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Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during b-adrenergic stimulation by invasive pressure- volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I) cranial, 10 cm below xiphoid process; II) medial, half-way between cranial and caudal; III) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank–Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume (V0), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V0, which induces negative LV pressures and increases LV suction. Accordingly, LBNP-induced central hypovolemia is associated with increased DS. [ABSTRACT FROM AUTHOR]

As a component of self-regulated learning, metacognition is gaining attention in the medical education research community. Metacognition, simply put, is thinking about one's thinking. Having a metacognitive habit of mind is essential for healthcare professionals. This study identified the metacognitive competencies of medical students as they completed a conceptual learning task, and provided insight into students' perceptions of self-regulated learning in their curriculum. Approach: Eleven third-year medical students from a Dutch University were purposively sampled to participate in this qualitative study. The study design included a think-aloud assignment followed by a semi-structured interview. During the assignment, participants were instructed to think aloud while solving questions about medical physiological concepts such as blood flow, pressure, and resistance. Think-aloud data were collected through audiotaping and used to identify participants' metacognitive competencies. The assignment also served as a prompt for an interview in which participants were questioned about metacognitive knowledge, monitoring, experiences, and perceptions of self-regulated learning in their curriculum. All data were transcribed verbatim and analyzed iteratively using a template analysis. Findings: Students differed in their use of metacognitive skills, with an overall focus on monitoring and, to a lesser extent, on planning and evaluation. Additionally, differences were found in students' metacognitive knowledge and metacognitive experiences. There was apparent use of inefficient, superficial predictive cues. Regarding perceptions of self-regulated learning skills, some students felt no need to develop such skills as they perceived medical education as an exercise in memorizing facts. Others emphasized the need for more insight into their actual level of knowledge and competence. Insights: Pre-clinical medical students require explicit teaching of metacognitive skills to facilitate self-regulated learning. Educators should aim to integrate metacognition in the everyday discourse of the classroom to foster an environment in which students discuss their own learning. Supplemental data for this article is available online at . [ABSTRACT FROM AUTHOR]

Aims: Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV‐pulmonary artery (PA) coupling, is defined by the ratio of RV end‐systolic to PA elastances (Ees/Ea). Using pressure–volume loop (PV‐L) technique we aimed to identify an Ees/Ea cut‐off predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to heart failure with reduced ejection fraction (HFREF). Methods and results: This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography and a baseline PV‐L and RV catheter measurement. A subgroup of patients (n = 50) without a pre‐implanted cardiac device underwent magnetic resonance imaging at baseline. The analysis revealed that 0.68 is an optimal Ees/Ea cut‐off (area under the curve: 0.697, P < 0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea ≥ 0.68 vs. <0.68, log‐rank 8.9, P = 0.003). In patients with PH (n = 76, 68%) multivariate Cox regression demonstrated the independent prognostic value of RV‐Ees/Ea in PH patients (hazard ratio 0.2, P < 0.038). Patients without PH (n = 36, 32%) and those with PH but RV‐Ees/Ea ≥ 0.68 showed comparable RV‐Ees/Ea ratios (0.88 vs. 0.9, P = 0.39), RV size/function, and survival. In contrast, secondary PH with RV‐PA coupling ratio Ees/Ea < 0.68 corresponded extremely close to cut‐off values that define RV dilatation/remodelling (RV end‐diastolic volume >160 mL, RV‐mass/volume‐ratio ≤0.37 g/mL) and dysfunction (right ventricular ejection fraction <38%, tricuspid annular plane systolic excursion <16 mm, fractional area change <42%, and stroke‐volume/end‐systolic volume ratio <0.59) and is associated with a dramatically increased short and medium‐term all‐cause mortality. Independent predictors of prognostically unfavourable RV‐PA coupling (Ees/Ea < 0.68) in secondary PH were a pre‐existent dilated RV [end‐diastolic volume >171 mL, odds ratio (OR) 0.96, P = 0.021], high pulsatile load (PA compliance <2.3 mL/mmHg, OR 8.6, P = 0.003), and advanced systolic left heart failure (left ventricular ejection fraction <30%, OR 1.23, P = 0.028). Conclusions: The RV‐PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodelling, and left ventricular dysfunction. Prognostically favourable coupling (RV‐Ees/Ea ≥ 0.68) in PH was associated with preserved RV size/function and mid‐term survival, comparable with HFREF without PH. [ABSTRACT FROM AUTHOR]

