following HDF parameters were calculated: (1) apical-basal strength, (2) lateral-septal strength, (3) the ratio of lateral-septal to apical-basal strength ratio, and (4) the force vector angle (1 and 2 representing the magnitude of HDF, 3 and 4 representing the orientation of HDF). In the propulsive phase of systole, the apical-basal impulse and the systolic force vector angle were measured. A total of 197 patients were included (age 64 ± 11 years, 62% male), with left ventricular ejection fraction ≤35%, QRS duration ≥130 ms and left bundle branch block. The magnitude of HDF was significantly lower and the orientation was significantly worse in patients with heart failure versus healthy controls. Immediately after CRT implantation, the apical-basal impulse and systolic force vector angle were significantly increased. Six months after CRT, improvement of apical-basal strength, lateral-septal to apical-basal strength ratio and the force vector angle occurred. When CRT was deactivated at 6 months, the increase in the magnitude of apical-basal HDF remained unchanged while the systolic force vector angle worsened significantly. In conclusion, HDF in CRT recipients reflect the acute effect of CRT and the effect of left ventricular reverse remodeling on intraventricular pressure gradients. Whether HDF analysis provides incremental value over established echocardiographic parameters, remains to be determined.

Acute Modification of Hemodynamic Forces in Patients with Severe Aortic Stenosis after Transcatheter Aortic Valve Implantation.

Transcatheter aortic valve implantation (TAVI) is the established first-line treatment for patient with severe aortic stenosis not suitable for surgery. Echocardiographic evaluation of hemodynamic forces (HDFs) is a growing field, holding the potential to early predict improvement in LV function. A prospective observational study was conducted. Transthoracic echocardiography was performed before and after TAVI. HDFs were analyzed along with traditional left ventricular (LV) function parameters. Twenty-five consecutive patients undergoing TAVI were enrolled: mean age 83 ± 5 years, 74.5% male, mean LV Ejection Fraction (LVEF) at baseline 57 ± 8%. Post-TAVI echocardiographic evaluation was performed 2.4 ± 1.06 days after the procedure. HDF amplitude parameters improved significantly after the procedure: LV Longitudinal Forces (LF) apex-base [mean difference (MD) 1.79%; 95% CI 1.07-2.5; p-value < 0.001]; LV systolic LF apex-base (MD 2.6%; 95% CI 1.57-3.7; p-value < 0.001); LV impulse (LVim) apex-base (MD 2.9%; 95% CI 1.48-4.3; p-value < 0.001). Similarly, HDFs orientation parameters improved: LVLF angle (MD 1.5°; 95% CI 0.07-2.9; p-value = 0.041); LVim angle (MD 2.16°; 95% CI 0.76-3.56; p-value = 0.004). Conversely, global longitudinal strain and LVEF did not show any significant difference before and after the procedure. Echocardiographic analysis of HDFs could help differentiate patients with LV function recovery after TAVI from patients with persistent hemodynamic dysfunction.

Introduction to hemodynamic forces by echocardiography.

Hemodynamic force (HDF) analysis represents a novel approach to quantify intraventricular pressure gradients, responsible for blood flow. A new mathematical model allows the derivation of HDF parameters from routine transthoracic echocardiography, making this tool more accessible for clinical use. HDF analysis is considered the fluid dynamics correlate of deformation imaging and may be even more sensitive to detect mechanical abnormalities. This has the potential to add incremental clinical value, allowing earlier detection of pathology or immediate evaluation of response to treatment. In this article, the theoretical background and physiological patterns of HDF in the left ventricle are provided. In pathological situations, the HDF pattern might alter, which is illustrated with a case of ST segment elevation myocardial infarction and non-ischemic cardiomyopathy with typical left bundle branch block.

Prognostic value of echocardiographic evaluation of cardiac mechanics in patients with aortic stenosis and preserved left ventricular ejection fraction.

