Noninvasive monitoring of serial changes in pulmonary vascular resistance and acute vasodilator testing using cardiac magnetic resonance

Objectives The study sought to evaluate the ability of cardiac magnetic resonance (CMR) to monitor acute and long-term changes in pulmonary vascular resistance (PVR) noninvasively. Background PVR monitoring during the follow-up of patients with pulmonary hypertension (PH) and the response to vasodilator testing require invasive right heart catheterization. Methods An experimental study in pigs was designed to evaluate the ability of CMR to monitor: 1) an acute increase in PVR generated by acute pulmonary embolization (n = 10); 2) serial changes in PVR in chronic PH (n = 22); and 3) changes in PVR during vasodilator testing in chronic PH (n = 10). CMR studies were performed with simultaneous hemodynamic assessment using a CMR-compatible Swan-Ganz catheter. Average flow velocity in the main pulmonary artery (PA) was quantified with phase contrast imaging. Pearson correlation and mixed model analysis were used to correlate changes in PVR with changes in CMR-quantified PA velocity. Additionally, PVR was estimated from CMR data (PA velocity and right ventricular ejection fraction) using a formula previously validated. Results Changes in PA velocity strongly and inversely correlated with acute increases in PVR induced by pulmonary embolization (r = –0.92), serial PVR fluctuations in chronic PH (r = –0.89), and acute reductions during vasodilator testing (r = –0.89, p ≤ 0.01 for all). CMR-estimated PVR showed adequate agreement with invasive PVR (mean bias –1.1 Wood units,; 95% confidence interval: –5.9 to 3.7) and changes in both indices correlated strongly (r = 0.86, p < 0.01). Conclusions CMR allows for noninvasive monitoring of acute and chronic changes in PVR in PH. This capability may be valuable in the evaluation and follow-up of patients with PH

A clinical method for mapping and quantifying blood stasis in the left ventricle

In patients at risk of intraventrcular thrombosis, the benefits of chronic anticoagulation therapy need to be balanced with the pro-hemorrhagic effects of therapy. Blood stasis in the cardiac chambers is a recognized risk factor for intracardiac thrombosis and potential cardiogenic embolic events. In this work, we present a novel flow image-based method to assess the location and extent of intraventricular stasis regions inside the left ventricle (LV) by digital processing flow-velocity images obtained either by phase-contrast magnetic resonance (PCMR) or 2D color-Doppler velocimetry (echo-CDV). This approach is based on quantifying the distribution of the blood Residence Time (TR) from time-resolved blood velocity fields in the LV. We tested the new method in illustrative examples of normal hearts, patients with dilated cardiomyopathy and one patient before and after the implantation of a left ventricular assist device (LVAD). The method allowed us to assess in-vivo the location and extent of the stasis regions in the LV. Original metrics were developed to integrate flow properties into simple scalars suitable for a robust and personalized assessment of the risk of thrombosis. From a clinical perspective, this work introduces the new paradigm that quantitative flow dynamics can provide the basis to obtain subclinical markers of intraventricular thrombosis risk. The early prediction of LV blood stasis may result in decrease strokes by appropriate use of anticoagulant therapy for the purpose of primary and secondary prevention. It may also have a significant impact on LVAD device design and operation set-up

1-Oleoyl lysophosphatidic acid: a new mediator of emotional behavior in rats.

The role of lysophosphatidic acid (LPA) in the control of emotional behavior remains to be determined. We analyzed the effects of the central administration of 1-oleoyl-LPA (LPA 18∶1) in rats tested for food consumption and anxiety-like and depression-like behaviors. For this purpose, the elevated plus-maze, open field, Y maze, forced swimming and food intake tests were performed. In addition, c-Fos expression in the dorsal periaqueductal gray matter (DPAG) was also determined. The results revealed that the administration of LPA 18∶1 reduced the time in the open arms of the elevated plus-maze and induced hypolocomotion in the open field, suggesting an anxiogenic-like phenotype. Interestingly, these effects were present following LPA 18∶1 infusion under conditions of novelty but not under habituation conditions. In the forced swimming test, the administration of LPA 18∶1 dose-dependently increased depression-like behavior, as evaluated according to immobility time. LPA treatment induced no effects on feeding. However, the immunohistochemical analysis revealed that LPA 18∶1 increased c-Fos expression in the DPAG. The abundant expression of the LPA1 receptor, one of the main targets for LPA 18∶1, was detected in this brain area, which participates in the control of emotional behavior, using immunocytochemistry. These findings indicate that LPA is a relevant transmitter potentially involved in normal and pathological emotional responses, including anxiety and depression

Time schedules and experimental designs.

