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Funding agencies: This study was partially financed through ALF Grants, Region Ostergotland LIO-284291, LIO-284411, and LIO-448281, and LIU Cancer Projects Grants 2012.

Significant mitral valve regurgitation creates progressive adverse remodeling of the left ventricle (LV). Replacement of the failing valve with a prosthesis generally improves patient outcomes but leaves the patient with non-physiological intracardiac flow patterns that might contribute to their future risk of thrombus formation and embolism. It has been suggested that the angular orientation of the implanted valve might modify the postoperative distortion of the intraventricular flow field. In this study, we investigated the effect of prosthetic valve orientation on LV flow patterns by using heart geometry from a patient with LV dysfunction and a competent native mitral valve to calculate intracardiac flow fields with computational fluid dynamics (CFD). Results were validated using in vivo 4D Flow MRI. The computed flow fields were compared to calculations following virtual implantation of a mechanical heart valve oriented in four different angles to assess the effect of leaflet position. Flow patterns were visualized in longand short-axes and quantified with flow component analysis. In comparison to a native valve, valve implantation increased the proportion of the mitral inflow remaining in the basal region and further increased the residual volume in the apical area. Only slight changes due to valve orientation were observed. Using our numerical framework, we demonstrated quantitative changes in left ventricular blood flow due to prosthetic mitral replacement. This framework may be used to improve design of prosthetic heart valves and implantation procedures to minimize the potential for apical flow stasis, and potentially assist personalized treatment planning. (c) 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funding Agencies|Knut and Alice Wallenberg Foundation through the project Seeing Organ Function; Swedish Heart Lung FoundationSwedish Heart-Lung Foundation; VinnovaVinnova; Swedish Research CouncilSwedish Research CouncilEuropean Commission; County Council of Ostergotland

4D Flow MRI has been used to quantify normal and deranged left ventricular blood flow characteristics on the basis of functionally distinct flow components. However, the application of this technique to the atria is challenging due to the presence of continuous inflow. This continuous inflow necessitates plane-based emission of particle traces from the inlet veins, leading to particles that represents different amounts of blood, and related quantification errors. The purpose of this study was to develop a novel fixed-volume approach for particle tracing and employ this method to develop quantitative analysis of 4D blood flow characteristics in the left atrium. 4D Flow MRI data were acquired during free-breathing using a navigator-gated gradient-echo sequence in three volunteers at 1.5 T. Fixed-volume particle traces emitted from the pulmonary veins were used to visualize left atrial blood flow and to quantitatively separate the flow into two functionally distinct flow components: Direct flow = particle traces that enter and leave the atrium in one heartbeat, Retained flow = particle traces that enter the atrium and remains there for one cardiac cycle. Flow visualization based on fixed-volume traces revealed that, beginning in early ventricular systole, flow enters the atrium and engages with residual blood volume to form a vortex. In early diastole during early ventricular filling, the organized vortical flow is extinguished, followed by formation of a second transient atrial vortex. Finally, in late diastole during atrial contraction, a second acceleration of blood into the ventricle is seen. The direct and retained left atrial flow components were between 44 and 57% and 43–56% of the stroke volume, respectively. In conclusion, fixed-volume particle tracing permits separation of left atrial blood flow into different components based on the transit of blood through the atrium.