Background: Teaching is an important professional skill for physicians and providing feedback is an important part of teaching. Medical students can practice their feedback skills by giving each other peer feedback. Therefore, we developed a peer feedback training in which students observed a peer that modelled the use of good feedback principles. Students then elaborated on the modelled feedback principles through peer discussion. This combination of peer modelling and discussing the modelled feedback principles was expected to enhance emulation of the feedback principles compared to (1) only peer modelling and (2) discussing the feedback principles without previous modelling. Methods: In a quasi-experimental study design, 141 medical students were assigned randomly to three training conditions: peer modelling plus discussion (MD), non-peer modelled example (NM) or peer modelling without discussion (M). Before and after the training, they commented on papers written by peers. These comments served as a pre- and a post-measure of peer feedback. The comments were coded into different functions and aspects of the peer feedback. Non-parametrical Kruskall-Wallis tests were used to check for pre- and post-measure between-group differences in the functions and aspects. Results: Before the training, there were no significant between-group differences in feedback functions and aspects. After the training, the MD-condition gave significantly more positive peer feedback than the NM-condition. However, no other functions or aspects were significantly different between the three conditions, mainly because the within-group interquartile ranges were large. Conclusions: The large interquartile ranges suggest that students differed substantially in the effort placed into giving peer feedback. Therefore, additional incentives may be needed to motivate students to give good feedback. Teachers could emphasise the utility value of peer feedback as an important professional skill and the importance of academic altruism and professional accountability in the peer feedback process. Such incentives may convince more students to put more effort into giving peer feedback. [ABSTRACT FROM AUTHOR]

Background: Blockade of cardiac sympathetic fibers by thoracic epidural anesthesia (TEA) was previously shown to reduce right and left ventricular systolic function and effective pulmonary arterial elastance. At conditions of constant paced heart rate, cardiac output and systemic hemodynamics were unchanged. In this study, we further investigated the effect of cardiac sympathicolysis during physical stress and increased oxygen demand. Methods: In a cross-over design, 12 patients scheduled to undergo thoracic surgery performed dynamic ergometric exercise tests with and without TEA. Hemodynamics were monitored and biventricular function was measured by transthoracic two-dimensional and M-mode echocardiography, pulsed wave Doppler and tissue Doppler imaging. Results: TEA attenuated systolic RV function (TV Sʹ: − 21%, P < 0.001) and LV function (MV Sʹ: − 14%, P = 0.025), but biventricular diastolic function was not affected. HR (− 11%, P < 0.001), SVI (− 15%, P = 0.006), CI (− 21%, P < 0.001) and MAP (− 12%, P < 0.001) were decreased during TEA, but SVR was not affected. Exercise resulted in significant augmentation of systolic and diastolic biventricular function. During exercise HR, SVI, CI and MAP increased (respectively, + 86%, + 19%, + 124% and + 17%, all P < 0.001), whereas SVR decreased (− 49%, P < 0.001). No significant interactions between exercise and TEA were found, except for RPP (P = 0.024) and MV E DT (P = 0.035). Conclusion: Cardiac sympathetic blockade by TEA reduced LV and RV systolic function but did not significantly blunt exercise-induced increases in LV and RV function. These data indicate that additional mechanisms besides those controlled by the cardiac sympathetic nervous system are involved in the regulation of cardiac function during dynamic exercise. Trial registration Clinical trial registration: Nederlands Trial Register, NTR 4880 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4880. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to validate the tricuspid annular plane systolic excursion/systolic pulmonary artery (PA) pressure (TAPSE/PASP) ratio with the invasive pressure–volume (PV) loop-derived end-systolic right ventricular (RV) elastance/PA elastance (Ees/Ea) ratio in patients with heart failure with reduced ejection fraction (HFREF) and secondary pulmonary hypertension (PH). Methods and results The relationship of TAPSE and TAPSE/PASP with RV-PV loop (single-beat)-derived contractility Ees, afterload Ea, and Ees/Ea was assessed in 110 patients with HFREF with and without secondary PH. The results were compared with other surrogate parameters such as the fractional area change/PASP ratio. The association of the surrogates with all-cause mortality was evaluated. In patients with PH (n  = 74, 67%), TAPSE significantly correlated with Ees (r  = 0.356), inverse with Ea (r  = −0.514) but was most closely associated with Ees/Ea (r  = 0.77). Placing TAPSE in a ratio with PASP slightly reduced the relationship to Ees/Ea (r  = 0.71) but was more closely related to the parameters of PA vascular load, diastolic RV function, and RV energetics. The area under the curve of TAPSE/PASP and TAPSE for discriminating overall survival in receiver operating characteristic analysis was not different (P  = 0.78. Prognostic relevant cut-offs were 17 mm for TAPSE and 0.38 mm/mmHg for TAPSE/PASP. Both parameters in multivariate cox regression remained independently prognostically relevant. Conclusion TAPSE is an easily and reliably obtainable and valid surrogate parameter for RV–PA coupling in PH due to HFREF. Putting TAPSE into a ratio with PASP did not further improve the coupling information or prognostic assessment. Trial Identifier DRKS—German Clinical Trials Register (DRKS00011133; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011133). [ABSTRACT FROM AUTHOR]