<p>Male Wistar rats were sham injected at least two times prior to LPA treatment to familiarize animals with the i.c.v. procedure. The open field test (OFT) and elevated plus maze (EPM) were performed under novelty (A) and habituation (B) conditions after 5 min of LPA 18∶1 infusion. For habituation, the rats were sham injected and tested in both paradigms 24 h before LPA infusion. Rats were exposed to the sample trial of the Y maze (YMT) 5 min after LPA 18∶1 administration, and performed the test trial 2 h later (C). The forced swimming test (FST) was performed after 5 min of LPA 18∶1 infusion (D). Food and water intake were evaluated at different times in 24 h food-deprived animals after 5 min of LPA 18∶1 infusion (E). c-Fos immunoreactivity (IR) was performed through perfusion after 90 min of LPA 18∶1 infusion (F).</p

Time-course effects of i.c.v. administration of LPA 18∶1 or vehicle on food and water intake in 24 h food-deprived Wistar rats.

<p>¹ Data are means ± SEM of 8 determinations per group.</p

Wistar rats were studied in the elevated plus maze (EPM) and open field test (OFT) under novelty and habituation conditions following LPA 18∶1 infusion at doses of 0, 0.4 and 2 µg.

<p>In the EPM, the time (s) exploring the exposed arms (A) and the total number of arm entries (B) were evaluated under novelty conditions. Similarly to the novelty conditions, the time exploring the open arms (C) and the total arm entries (D) were evaluated in animals previously habituated to the EPM (A). Locomotor activity was measured based on the number of crossings (E) and the time (%) spent in the center of the field (F) under novelty conditions. Again, both the number of crossings (G) and the percentage of time spent in the center (H) were evaluated under habituation conditions. The bars are the means ± SEM (n = 7–12 animals per group). The data were analyzed using one-way ANOVA. *p<0.05 and ***p<0.001 denote significant differences versus the vehicle-treated group, determined using Bonferroni’s <i>post-hoc</i> test.</p

Rats were studied for novelty recognition in the Y maze (YMZ).

<p>LPA 18∶1 infusion at doses of 0, 0.4 and 2 <b>µ</b>g was carried out 5 min before the sample trial, and the test trial was performed 2 h later. The percent of rats of each group that first entered the novel arm (A), the total time of novel arm exploration (B) and the total arm entries (C) in the test trial were avaluated. The bars are the means ± SEM (n = 11–12 animals per group). The data were analyzed using a Chi-square test (A) or an one-way ANOVA followed by Bonferroni’s <i>post-hoc</i> tests (B–C). *p<0.05 denote significant differences versus the vehicle-treated group. The comparison of the 2 <b>µ</b>g and the vehicle group in (B) was significant at p = 0.0558.</p

c-Fos immunohistochemistry in the rat dorsal periaqueductal gray matter (PAG) following LPA 18∶1 infusion at doses of 0 and 2 µg.

<p>Analyses were performed in the dorsomedial and dorsolateral divisions of the PAG (<b>A</b>). Stereological quantification of c-Fos immunoreactive (IR) nuclei in the DPAG (<b>B</b>). Low magnification microphotographs for c-Fos immunohistochemistry are depicted for the vehicle (<b>C</b>)- and LPA 18∶1 (<b>D</b>)-treated groups. In addition, high magnification images for the vehicle (<b>E</b>)- and LPA 18∶1 (<b>F</b>)-treated groups are shown. Each point represents the total number of immunopositive nuclei per animal. The dotted lines are medians (n = 4 animals pr group). The data were analyzed using Kruskal-Wallis one-way ANOVA. *p<0.05 denotes significant differences versus the vehicle-treated group, determined using Dunn’s <i>post-hoc</i> test. The arrowheads indicate immunopositive nuclei for c-Fos.</p

Wistar rats were studied in the forced swimming test (FST) following LPA 18∶1 infusion at doses of 0, 0.4 and 2 µg.

<p>The immobility time (s) was evaluated in these animals. The bars are the means ± SEM (n = 8 animals per group). The data were analyzed using one-way ANOVA. *p<0.05 and **p<0.01 denote significant differences versus the vehicle-treated group, determined using Bonferroni’s <i>post-hoc</i> test.</p