Aims: 4D flow magnetic resonance imaging (MRI) allows quantitative assessment of left ventricular (LV) function according to characteristics of the dynamic flow in the chamber. Marked abnormalities in flow components volume and kinetic energy (KE) have previously been demonstrated in moderately dilated and depressed LVs compared to healthy subjects. We hypothesized that these 4D flow-based measures would detect even subtle LV dysfunction and remodeling. Methods and Results: We acquired 4D flow and morphological MRI data from 26 patients with chronic ischemic heart disease with New York Heart Association (NYHA) class I and II and with no to mild LV systolic dysfunction and remodeling, and from 10 healthy controls. A previously validated method was used to separate the LV end-diastolic volume (LVEDV) into functional components: direct flow, which passes directly to ejection, and non-ejecting flow, which remains in the LV for at least 1 cycle. The direct flow and non-ejecting flow proportions of end-diastolic volume and KE were assessed. The proportions of direct flow volume and KE fell with increasing LVEDV-index (LVEDVI) and LVESV-index (LVESVI) (direct flow volume r = -0.64 and r = -0.74, both Pamp;lt;0.001; direct flow KE r = -0.48, P = 0.013, and r = -0.56, P = 0.003). The proportions of non-ejecting flow volume and KE rose with increasing LVEDVI and LVESVI (non-ejecting flow volume: r = 0.67 and r = 0.76, both Pamp;lt;0.001; non-ejecting flow KE: r = 0.53, P = 0.005 and r = 0.52, P = 0.006). The proportion of direct flow volume correlated moderately to LVEF (r = 0.68, P amp;lt; 0.001) and was higher in a sub-group of patients with LVEDVI amp;gt; 74 ml/m(2) compared to patients with LVEDVI amp;lt; 74 ml/m(2) and controls (both Pamp;lt;0.05). Conclusion: Direct flow volume and KE proportions diminish with increased LV volumes, while non-ejecting flow proportions increase. A decrease in direct flow volume and KE at end-diastole proposes that alterations in these novel 4D flow-specific markers may detect LV dysfunction even in subtle or subclinical LV remodeling. Funding Agencies|Swedish Heart Lung foundation [20140398]; Swedish Research Council [2014-6191]; European Union FP7 [223615]; Medical Research Council of Southeast Sweden [FORSS-35141, FORSS-88731, FORSS-157921]; County Council of Ostergotland/Heart and Medicine Center [20090120]

Author(s): Lange, David C; Glidden, David; Secemsky, Eric A; Ordovas, Karen; Deeks, Steven G; Martin, Jeffrey N; Bolger, Ann F; Hsue, Priscilla Y | Abstract: BackgroundHIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals.Methods and resultsWe studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell's C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p l 0.05 for all).ConclusionIn HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death.

Purpose: To assess the spatial heterogeneity of the four-dimensional (4D) relative pressure fields in the healthy human left ventricle (LV) and provide reference data for normal LV relative pressure. Methods: Twelve healthy subjects underwent a cardiac MRI examination where 4D flow and morphological data were acquired. The latter data were segmented and used to define the borders of the LV for computation of relative pressure fields using the pressure Poisson equation. The LV lumen was divided into 17 pie-shaped segments. Results: In the normal left ventricle, the relative pressure in the apical segments was significantly higher relative to the basal segments (P < 0.0005) along both the anteroseptal and inferolateral sides after the peaks of early (E-wave) and late (A-wave) diastolic filling. The basal anteroseptal segment showed significantly lower median pressure than the opposite basal inferolateral segment during both E-wave (P < 0.0005) and A-wave (P = 0.0024). Conclusion: Relative pressure in the left ventricle is heterogeneous. During diastole, the main pressure differences in the LV occur along the basal-apical axis. However, pressure differences were also found in the short axis direction and may reflect important aspects of atrioventricular coupling. Additionally, this study provides reference data on LV pressure dynamics for a group of healthy subjects. (C) 2014 Wiley Periodicals, Inc. Funding Agencies|Swedish Research Council [621-2011-5204]; Swedish Heart and Lung foundation [hlf 2010/273-31]; Emil and Vera Cornell Foundation; European Research Council [HEART4FLOW, 310612]

Aims : Patients with mild heart failure (HF) who are clinically compensated may have normal left ventricular (LV) stroke volume (SV). Despite this, altered intra-ventricular flow patterns have been recognized in these subjects. We hypothesized that, compared with normal LVs, flow in myopathic LVs would demonstrate a smaller proportion of inflow volume passing directly to ejection and diminished the end-diastolic preservation of the inflow kinetic energy (KE). Methods and results : In 10 patients with dilated cardiomyopathy (DCM) (49 ± 14 years, six females) and 10 healthy subjects (44 ± 17 years, four females), four-dimensional MRI velocity and morphological data were acquired. A previously validated method was used to separate the LV end-diastolic volume (EDV) into four flow components based on the blood's locations at the beginning and end of the cardiac cycle. KE was calculated over the cardiac cycle for each component. The EDV was larger (P = 0.021) and the ejection fraction smaller (P < 0.001) in DCM compared with healthy subjects; the SV was equivalent (DCM: 77 ± 19, healthy: 79 ± 16 mL). The proportion of the total LV inflow that passed directly to ejection was smaller in DCM (P = 0.000), but the end-diastolic KE/mL of the direct flow was not different in the two groups (NS). Conclusion : Despite equivalent LVSVs, HF patients with mild LV remodelling demonstrate altered diastolic flow routes through the LV and impaired preservation of inflow KE at pre-systole compared with healthy subjects. These unique flow-specific changes in the flow route and energetics are detectable despite clinical compensation, and may prove useful as subclinical markers of LV dysfunction.