Obtaining adequate understanding of scientific concepts is considered challenging due to learners' misconceptions about natural phenomena. Misconceptions may coexist with scientific knowledge in the brain. Therefore, misconceptions must be cognitively inhibited in order to select the scientific knowledge. There is, however, lack of substantial neuroscientific evidence supporting this hypothesis. In this study, we sought for this evidence by investigating medical students who solved a cardiovascular conceptual problem in a magnetic resonance imaging scanner. Brain activation was compared between understanders who had the scientific knowledge, and misunderstanders who held a misconception. No significant activation was found in brain areas related to cognitive inhibition in understanders compared with misunderstanders. Therefore, we could not confirm the idea that cognitive inhibition is involved in overcoming a misconception. Instead, we found that the putamen was significantly activated in misunderstanders compared with understanders, suggesting a role for episodic memory in learners holding a misconception. Lay abstract: We investigated the role of cognitive inhibition in conceptual understanding in medical students performing a learning task in a MRI scanner. Brain activation was compared between understanders who had the scientific knowledge, and misunderstanders who held a misconception. Results could not confirm the hypothesis that scientific knowledge and misconceptions may coexist in the brain and that cognitive inhibition is needed overcoming a misconception. Rather, our findings suggest involvement of episodic memory in learners with misconceptions, emphasizing the importance of taking into account students' prior knowledge in science teaching. [ABSTRACT FROM AUTHOR]

Key points: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism.The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly‐bound myosin cross‐bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+/calmodulin‐dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin‐binding protein‐C, myosin light chain 2), maximizing the recruitment of available strongly‐bound myosin cross‐bridges.Short‐lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation.Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. The present study investigated whether oxidative stress and Ca2+/calmodulin‐dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure–volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild‐type (WT) and CaMKII‐double knockout mice (DKOCaMKII). In snap‐frozen WT hearts, force–pCa relationship, H2O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end‐diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII‐hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac‐myosin binding protein‐C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds. Key points: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism.The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly‐bound myosin cross‐bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+/calmodulin‐dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin‐binding protein‐C, myosin light chain 2), maximizing the recruitment of available strongly‐bound myosin cross‐bridges.Short‐lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation.Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. [ABSTRACT FROM AUTHOR]

