J. Tim Marcus

Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

OBJECTIVES The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. BACKGROUND Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. METHODS A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. RESULTS Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. CONCLUSIONS After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Interventricular Mechanical Asynchrony in Pulmonary Arterial Hypertension Left-to-Right Delay in Peak Shortening Is Related to Right Ventricular Overload and Left Ventricular Underfilling

OBJECTIVES The purpose of this study was to explore in pulmonary arterial hypertension (PAH) whether the cause of interventricular asynchrony lies in onset of shortening or duration of shortening. BACKGROUND In PAH, leftward ventricular septal bowing (LVSB) is probably caused by a left-to-right (L-R) delay in myocardial shortening. METHODS In 21 PAH patients (mean pulmonary arterial pressure 55 +/- 13 mm Hg and electrocardiogram-QRS width 100 +/- 16 ms), magnetic resonance imaging myocardial tagging (14 ms temporal resolution) was applied. For the left ventricular (LV) free wall, septum, and right ventricular (RV) free wall, the onset time (T(onset)) and peak time (T(peak)) of circumferential shortening were calculated. The RV wall tension was estimated by the Laplace law. RESULTS The T(onset) was 51 +/- 23 ms, 65 +/- 4 ms, and 52 +/- 22 ms for LV, septum, and RV, respectively. The T(peak) was 293 +/- 58 ms, 267 +/- 22 ms, and 387 +/- 50 ms for LV, septum, and RV, respectively. Maximum LVSB was at 395 +/- 45 ms, coinciding with septal overstretch and RV T(peak). The L-R delay in T(onset) was -1 +/- 16 ms (p = 0.84), and the L-R delay in T(peak) was 94 +/- 41 ms (p < 0.001). The L-R delay in T(peak) was not related to the QRS width but was associated with RV wall tension (p < 0.05). The L-R delay in T(peak) correlated with leftward septal curvature (p < 0.05) and correlated negatively with LV end-diastolic volume (p < 0.05) and stroke volume (p < 0.05). CONCLUSIONS In PAH, the L-R delay in myocardial peak shortening is caused by lengthening of the duration of RV shortening. This L-R delay is related to LVSB, decreased LV filling, and decreased stroke volume.

Quantification of regional contractile function after infarction: strain analysis superior to wall thickening analysis in discriminating infarct from remote myocardium

OBJECTIVES Using two-dimensional wall thickening (WT) (expressed as percentage) and strain analysis, regional contractile myocardial function was quantified and compared in 13 control subjects and 13 patients with a first myocardial infarction (MI). The findings in the patient group were related to global ventricular function and infarct size. BACKGROUND In patients with coronary artery disease, regions with dysfunctional myocardium cannot be differentiated easily from regions with normal function by planar WT analysis. Physiologic factors, in combination with limitations of conventional imaging techniques, affect the calculation of WT. Quantitative assessment of contractile function by magnetic resonance (MR) tissue tagging and strain analysis may be less affected by these factors. METHODS Two-dimensional regional WT and strain were calculated in three short-axis MR cine and tagged images, respectively. Left ventricular volumes and ejection fraction (EF) were obtained from a series of contiguous short-axis cine images. RESULTS In patients with infarct-related ventricles, WT and strain analysis both revealed reduced myocardial function, as compared with control subjects (p < 0.005 and p < 0.001, respectively). However, WT analysis yielded no significant regional differences in function between infarct-related and remote myocardium (p = 0.064), whereas strain analysis did (p < 0.005). For detecting dysfunctional myocardium of electrocardiographically and angiographically defined infarct areas, WT analysis had a sensitivity of 69% and a specificity of 92%, whereas strain analysis demonstrated a sensitivity of 92% and a specificity of 99%. The EF correlated with WT (r = 0.76, p < 0.005) and strain (r = 0.89, p < 0.001). CONCLUSIONS Two-dimensional strain analysis is more accurate than planar WT analysis in discriminating dysfunctional from functional myocardium, and it provides a strong correlation between regional myocardial and global ventricular function.