Background Blood flow within the cardiovascular system is driven by pressure differences, where blood accelerates from higher to lower pressure areas. Invasive methods of pressure measurement, which are commonly applied to assessment of diastolic function, may not capture the heterogeneity of regional intracardiac pressure differences. We utilized pressure fields based on time-resolved 3D CMR data to investigate the timing and distribution of intracardiac pressure gradients in the left heart throughout diastole.

Background Turbulent blood flow is a cause of energy loss in the cardiovascular system, and can thus be seen as a measure of flow inefficiency. Novel 4D flow CMR methods permit estimation of intracardiac turbulent kinetic energy (TKE). On the basis of the Reynolds number, one might expect that larger left ventricular (LV) size would promote higher TKE values, and thus lower flow efficiency. In this study, we hypothesized that the TKE of diastolic inflow would be larger in the dilated LVs of heart failure patients compared to normal LVs.

Results The LV ED diameter was larger and LV ejection fraction was smaller in DCM compared to H (61±6 vs 46±4 mm, and 42±5 vs 61±3 %, respectively, both p

Background Right ventricular (RV) function has important prognostic value in both rightand left-sided acquired and congenital heart diseases (1). Assessment of RV function is challenging because of its complex crescent shaped geometry and load conditions being significantly influenced by respiration. Incremental insights into RV blood flow patterns have the potential to add to our understanding of RV function (2), but remain incompletely characterized.

Background: The beating heart is the generator of blood flow through the cardiovascular system. Within the hearts own chambers, normal complex blood flow patterns can be disturbed by diseases. Methods for the quantification of intra-cardiac blood flow, with its 4D (3D+time) nature, are lacking. We sought to develop and validate a novel semi-automatic analysis approach that integrates flow and morphological data. Method: In six healthy subjects and three patients with dilated cardiomyopathy, three-directional, three-dimensional cine phase-contrast cardiovascular magnetic resonance (CMR) velocity data and balanced steady-state free-precession long- and short-axis images were acquired. The LV endocardium was segmented from the short-axis images at the times of isovolumetric contraction (IVC) and isovolumetric relaxation (IVR). At the time of IVC, pathlines were emitted from the IVC LV blood volume and traced forwards and backwards in time until IVR, thus including the entire cardiac cycle. The IVR volume was used to determine if and where the pathlines left the LV. This information was used to automatically separate the pathlines into four different components of flow: Direct Flow, Retained Inflow, Delayed Ejection Flow and Residual Volume. Blood volumes were calculated for every component by multiplying the number of pathlines with the blood volume represented by each pathline. The accuracy and inter- and intra-observer reproducibility of the approach were evaluated by analyzing volumes of LV inflow and outflow, the four flow components, and the end-diastolic volume. Results: The volume and distribution of the LV flow components were determined in all subjects. The calculated LV outflow volumes [ml] (67 +/- 13) appeared to fall in between those obtained by through-plane phase-contrast CMR (77 +/- 16) and Doppler ultrasound (58 +/- 10), respectively. Calculated volumes of LV inflow (68 +/- 11) and outflow (67 +/- 13) were well matched (NS). Low inter- and intra-observer variability for the assessment of the volumes of the flow components was obtained. Conclusions: This semi-automatic analysis approach for the quantification of 4D blood flow resulted in accurate LV inflow and outflow volumes and a high reproducibility for the assessment of LV flow components. The original article is: Jonatan Eriksson, Carljohan Carlhäll, Petter Dyverfeldt, Jan Engvall, Ann F Bolger and Tino Ebbers, Semi-automatic quantification of 4D left ventricular blood flow, 2010, JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE, (12), 9. http://dx.doi.org/10.1186/1532-429X-12-9