Aims Restrictive mitral annuloplasty (RMA) can provide a durable solution for functional mitral regurgitation (MR), but might result in obstruction to antegrade mitral flow. Aim of this study was to assess the magnitude of change in mitral valve area (MVA) during exercise after RMA, to relate the change in MVA to left ventricular (LV) geometry and function, and to assess its haemodynamic and clinical impact. Methods and results Bicycle exercise echocardiography was performed in 32 patients after RMA. Echocardiographic data at rest and during exercise were compared with preoperative echocardiographic data. Clinical endpoints were collected following the study visit. MVA increased during exercise in 25 patients (1.6 ± 0.4 cm2 to 2.0 ± 0.6 cm2, P  < 0.001), whereas MVA decreased in 7 patients (1.8 ± 0.5 cm2 to 1.5 ± 0.4 cm2, P  = 0.020). Patients with an increased MVA showed a significant reduction in LV volumes at rest compared to preoperatively, and an increase in stroke volume and cardiac output (CO) during exercise. In patients with decreased MVA, LV reverse remodelling was absent and myocardial flow reserve limited. Patients with decreased exercise MVA had a higher increase in mean pulmonary artery pressure (PAP) with respect to CO and worse survival 36 months after the study visit (69±19% vs. 92±5%, P  = 0.005). Conclusions Both increased and decreased MVA were observed during exercise echocardiography after RMA for functional MR. Change in MVA was related to the extent of LV geometrical and functional changes. A decreased MVA during exercise was associated with a higher increase in mean PAP with respect to CO, and worse survival. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the definitions and applications of 'spaced learning' and to propose future directions for advancing its study and practice in health professions education. Method: The authors searched five online databases for articles published on spaced learning in health professions education prior to February 2018. Two researchers independently screened articles for eligibility with set inclusion criteria. They extracted and analysed key data using both quantitative and qualitative methods. Results: Of the 2972 records retrieved, 120 articles were included in the review. More than 90% of these articles were published in the last 10 years. The definition of spaced learning varied widely and was often not theoretically grounded. Spaced learning was applied in distinct contexts, including online learning, simulation training and classroom settings. There was a large variety of spacing formats, ranging from dispersion of information or practice on a single day, to intervals lasting several months. Generally, spaced learning was implemented in practice or testing phases and rarely during teaching. Conclusions: Spaced learning is infrequently and poorly defined in the health professions education literature. We propose a comprehensive definition of spaced learning and emphasise that detailed descriptions of spacing formats are needed in future research to facilitate the operationalisation of spaced learning research and practice in health professions education. Digging into the educationally strategic phenomenon of spaced learning, the authors discover variety that leads them to propose a comprehensive definition and emphasise that detailed format descriptions are needed to facilitate further development. [ABSTRACT FROM AUTHOR]

Background: Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min- 1 is obtained sharing the same unit as CPO (W). We aimed to validate CPO as a marker of LV SW min- 1 under various inotropic states.Methods: We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68 ± 1 kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0 °C, 38.0 °C and 40.5 °C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min- 1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVPmax) and maximal rate of rise of LVP (LV dP/dtmax).Results: CPO showed the best correlation with LV SW min- 1 (r2 = 0.89; p < 0.05) while LV EF did not correlate at all (r2 = 0.01; p = 0.259). Further parameters correlated moderately with LV SW min- 1 (LVPmax r2 = 0.47, RPP r2 = 0.67; and TP r2 = 0.54). LV dP/dtmax correlated worst with LV SW min- 1 (r2 = 0.28).Conclusion: CPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU. [ABSTRACT FROM AUTHOR]

Background: Hypercholesterolemia is a major risk factor for ischemic heart disease including acute myocardial infarction. However, long-term effects of hypercholesterolemia in a rodent myocardial ischemia-reperfusion injury model are unknown. Therefore, the effects of diet-induced hypercholesterolemia on cardiac function and remodeling were investigated up to eight weeks after myocardial ischemia-reperfusion (MI-R) injury which was induced in either normocholesterolemic (NC-MI) or hypercholesterolemic (HC-MI) APOE*3-Leiden mice. Methods: Left ventricular (LV) dimensions were serially assessed using parasternal long-axis echocardiography followed by LV pressure-volume measurements. Subsequently, infarct size and the inflammatory response were analyzed by histology and fluorescence-activated cell sorting (FACS) analysis. Results: Intrinsic LV function eight weeks after MI-R was significantly impaired in HC-MI compared to NC-MI mice as assessed by end-systolic pressure, dP/dtMAX, and -dP/dtMIN. Paradoxically, infarct size was significantly decreased in HC-MI compared to NC-MI mice, accompanied by an increased wall thickness. Hypercholesterolemia caused a pre-ischemic peripheral monocytosis, in particular of Ly-6Chi monocytes whereas accumulation of macrophages in the ischemic-reperfused myocardium of HC-MI mice was decreased. Conclusion: Diet-induced hypercholesterolemia caused impaired LV function eight weeks after MI-R injury despite a reduced post-ischemic infarct size. This was preceded by a pre-ischemic peripheral monocytosis, while there was a suppressed accumulation of inflammatory cells in the ischemic-reperfused myocardium after eight weeks. This experimental model using hypercholesterolemic APOE*3-Leiden mice exposed to MI-R seems suitable to study novel cardioprotective therapies in a more clinically relevant animal model. [ABSTRACT FROM AUTHOR]