Right Ventricular Diastolic Impairment in Patients With Pulmonary Arterial Hypertension

Background— The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients. Methods and Results— Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean±SEM. RV diastolic stiffness (&bgr;) was significantly increased in PAH patients (PAH, 0.050±0.005 versus control, 0.029±0.003; P<0.05) and was closely associated with disease severity. Subsequently, we searched for possible underlying mechanisms using RV tissue of PAH patients undergoing heart/lung transplantation and nonfailing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH, 453±31 &mgr;m2 versus control, 218±21 &mgr;m2; P<0.001), indicating RV hypertrophy. In addition, the amount of RV fibrosis was enhanced in PAH tissue (PAH, 9.6±0.7% versus control, 7.2±0.6%; P<0.01). To investigate the contribution of stiffening of the sarcomere (the contractile apparatus of RV cardiomyocytes) to RV diastolic stiffness, we isolated and membrane-permeabilized single RV cardiomyocytes. Passive tension at different sarcomere lengths was significantly higher in PAH patients compared with control subjects (>200%; Pinteraction<0.001), indicating stiffening of RV sarcomeres. An important regulator of sarcomeric stiffening is the sarcomeric protein titin. Therefore, we investigated titin isoform composition and phosphorylation. No alterations were observed in titin isoform composition (N2BA/N2B ratio: PAH, 0.78±0.07 versus control, 0.91±0.08), but titin phosphorylation in RV tissue of PAH patients was significantly reduced (PAH, 0.16±0.01 arbitrary units versus control, 0.20±0.01 arbitrary units; P<0.05). Conclusions— RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres.

A comparison of noninvasive MRI-based methods of estimating pulmonary artery pressure in pulmonary hypertension.

To assess the accuracy of several noninvasive MRI‐based estimators of pulmonary artery pressure by comparing them with invasive pressure measurement.

Right ventricular ejection fraction is better reflected by transverse rather than longitudinal wall motion in pulmonary hypertension

BackgroundLongitudinal wall motion of the right ventricle (RV), generally quantified as tricuspid annular systolic excursion (TAPSE), has been well studied in pulmonary hypertension (PH). In contrast, transverse wall motion has been examined less. Therefore, the aim of this study was to evaluate regional RV transverse wall motion in PH, and its relation to global RV pump function, quantified as RV ejection fraction (RVEF).MethodsIn 101 PH patients and 29 control subjects cardiovascular magnetic resonance was performed. From four-chamber cine imaging, RV transverse motion was quantified as the change of the septum-free-wall (SF) distance between end-diastole and end-systole at seven levels along an apex-to-base axis. For each level, regional absolute and fractional transverse distance change (SFD and fractional-SFD) were computed and related to RVEF. Longitudinal measures, including TAPSE and fractional tricuspid-annulus-apex distance change (fractional-TAAD) were evaluated for comparison.ResultsTransverse wall motion was significantly reduced at all levels compared to control subjects (p < 0.001). For all levels, fractional-SFD and SFD were related to RVEF, with the strongest relation at mid RV (R2 = 0.70, p < 0.001 and R2 = 0.62, p < 0.001). For TAPSE and fractional-TAAD, weaker relations with RVEF were found (R2 = 0.21, p < 0.001 and R2 = 0.27, p < 0.001).ConclusionsRegional transverse wall movements provide important information of RV function in PH. Compared to longitudinal motion, transverse motion at mid RV reveals a significantly stronger relationship with RVEF and thereby might be a better predictor for RV function.