Purpose To evaluate the feasibility of generalized phase-contrast magnetic resonance imaging (PC-MRI) for the noninvasive assessment of fluctuating velocities in cardiovascular blood flow. Materials and Methods Multidimensional PC-MRI was used in a generalized manner to map mean flow velocities and intravoxel velocity standard deviation (IVSD) values in one healthy aorta and in three patients with different cardiovascular diseases. The acquired data were used to assess the kinetic energy of both the mean (MKE) and the fluctuating (TKE) velocity field. Results In all of the subjects, both mean and fluctuating flow data were successfully acquired. The highest TKE values in the patients were found at sites characterized by abnormal flow conditions. No regional increase in TKE was found in the normal aorta. Conclusion PC-MRI IVSD mapping is able to detect flow abnormalities in a variety of human cardiovascular conditions and shows promise for the quantitative assessment of turbulence. This approach may assist in clarifying the role of disturbed hemodynamics in cardiovascular diseases.

The purpose of this science advisory is to summarize the currently available data concerning thiazolidinediones and cardiovascular risk, with a focus on ischemic heart disease (IHD) events, and to provide practical recommendations to healthcare workers seeking to minimize the burden of cardiovascular disease (CVD) and other complications in their patients with type 2 diabetes mellitus. On May 21, 2007, the US Food and Drug Administration (FDA) released a safety alert concerning a possible increased risk of ischemic cardiovascular events in patients prescribed the thiazolidinedione rosiglitazone. This safety alert was prompted by the results of a large meta-analysis that reported that treatment with rosiglitazone resulted in a 43% increase in risk for myocardial infarction (MI) and a possible increase in risk for cardiovascular death.1 These data were particularly alarming because the metabolic effects of thiazolidinediones were widely presumed, although not proven, to reduce the risk for IHD. Subsequently, a number of additional reports using alternative meta-analytic techniques,2,3 new meta-analyses,4–10 recently published results of new clinical trials,11–15 and observational studies of both rosiglitazone and pioglitazone16–24 have provided variable evidence regarding an adverse cardiovascular effect of these agents. On November 14, 2007, after a specially convened FDA Advisory Panel meeting on July 30, 2007, the FDA decided not to withdraw rosiglitazone from the market. They issued new prescribing information that included a new boxed warning regarding the potential risk for myocardial ischemia, particularly in patients with heart disease taking nitrates, and in patients for whom rosiglitazone was added to established insulin therapy.25 Diabetes mellitus is increasing in prevalence in the United States and worldwide. An estimated 23.6 million people in the United States, 7.8% of the population, had diabetes in 2007, with more than 90% of cases being type 2 diabetes mellitus. Diabetes increases the risk of …

Objectives: The purpose of this study was to explore whether geometric changes that predispose to left ventricular outflow tract obstruction after mitral ring annuloplasty are coupled to subvalvular apparatus disturbances. Methods: Radiopaque markers were implanted in sheep: 9 in the ventricle, 1 in the high interventricular septum, 1 on each papillary muscle tip, 8 around the mitral anulus, 4 on the anterior mitral leaflet, and 2 on the posterior leaflet. One group served as control (n = 5); the others were randomized to undergo annuloplasty with the Duran ring (n = 6; Medtronic, Inc, Minneapolis, Minn) or Carpentier-Edwards Physio ring (n = 6; Baxter Healthcare Corp, Irvine, Calif). After a 7- to 10-day recovery period, 3-dimensional marker coordinates were measured with biplane videofluoroscopy. Results: At the beginning of ejection, (1) the anterior leaflet was displaced toward the left ventricular outflow tract; (2) the normal atrially flexed anterior anulus was flattened into the left ventricular outflow tract; (3) the posterior anulus was displaced toward the left ventricular outflow tract; (4) the anterior papillary muscle was displaced septally; and (5) the posterior papillary muscle was dislocated inwardly toward the anterior papillary muscle in the Physio ring group compared with the control group. During ejection, all these structures moved septally, encroaching further on the left ventricular outflow tract. In the Duran ring group, only the posterior anulus was displaced toward the left ventricular outflow tract; the anterior leaflet was not displaced toward the left ventricular outflow tract, and it did not move septally during ejection. Conclusions: The semirigid Physio ring was associated with perturbations in annular dynamics that caused changes in papillary muscle geometry. We propose an integrated valvular–subvalvular mechanism to explain displacement of the anterior leaflet into the left ventricular outflow tract after mitral ring annuloplasty. (J Thorac Cardiovasc Surg 1999;117:472-80)