Left ventricular ejection function (LVEF) is not reliable in identifying subtle systolic dysfunction. Speckle Tracking (ST) plays a promising role and hemodynamic forces (HDFs) are emerging as marker of LV function. The role of LV myocardial deformation and HDFs was investigated in a cohort of patients with aortic stenosis (AS) and normal LVEF. Two hundred fifty three patients (median age 79 years, IQR 73 - 83 years) with mild (n = 87), moderate (n =77) and severe AS (n =89) were retrospectively enrolled. 2D echocardiographic global longitudinal strain (GLS), circumferential strain (GCS) and HDFs were determined. The worsening of AS was associated with raising inappropriate LV mass (p < 0.001) and declined LVEF, despite being in the normal range (p < 0.001). ST and HDFs parameters declined as the AS became severe (p<0.0001, for all). When patients were grouped based on the median of LV endocardial GLS value (> -19,9%) and LV systolic longitudinal force (LVsysLF) value (< 12,49), patients with impaired ST and lower HDFs components had increased incidence of aortic valve replacement (AVR) and worse survival (p <0.024 and p <0.037, respectively). Among ST and HDFs parameters, only LVsysLF was independently associated with AVR and all causes mortality on multivariable Cox regression analysis (HR 0.94; 95% CI 0.89-0.99; p= 0.012). Reduced values of LVsysLF were associated with AVR and reduced survival in AS patients. LVsysLF could provide useful information in the stratification of patients with AS and possibly in the choice of timing for AVR.

Longitudinal CMR assessment of cardiac global longitudinal strain and hemodynamic forces in a mouse model of heart failure.

To longitudinally assess left ventricle (LV) global longitudinal strain (GLS) and hemodynamic forces during the early stages of cardiac dysfunction in a mouse model of heart failure with preserved ejection fraction (HFpEF). Cardiac MRI measurements were performed in control mice (n = 6), and db/db mice (n = 7), whereby animals were scanned four times between the age of 11-15 weeks. After the first scan, the db/db animals received a doxycycline intervention to accelerate progression of HFpEF. Systolic function was evaluated based on a series of prospectively ECG-triggered short-axis CINE images acquired from base to apex. Cardiac GLS and hemodynamic forces values were evaluated based on high frame rate retrospectively gated 2-, 3-, and 4-chamber long-axis CINE images. Ejection fraction (EF) was not different between control and db/db animals, despite that cardiac output, as well as end systolic and end diastolic volume were significantly higher in control animals. Whereas GLS parameters were not significantly different between groups, hemodynamic force root mean square (RMS) values, as well as average hemodynamic forces and the ratio between hemodynamic forces in the inferolateral-anteroseptal and apical-basal direction were lower in db/db mice compared to controls. More importantly, hemodynamic forces parameters showed a significant interaction effect between time and group. Our results indicated that hemodynamic forces parameters were the only functional outcome measure that showed distinct temporal differences between groups. As such, changes in hemodynamic forces reflect early alterations in cardiac function which can be of added value in (pre)clinical research on HFpEF.

Design and Verification of a Novel Perfusion Bioreactor to Evaluate the Performance of a Self-Expanding Stent for Peripheral Artery Applications.