Misconceptions about physiology are a major threat to accurate scientific and clinical reasoning in medical education. Awareness is often mentioned as a prerequisite to achieve conceptual understanding; however, students are frequently unaware of their incorrect understanding. We explored the multitier approach as a tool to obtain insight into students’ awareness and misconceptions regarding cardiovascular physiology. Biomedical sciences students (N = 81) participated in a diagnostic multitier assessment on cardiovascular physiology. Each question consisted of an answer tier and an explanation tier. Both tiers were paired with confidence tiers, i.e., 5-point Likert scales, which were used as an indicator for metacognitive evaluation, i.e., awareness. The average test score was 3.07 (maximum 4.0) for the answer tier only, and reduced to 1.57 when answer and explanation tiers were combined. A weak correlation (R² = 0.13, P = 0.001) between students’ confidence and their test scores was found for the combined responses. Correct combined answers were associated with an increase in confidence score of 0.27 vs. incorrect answers. Using a Bland-Altman analysis, we showed that students generally overestimated their knowledge. In total, 28.7% of all responses were classified as misconceptions, defined as incorrect answers paired with high confidence. In all, findings indicate that the multitier approach is useful to study students’ conceptual understanding and uncover misconceptions on cardiovascular physiology. Furthermore, this study supports the need for metacognitive measures in order to improve teaching and learning in medical education. [ABSTRACT FROM AUTHOR]

Comprehension of physiology is essential for development of clinical reasoning. However, medical students often struggle to understand physiological concepts. Interactive learning through Peer instruction (PI) is known to stimulate students' comprehension, but its relative efficacy and working mechanisms remain to be elucidated. In this study, we investigated if and how PI could optimize comprehension of physiological concepts and transfer relative to Self-explanation (SE) which is considered a lower-order type of overt learning. First-year medical students (n = 317) were randomly assigned to either PI or SE in a pre-post test design, followed by a set of near and far transfer questions. In both PI and SE groups post-test scores were significantly improved (p < 0.0001) with PI outperforming SE (+ 35% vs. + 23%, p = 0.006). Interestingly, a substantial number of students with initial incorrect answers even had enhanced scores after discussion with an incorrect peer. Both methods showed higher transfer scores than control (p = 0.006), with a tendency for higher near transfer scores for PI. These findings support PI as a valuable method to enhance comprehension of physiological concepts. Moreover, by comparing the effects of interactive PI with constructive SE we have established new insights that complement educational theories on overt learning activities. [ABSTRACT FROM AUTHOR]

Introduction: Students learn more effectively when they know what they do not know. Gaining insight into students' metacognitive awareness is needed as misalignment between actual and self-perceived knowledge impedes their learning process. The optimal method of measuring self-perceived knowledge is still under debate. In this study, we evaluate the use of psychology-derived post-decision wagering for mapping students self-perceived knowledge.Methods: Students (n = 71) performed a pre-test on medical physiology, followed by a teacher-moderated discussion and a post-test with isomorph questions. Half of the students rated their self-perceived knowledge on each question using post-decision wagering, i. e. betting 1-5 points on the correctness of their answer, whereas the other half used a 5-point Likert scale to rate their confidence.Results: Self-perceived knowledge scores were higher for post-decision wagering (pre: 3.75 ± 0.14, post: 4.60 ± 0.07) compared with Likert scales (pre: 3.13 ± 0.08, post: 3.92 ± 0.08) despite similar actual knowledge scores. Furthermore, Likert ratings showed a near-normal distribution, whereas wagers were placed preferentially using the outer ends of the scale. Correlations between mean actual and self-perceived knowledge scores were low in both groups. On average, 8.5% of responses were classified as misconceptions, defined as highly confident incorrect answers.Discussion: Despite the presumed reliability of post-decision wagering, our findings suggest that we should adhere to the use of Likert scales as a balanced measure for self-perceived knowledge in medical education. Moreover, the prevalence of misconceptions did not alter after instruction, indicating a need for instructional designs that enhance students' conceptual understanding in basic sciences. [ABSTRACT FROM AUTHOR]