Method Seven dilated cardiomyopathy (DCM) patients (4 female, aged 52 ± 14 years, ejection fraction 43 ± 5% [mean ± SD]) and six healthy subjects (3 female, aged 58 ± 4 years) were studied. 4D velocity data and morphological b-SSFP images were acquired on a 1.5 T MRI-scanner (Philips Achieva). The LV endocardium was segmented (http:// segment.heiberg.se) from the short axis images at the times of isovolumetric contraction (IVC) and isovolumetric relaxation (IVR). Pathlines were emitted from the IVC LV blood volume and traced forward and backward in time until IVR, thus including the entire cardiac cycle. The IVR volume was used to determine if and where the traces left the LV. This information was used to automatically separate inflow pathlines into two components [1]: direct flow that enters and leaves the LV within the same cardiac cycle, and retained inflow that does not leave the LV within a single cardiac cycle. By knowing the volume occupied by each trace, its velocity and the density of blood, the change in KE was calculated from the time of the traces' entrance into the LV (by crossing a plane at the mitral annulus) until the time of IVC. from 13th Annual SCMR Scientific Sessions Phoenix, AZ, USA. 21-24 January 2010

Summary Although total left ventricular (LV) stroke volume (SV) is equal in healthy subjects and heart failure patients with mild LV remodeling, the SV’s transventricular flow paths to ejection and diastolic energetics are different. These flow-specific markers of inefficiency of the failing heart are detectable prior to clinical decompensation, and might be predictors of progressive adverse cardiac remodeling. Background Heart failure is a common disorder with a dismal prognosis. Cardiac remodeling is a key component of heart failure that progresses from adaptive to maladaptive as the disease worsens, and is associated with increased risks of symptoms and mortality. In earlier stages of heart failure with adaptive remodeling, patients may remain clinically compensated and the failing heart’ sl eft ventricular (LV) stroke volume (SV) remains the same as in the normal heart. Recently, time-varying and complex three-dimensional flow patterns and energetics within the normal LV have been demonstrated. Based on such 4D flow-specific measures, we hypothesized that while the SV of normal and failing LVs may be equal, the SV’s diastolic kinetic energy (KE) and transventricular routes to ejection are different in the two states. Methods In ten patients with dilated cardiomyopathy (DCM) (6 females, 49±14 years [mean±SD]) and ten healthy subjects (4 female, 44±17 years), 4D phase-contrast CMR velocity data and morphological data were acquired at 1.5T (Philips Achieva). A previously validated method was used for the analysis: The LV endocardium was segmented from the morphological images at end-diastole (ED) and end-systole. Pathlines were emitted from the ED blood volume and traced forward and backward in time until end-systole, allowing separation of the Total SV into two flow components (figure 1): 1) Blood that enters and leaves the LV during the analyzed cardiac cycle (Direct SV), and 2) Blood that leaves but does not enter the LV during the analyzed cardiac cycle (Delayed SV). The KE was calculated over the cardiac cycle for these flow components based on the volume occupied by each pathline, its velocity, and blood density. Results The LV ED volume was larger and LV ejection fraction was smaller in DCM compared to healthy (179±33 vs 147±22 ml, p=0.021, and 42±5 vs 54±6 %, p

Background Left bundle branch block (LBBB) leads to dyssynchronous left ventricular (LV) contraction and relaxation which may contribute to LV dysfunction and ultimately heart failure. LBBB-related mechanical dyssynchrony often responds to cardiac resynchronization therapy (CRT). However, this therapy is expensive and the number of non-responders remains significant. Reliable functional markers of dyssynchronous LV pumping that can predict response to CRT have proved elusive. Almost all studies of LV mechanical dyssynchrony focus on wall motion properties rather than aspects of intraventricular flow. 4D flow CMR specific measures have recently emerged as markers of LV function in failing hearts. Reduced volume and kinetic energy (KE) of the portion of LV inflow which passes directly to outflow (Direct Flow) has been demonstrated in failing LVs compared to normal LVs. In this study we hypothesized that the volume and KE of Direct Flow would be further reduced in myopathic LVs with LBBB compared to similarly dysfunctional and remodeled LVs without LBBB.