Endovascular stenting presents a promising approach to treat peripheral artery stenosis. However, a significant proportion of patients require secondary interventions due to complications such as in-stent restenosis and late stent thrombosis. Clinical failure of stents is not only attributed to patient factors but also on endothelial cell (EC) injury response, stent deployment techniques, and stent design. Three-dimensional in vitro bioreactor systems provide a valuable testbed for endovascular device assessment in a controlled environment replicating hemodynamic flow conditions found in vivo. To date, very few studies have verified the design of bioreactors based on applied flow conditions and their impact on wall shear stress, which plays a key role in the development of vascular pathologies. In this study, we develop a computationally informed bioreactor capable of capturing responses of human umbilical vein endothelial cells seeded on silicone tubes subjected to hemodynamic flow conditions and deployment of a self-expanding nitinol stents. Verification of bioreactor design through computational fluid dynamics analysis confirmed the application of pulsatile flow with minimum oscillations. EC responses based on morphology, nitric oxide (NO) release, metabolic activity, and cell count on day 1 and day 4 verified the presence of hemodynamic flow conditions. For the first time, it is also demonstrated that the designed bioreactor is capable of capturing EC responses to stent deployment beyond a 24-hour period with this testbed. A temporal investigation of EC responses to stent implantation from day 1 to day 4 showed significantly lower metabolic activity, EC proliferation, no significant changes to NO levels and EC's aligning locally to edges of stent struts, and random orientation in between the struts. These EC responses were indicative of stent-induced disturbances to local hemodynamics and sustained EC injury response contributing to neointimal growth and development of in-stent restenosis. This study presents a novel computationally informed 3D in vitro testbed to evaluate stent performance in presence of hemodynamic flow conditions found in native peripheral arteries and could help to bridge the gap between the current capabilities of 2D in vitro cell culture models and expensive pre-clinical in vivo models.

Statistical shape modeling reveals the link between right ventricular shape, hemodynamic force, and myocardial function in patients with repaired tetralogy of Fallot.

Patients with repaired tetralogy of Fallot (rTOF) can develop chronic pulmonary insufficiency (PI) with right ventricular (RV) dilation, progressive RV dysfunction, and decreased exercise capacity. Pulmonary valve replacement (PVR) can help reduce the amount of PI and RV dilation; however, optimal timing remains controversial; a better understanding of rTOF pathophysiology is of fundamental importance to inform clinical management of patients with rTOF and optimal timing of PVR. In this study, we hypothesize a tight interplay between RV shape, intracardiac biomechanics, and ventricular function in patients with rTOF. To explore this hypothesis and derive quantitative measures, we combined statistical shape modeling with physics-based analysis of in vivo 4D flow data in 36 patients with rTOF. Our study demonstrated for the first time a correlation between regional RV shape variations, hemodynamic forces (HDF), and clinical dysfunction in patients with rTOF. The main findings of this work include 1) general increase in RV size, due to both volume overload and physiological growth, correlated with decrease in strain magnitude in the respective directions, and with increased QRS; 2) regional PI-induced remodeling accounted for ∼10% of the shape variability of the population, and was associated with increased diastolic HDF along the diaphragm-to-right ventricular outflow tract (RVOT) direction, resulting in a net RV deformation along the same direction and decreased tricuspid annular plane systolic excursion (TAPSE); and 3) three shape modes independently correlated with systolic HDF and exercise capacity. Identification of patients based on the shape variations described in this study could help identify those at risk for irreversible dysfunction and guide optimal timing of PVR.NEW & NOTEWORTHY We combine statistical shape modeling with physics-based analysis of 4D flow data to elucidate the interplay between RV shape, hemodynamic forces, and clinical dysfunction in repaired tetralogy of Fallot. We are the first to show that ventricular remodeling is related to hemodynamic force magnitude and direction, global and regional functional parameters, and exercise intolerance. Identification of patients based on the shape variations described in this study could help identify those at risk for irreversible dysfunction.

Cardiac and Vascular Remodeling After 6 Months of Therapy With Sacubitril/Valsartan: Mechanistic Insights From Advanced Echocardiographic Analysis.