Aims: The optimal site for biventricular endocardial (BIVENDO) pacing remains undefined. Acute haemodynamic response (AHR) is reproducible marker of left ventricular (LV) contractility, best expressed as the change in the maximum rate of LV pressure (LV-dp/dtmax), from a baseline state. We examined the relationship between factors known to impact LV contractility, whilst delivering BIVENDO pacing at a variety of LV endocardial (LVENDO) locations.Methods and results: We compiled a registry of acute LVENDO pacing studies from five international centres: Johns Hopkins-USA, Bordeaux-France, Eindhoven-The Netherlands, Oxford-United Kingdom, and Guys and St Thomas' NHS Foundation Trust, London-UK. In all, 104 patients incorporating 687 endocardial and 93 epicardial pacing locations were studied. Mean age was 66 ± 11 years, mean left ventricular ejection fraction 24.6 ± 7.7% and mean QRS duration of 163 ± 30 ms. In all, 50% were ischaemic [ischaemic cardiomyopathy (ICM)]. Scarred segments were associated with worse haemodynamics (dp/dtmax; 890 mmHg/s vs. 982 mmHg/s, P < 0.01). Delivering BiVENDO pacing in areas of electrical latency was associated with greater improvements in AHR (P < 0.01). Stimulating late activating tissue (LVLED >50%) achieved greater increases in AHR than non-late activating tissue (LVLED < 50%) (8.6 ± 9.6% vs. 16.1 ± 16.2%, P = 0.002). However, the LVENDO pacing location with the latest Q-LV, was associated with the optimal AHR in just 62% of cases.Conclusions: Identifying viable LVENDO tissue which displays late electrical activation is crucial to identifying the optimal BiVENDO pacing site. Stimulating late activating tissue (LVLED >50%) yields greater improvements in AHR however, the optimal location is frequently not the site of latest activation. [ABSTRACT FROM AUTHOR]

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 µg· kg-1·min-1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs (n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. [ABSTRACT FROM AUTHOR]

Aims: The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease. Methods and results: Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb postnatally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers. Conclusion: This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation. [ABSTRACT FROM AUTHOR]

Patients with hypertension and hyperaldosteronism show an increased risk of stroke compared with patients with essential hypertension. Aim of the study was to assess the effects of aldosterone on left atrial function in rats as a potential contributor to thromboembolism. Osmotic mini-pumps delivering 1.5 µg aldosterone/h were implanted in rats subcutaneously (Aldo, n = 39; controls, n = 38). After 8 wk, left ventricular pressure-volume analysis of isolated working hearts was performed, and left atrial systolic and diastolic function was also assessed by atrial pressure-diameter loops. Moreover, left atrial myocytes were isolated to investigate their global and local Ca2+ handling and contractility. At similar heart rates, pressure-volume analysis of isolated hearts and in vivo hemodynamic measurements revealed neither systolic nor diastolic left ventricular dysfunction in Aldo. In particular, atrial filling pressures and atrial size were not increased in Aldo. Aldo rats showed a significant reduction of atrial late diastolic A wave, atrial active work index, and increased V waves. Consistently, in Aldo rats, sarcomere shortening and the amplitude of electrically evoked global Ca2+ transients were substantially reduced. Sarcoplasmic reticulum-Ca2+ content and fractional Ca2+ release were decreased, substantiated by a reduced sarcoplasmic reticulum calcium ATPase activity, resulting from a reduced CAMKII-evoked phosphorylation of phospholamban. Hyperaldosteronism induced atrial systolic and diastolic dysfunction, while atrial size and left ventricular hemodynamics, including filling pressures, were unaffected in rats. The described model suggests a direct causal link between hyperaldosteronism and decreased atrial contractility and diastolic compliance. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WDtreated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model. [ABSTRACT FROM AUTHOR]