Progressive Changes in Right Ventricular Geometric Shortening and Long-term Survival in Pulmonary Arterial Hypertension

BACKGROUND Until now, many investigators have focused on describing right ventricular (RV) dysfunction in groups of patients with pulmonary arterial hypertension (PAH), but very few have addressed the deterioration of RV function over time. The aim of this study was to investigate time courses of RV geometric changes during the progression of RV failure. METHODS Forty-two patients with PAH were selected who underwent right-sided heart catheterization and cardiac MRI at baseline and after 1-year follow-up. Based on the survival after this 1-year run-in period, patients were classified into two groups: survivors (26 patients; subsequent survival of > 4 years) and nonsurvivors (16 patients; subsequent survival of < 4 years). Four-chamber cine imaging was used to quantify RV longitudinal shortening (apex-base distance change), RV transverse shortening (septum-free wall distance change), and RV fractional area change (RVFAC) between end diastole and end systole. RESULTS Longitudinal shortening, transverse shortening, and RVFAC measured at the beginning of the run-in period and 1 year later were significantly higher in subsequent survivors than in nonsurvivors (P < .05). Longitudinal shortening did not change during the run-in period in either patient group. Transverse shortening and RVFAC did not change during the run-in period in subsequent survivors but did decrease in subsequent nonsurvivors (P < .05). This decrease was caused by increased leftward septal bowing. CONCLUSIONS Progressive RV failure in PAH is associated with a parallel decline in longitudinal and transverse shortening until a floor effect is reached for longitudinal shortening. A further reduction of RV function is due to progressive leftward septal displacement. Because transverse shortening incorporates both free wall and septum movements, this parameter can be used to monitor the decline in RV function in end-stage PAH.

Steady-state free precession with myocardial tagging: CSPAMM in a single breathhold

A method is presented that combines steady‐state free precession (SSFP) cine imaging with myocardial tagging. Before the tagging preparation at each ECG‐R wave, the steady‐state magnetization is stored as longitudinal magnetization by an α/2 flip‐back pulse. Imaging is continued immediately after tagging preparation, using linearly increasing startup angles (LISA) with a rampup over 10 pulses. Interleaved segmented k‐space ordering is used to prevent artifacts from the increasing signal during the LISA rampup. First, this LISA‐SSFP method was evaluated regarding ghost artifacts from the steady‐state interruption by comparing LISA with an α/2 startup method. Next, LISA‐SSFP was compared with spoiled gradient echo (SGRE) imaging, regarding tag contrast‐to‐noise ratio and tag persistence. The measurements were performed in phantoms and in six subjects applying breathhold cine imaging with tagging (temporal resolution 51 ms). The results show that ghost artifacts are negligible for the LISA method. Compared to the SGRE reference, LISA‐SSFP was two times faster, with a slightly better tag contrast‐to‐noise. Additionally, the tags persisted 126 ms longer with LISA‐SSFP than with SGRE imaging. The high efficiency of LISA‐SSFP enables the acquisition of complementary tagged (CSPAMM) images in a single breathhold. Magn Reson Med 49:722–730, 2003.

Improved harmonic phase myocardial strain maps

Magnetic resonance tagging has proven a valuable tool in the quantification of myocardial deformation. However, time‐consuming postprocessing has discouraged the use of this technique in clinical routine. Recently, the harmonic phase (HARP) technique was introduced for automatic calculation of myocardial strain maps from tagged images. In this study, a comparison was made between HARP instantaneous strain maps calculated from single tagged images (SPAMM) and those calculated from subtracted tagged images (CSPAMM). The performance was quantified using simulated images of an incompressible cylinder in the ‘end‐systolic’ state with realistic image contrast and noise. The error in the second principal stretch ratio was 0.009 ± 0.032 (mean ± SD) for the SPAMM acquisition, and 0.007 ± 0.016 for CSPAMM at identical contrast‐to‐noise ratio. Furthermore, differences between the methods were illustrated with in vivo strain maps. Those calculated from CSPAMM images showed fewer artifacts and were less sensitive to the choice of cut‐off frequencies in the HARP band‐pass filter. A prerequisite for the method to become practical is that the CSPAMM images should be acquired in a single breathhold. Magn Reson Med 46:993–999, 2001.

Changes in Right Ventricular Function Measured by Cardiac Magnetic Resonance Imaging in Patients Receiving Pulmonary Arterial Hypertension–Targeted Therapy The EURO-MR Study

Background—Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. Methods and Results—In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). Conclusions—On-treatment changes in cardiac MRI–derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.