Background: Effects of Sacubitril/Valsartan (S/V) on left ventricular (LV) mechanics and ventricular-arterial coupling in patients with heart failure with reduced ejection fraction (HFrEF) are not completely understood. The aim of this study was to evaluate both cardiac and vascular remodeling in a group of HFrEF patients undergoing S/V therapy. Methods: Fifty HFrEF patients eligible to start a therapy with S/V were enrolled. Echocardiographic evaluation was performed at baseline and after 6 months of follow-up (FU). Beside standard evaluation, including global longitudinal strain (GLS), estimated hemodynamic forces (HDFs) and non-invasive pressure-volume curves (PV loop) were assessed using dedicated softwares. HDFs were evaluated over the entire cardiac cycle, in systole and diastole, both in apex to base (A-B) and latero-septal (L-S) directions. The distribution of LV HDFs was evaluated by L-S over A-B HDFs ratio (L-S/A-B HDFs ratio). Parameters derived from estimated PV loop curves were left ventricular end-systolic elastance (Ees), arterial elastance (Ea), and ventricular-arterial coupling (VAC). Results: At 6 months of FU indexed left ventricular end-diastolic and end-systolic volumes decreased (EDVi: 101 ± 28 mL vs. 86 ± 30 mL, p < 0.001; ESVi: 72 ± 23 mL vs. 55 ± 24 mL, p < 0.001), ejection fraction and GLS significantly improved (EF: 29 ± 6% vs. 37 ± 7%, p < 0.001; GLS: -9 ± 3% vs. -13 ± 4%, p < 0.001). A reduction of Ea (2.11 ± 0.91 mmHg/mL vs. 1.72 ± 0.44 mmHg/mL, p = 0.008) and an improvement of Ees (1.01 ± 0.37 mmHg/mL vs. 1.35 ± 0.6 mmHg/mL, p < 0.001) and VAC (2.3 ± 1.1 vs. 1.5 ± 0.7, p < 0.001) were observed. Re-alignment of HDFs occurred, with a reduction of diastolic L-S/A-B HDFs ratio [23 (20-35)% vs. 20 (11-28) %, p < 0.001]. Conclusion: S/V therapy leads to a complex phenomenon of reverse remodeling involving increased myocardial contractility, HDFs distribution improvement, and afterload reduction.

Inward Rectifier Potassium Channels: Membrane Lipid-Dependent Mechanosensitive Gates in Brain Vascular Cells.

Cerebral arteries contain two primary and interacting cell types, smooth muscle (SMCs) and endothelial cells (ECs), which are each capable of sensing particular hemodynamic forces to set basal tone and brain perfusion. These biomechanical stimuli help confer tone within arterial networks upon which local neurovascular stimuli function. Tone development is intimately tied to arterial membrane potential (V M ) and changes in intracellular [Ca2+] driven by voltage-gated Ca2+ channels (VGCCs). Arterial V M is in turn set by the dynamic interplay among ion channel species, the strongly inward rectifying K+ (Kir) channel being of special interest. Kir2 channels possess a unique biophysical signature in that they strongly rectify, display negative slope conductance, respond to elevated extracellular K+ and are blocked by micromolar Ba2+. While functional Kir2 channels are expressed in both smooth muscle and endothelium, they lack classic regulatory control, thus are often viewed as a simple background conductance. Recent literature has provided new insight, with two membrane lipids, phosphatidylinositol 4,5-bisphosphate (PIP2) and cholesterol, noted to (1) stabilize Kir2 channels in a preferred open or closed state, respectively, and (2) confer, in association with the cytoskeleton, caveolin-1 (Cav1) and syntrophin, hemodynamic sensitivity. It is these aspects of vascular Kir2 channels that will be the primary focus of this review.

Comparison of Four-Dimensional Magnetic Resonance Imaging Analysis of Left Ventricular Fluid Dynamics and Energetics in Ischemic and Restrictive Cardiomyopathies.