Electrical Impact of the Left Ventricular Pacing Site in CRT Introduction Recent studies have demonstrated that left ventricular (LV) pacing site is a critical parameter in optimizing cardiac resynchronization therapy (CRT). The present study evaluates the effect of pacing from different LV locations on QRS duration (QRSd) and their relationship to acute hemodynamic response in congestive heart failure patients. Methods and Results Thirty-five patients with nonischemic dilated cardiomyopathy and left bundle branch block referred for CRT device implantation were studied. Eleven predetermined LV pacing sites were systematically assessed in random order: epicardial: coronary sinus (CS); endocardial: basal and mid-cavity (septal, anterior, lateral, and inferior), apex, and the endocardial site facing the CS pacing site. For each patient QRSd and +dP/dtmax during baseline (AAI) and DDD LV pacing at 2 atrioventricular delays were compared. Response to CRT was significantly better in patients with wider baseline QRSd (≥150 milliseconds). Hemodynamic response was inversely correlated to increase of QRSd during LV pacing (short atrioventricular [AV] delay: r = 0.44, P < 0.001; long AV delay: r = 0.59, P < 0.001). Compared to baseline, LV pacing at the site of shortest QRSd significantly improved +dP/dtmax (+18 ± 25%, P < 0.001) but was not superior to other conventional strategy (lateral wall, CS pacing, and echo-guided) and was inferior to a hemodynamically guided strategy. Conclusions In our study, we have demonstrated that changes of QRSd during LV pacing correlated with acute hemodynamic response and that LV pacing location was a primary determinant of paced QRSd. Although QRSd did not predict the maximum hemodynamic response, our results confirm the link between electrical activation and hemodynamic response of the LV during CRT. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) function is an important determinant of prognosis in congenital heart diseases, pulmonary hypertension, and heart failure. Preventive sildenafil treatment has been shown to enhance systolic RV function and improve exercise capacity in a model of fixed RV pressure load. However, it is unknown whether sildenafil has beneficial effects when treatment is started in established RV dysfunction, which is clinically more relevant. Our aim was to assess the effects of sildenafil treatment on RV function and fibrosis in a model of established RV dysfunction due to fixed afterload. Rats were subjected to pulmonary artery banding (PAB), which induced RV dysfunction after 4 wk, characterized by reduced exercise capacity, decreased tricuspid annular plane systolic excursion, and RV dilatation. From week 4 onward, 50% of rats were treated with sildenafil (100 mg·kg-1·day-1, n = 9; PAB-SIL group) or vehicle (n = 9; PAB-VEH group). At 8 wk, exercise capacity was assessed using cage wheels, and RV function was assessed using invasive RV pressure-volume measurements under anesthesia. Sildenafil treatment, compared with vehicle, improved RV ejection fraction (44 ± 2% vs. 34 ± 2%, P < 0.05, PAB-SIL vs. PAB-VEH groups), reduced RV end-diastolic pressure (2.3 ± 0.5 vs. 5.1 ± 0.9 mmHg, P < 0.05), and RV dilatation (end-systolic volume: 468 ± 45 vs. 643 ± 71 μl, P = 0.05). Sildenafil treatment also attenuated RV fibrosis (30 ± 6 vs. 17 ± 3‰, P < 0.05) but did not affect end-systolic elastance, exercise capacity, or PKG or PKA activity. In conclusion, sildenafil improves RV diastolic function and attenuates interstitial fibrosis in rats with established RV dysfunction, independent from afterload. These results indicate that sildenafil treatment has therapeutic potential for established RV dysfunction. [ABSTRACT FROM AUTHOR]

Background. Heart development is a complex process, and abnormal development may result in congenital heart disease (CHD). Currently, studies on animal models mainly focus on cardiac morphology and the availability of hemodynamic data, especially of the right heart half, is limited. Here we aimed to assess the morphological and hemodynamic parameters of normal developing mouse embryos/fetuses by using a high-frequency ultrasound system. Methods. A timed breeding program was initiated with a WT mouse line (Swiss/129Sv background). All recordings were performed transabdominally, in isoflurane sedated pregnant mice, in hearts of sequential developmental stages: 12.5, 14.5, and 17.5 days after conception (n = 105). Results. Along development the heart rate increased significantly from 125 ± 9.5 to 219 ± 8.3 beats per minute. Reliable flow measurements could be performed across the developing mitral and tricuspid valves and outflow tract. M-mode measurements could be obtained of all cardiac compartments. An overall increase of cardiac systolic and diastolic function with embryonic/fetal development was observed. Conclusion. High-frequency echocardiography is a promising and useful imaging modality for structural and hemodynamic analysis of embryonic/fetal mouse hearts. [ABSTRACT FROM AUTHOR]