BACKGROUND: Time-resolved three-directional velocity-encoded (4D flow) magnetic resonance imaging (MRI) enables the quantification of left ventricular (LV) intracavitary fluid dynamics and energetics, providing mechanistic insight into LV dysfunctions. Before becoming a support to diagnosis and patient stratification, this analysis should prove capable of discriminating between clearly different LV derangements. PURPOSE: To investigate the potential of 4D flow in identifying fluid dynamic and energetics derangements in ischemic and restrictive LV cardiomyopathies. STUDY TYPE: Prospective observational study. POPULATION: Ten patients with post-ischemic cardiomyopathy (ICM), 10 patients with cardiac light-chain cardiac amyloidosis (AL-CA), and 10 healthy controls were included. FIELD STRENGTH/SEQUENCE: 1.5 T/balanced steady-state free precession cine and 4D flow sequences. ASSESSMENT: Flow was divided into four components: direct flow (DF), retained inflow, delayed ejection flow, and residual volume (RV). Demographics, LV morphology, flow components, global and regional energetics (volume-normalized kinetic energy [KEV ] and viscous energy loss [ELV ]), and pressure-derived hemodynamic force (HDF) were compared between the three groups. STATISTICAL TESTS: Intergroup differences in flow components were tested by one-way analysis of variance (ANOVA); differences in energetic variables and peak HDF were tested by two-way ANOVA. A P-value of <0.05 was considered significant. RESULTS: ICM patients exhibited the following statistically significant alterations vs. controls: reduced KEV , mostly in the basal region, in systole (-44%) and in diastole (-37%); altered flow components, with reduced DF (-33%) and increased RV (+26%); and reduced basal-apical HDF component on average by 63% at peak systole. AL-CA patients exhibited the following alterations vs. controls: significantly reduced KEV at the E-wave peak in the basal segment (-34%); albeit nonstatistically significant, increased peaks and altered time-course of the HDF basal-apical component in diastole and slightly reduced HDF components in systole. DATA CONCLUSION: The analysis of multiple 4D flow-derived parameters highlighted fluid dynamic alterations associated with systolic and diastolic dysfunctions in ICM and AL-CA patients, respectively. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Reference Ranges of Left Ventricular Hemodynamic Forces in Healthy Adults: A Speckle-Tracking Echocardiographic Study.

BACKGROUND: The normal limits of left ventricular (LV) hemodynamic forces (HDFs) are not exactly known. The aim of this study was to explore the full spectrum of HDF parameters in healthy subjects and determine their physiologic correlates. METHODS: 269 healthy subjects were enrolled (mean age: 43 ± 14 years; 123 (45.7%) men). All participants underwent an echo-Doppler examination. Tri-plane tissue tracking from apical views was used to measure 2D global endocardial longitudinal strain (GLS), circumferential strain (GCS), and LV HDFs. HDFs were normalized with LV volume and divided by specific weight. RESULTS: LV systolic longitudinal HDFs (%) were higher in men (20.8 ± 6.5 vs. 18.9 ± 5.6, p = 0.009; 22.0 ± 6.7 vs. 19.8 ± 5.6, p = 0.004, respectively). There was a significant correlation between GCS (increased) (r = -0.240, p < 0.001) and LV longitudinal HDFs (reduced) (r = -0.155, p = 0.01) with age. In a multivariable analysis age, BSA, pulse pressure, heart rate and GCS were the only independent variables associated with LV HDFs (ß coefficient = -0.232, p < 0.001; 0.149, p = 0.003; 0.186, p < 0.001; 0.396, p < 0.001; -0.328, p < 0.001; respectively). CONCLUSION: We report on the physiologic range of LV HDFs. Knowledge of reference values of HDFs may prompt their implementation into clinical routine and allow a more comprehensive assessment of the LV function.

A Novel Approach to Left Ventricular Filling Pressure Assessment: The Role of Hemodynamic Forces Analysis.

Background: Diastolic function in patients with heart failure is usually impaired, resulting in increased left ventricular (LV) filling pressures, whose gold standard assessment is right heart catheterization (RHC). Hemodynamic force (HDF) analysis is a novel echocardiographic tool, providing an original approach to cardiac function assessment through the speckle-tracking technology. The aim of our study was to evaluate the use of HDFs, both alone and included in a new predictive model, as a potential novel diagnostic tool of the diastolic function. Methods: HDF analysis was retrospectively performed in 67 patients enrolled in the "Right1 study." All patients underwent RHC and echocardiography up to 2 h apart. Increased LV filling pressure (ILFP) was defined as pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg. Results: Out of 67 patients, 33 (49.2%) showed ILFP at RHC. Diastolic longitudinal force (DLF), the mean amplitude of longitudinal forces during diastole, was associated with the presence of ILFP (OR = 0.84 [0.70; 0.99], p = 0.046). The PCWP prediction score we built including DLF, ejection fraction, left atrial enlargement, and e' septal showed an AUC of 0.83 [0.76-0.89], with an optimal internal validation. When applied to our population, the score showed a sensitivity of 72.7% and a specificity of 85.3%, which became 66.7 and 94.4%, respectively, when applied to patients classified with "indeterminate diastolic function" according to the current recommendations. Conclusion: HDF analysis could be an additional useful tool in diastolic function assessment. A scoring system including HDFs might improve echocardiographic accuracy in estimating LV filling pressures. Further carefully designed studies could be useful to clarify the additional value of this new technology.

Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation.

(1) Background: Traumatic brain injury (TBI) frequently occurs worldwide, resulting in high morbidity and mortality. Here, we hypothesized that TBI impairs an autoregulatory mechanism, namely the flow-induced constriction of isolated rat middle cerebral arteries (MCAs). (2) Methods: TBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure-flow chamber. The internal diameter was measured by a video-microscopy. (3) Results: In MCAs from intact rats, increases in flow and pressure + flow elicited constrictions (-26 ± 1.9 µm and -52 ± 2.8 µm, p < 0.05), which were significantly reduced after TBI or in the presence of thromboxane-prostanoid (TP receptor) antagonist SQ 29,548. Flow-induced constrictions were significantly reduced by HET0016, inhibitor of cytochrome P450 4A (CYP450 4A). Arachidonic acid, (AA, 10-7 M), and CYP-450 4A metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) elicited constrictions of intact MCA (-26 ± 2.3% and -31 ± 3.6%), which were significantly reduced after TBI (to 11 ± 1.3% and -16 ±2.5%). The TP receptor agonist U46619 (10-7 M) elicited substantial constrictions of MCA from intact rats (-21 ± 3.3%), which were also significantly reduced, after TBI (to -16 ± 2.4%). (4) Conclusions: Flow-induced constrictor response of MCA is impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins and the mitigated sensitivity of thromboxane-prostanoid receptors.

A converging artery-sized model for shear adhesion mapping of particles.

Drug carriers for targeting cardiovascular diseases have been gaining a respectable attention, however, designing such carriers is challenging due to the biophysical complexity of the vascular system. Wall shear stress (WSS), exerted by blood flow on the endothelium surface, is a crucial factor in the circulatory system. WSS affects the adhesion and preferential accumulation of drug carriers. Here, we propose, an innovative approach to investigate particle adhesion in a converging artery-sized model, lined with human endothelial cells. Unlike widely used microfluidic and in vivo setups, our model enables to investigate particle accumulation in a continuous WSS range, performed in a single experiment, and at the right scale relevant for human arteries. First, we characterized the flow and the WSS map along the designed model, which can span along the entire arterial WSS range. We then used the model to examine the effect of particle size and the suspension buffer on particle adhesion distribution. The results demonstrated the role of particle size, where the same particles with a diameter of 2 µm exhibit shear-decreased adhesion while 500 nm particles exhibit shear-enhanced adhesion. Furthermore, under the same WSS, particles show a similar behavior when suspended in a Dextran buffer, having a viscosity analogous to blood, compared to a phosphate buffer solution without Dextran. Moreover, experiments with RBCs in the phosphate buffer, at a 40% physiological hematocrit, decreased particle adhesion and affected their deposition pattern. Altogether, our study suggests an original platform for investigating and optimizing intravascular drug carriers and their targeting properties.