Aims In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model. Methods and results Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure–volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva. Conclusion In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans. [ABSTRACT FROM PUBLISHER]

Right ventricular (RV) failure due to chronically abnormal loading is a main determinant of outcome in pulmonary hypertension (PH) and congenital heart disease. However, distinct types of RV loading have been associated with different outcomes. To determine whether the adaptive RV response depends on loading type, we compared hemodynamics, exercise, and hypertrophy in models of pressure overload due to pulmonary artery banding (PAB), pressure overload due to PH, combined pressure and volume overload, and isolated volume load. Ninety-four rats were subjected to either PAB, monocrotaline-induced PH (PH), aortocaval shunt (shunt), or combined monocrotaline and aortocaval shunt (PH shunt). We performed pressure-volume analysis and voluntary exercise measurements at 4 wk. We compared PAB to PH (part I) and PH shunt to either isolated PH or shunt (part II). In part I, enhanced contractility (end-systolic elastance and preload recruitable stroke work) was present in PH and PAB, but strongest in PAB. Frank- Starling mechanism was active in both PAB and PH. In PAB this was accompanied by diastolic dysfunction (increased end-diastolic elastance, relaxation constant), clinical signs of RV failure, and reduced exercise. These distinct responses were not attributable to differences in hypertrophy. In part II, in PH shunt the contractility response was blunted compared with PH, which caused pseudonormalization of parameters. Additional volume overload strongly enhanced hypertrophy in PH. We conclude that different types of loading result in distinct patterns of RV adaptation. This is of importance for the approach to patients with chronically increased RV load and for experimental studies in various types of RV failure. [ABSTRACT FROM AUTHOR]

Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg-1·day-1) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with Nω-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg-1·day-1) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD. [ABSTRACT FROM AUTHOR]

Aim Right ventricular (RV) failure due to pressure or volume overload is a major risk factor for early mortality in congenital heart disease and pulmonary hypertension, but currently treatments are lacking. We aimed to demonstrate that the phosphodiesterase 5A inhibitor sildenafil can prevent adverse remodelling and improve function in chronic abnormal RV overload, independent from effects on the pulmonary vasculature. Methods and results In rat models of either pressure or volume overload, we performed pressure–volume studies to measure haemodynamic effects and voluntary exercise testing as clinical outcome after 4 weeks of sildenafil (or vehicle) administration. In the pressure-loaded right ventricle, sildenafil enhanced contractility [end-systolic elastance (mmHg/mL) 247 ±68 vs.155 ±71, sildenafil vs. vehicle, P < 0.05], prevented RV dilatation [end-diastolic volume (μL) 733 ±50 vs. 874 ±39, P < 0.05], reduced wall stress [peak wall stress (mmHg) 323 ±46 vs. 492 ±62, P < 0.05], and partially preserved exercise tolerance [running distance (%) –33 ±15 vs. –62 ±12, P < 0.05]. Protein kinase A was not activated by sildenafil and thus did not mediate the observed effects. In contrast, protein kinase G-1 was activated by sildenafil, but hypertrophy was not inhibited. Importantly, sildenafil did not prevent diastolic dysfunction, whereas RV fibrosis appeared to be increased in sildenafil-treated rats. In the volume-loaded right ventricle, sildenafil treatment did not show any beneficial effects. Conclusion We demonstrate sildenafil to have beneficial, afterload-independent effects on the pressure-loaded right ventricle, but not on the volume-loaded right ventricle. These results indicate that sildenafil may offer a specific treatment for the pressure-loaded right ventricle, although persistent diastolic dysfunction and RV fibrosis could be of concern. [ABSTRACT FROM AUTHOR]

Aims Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF). However, it is unclear whether this is the consequence of altered haemodynamics or a direct aldosterone effect. It was the aim of the study to demonstrate load-independent effects of aldosterone on atrial structure and electrophysiology. Methods Osmotic mini-pumps delivering 1.5 µg/h aldosterone were implanted subcutaneously in rats (Aldo). Rats without aldosterone treatment served as controls. After 8 weeks, surface electrocardiogram, the inducibility of AF, and atrial pressures were recorded in vivo. In isolated working hearts, left ventricular function was measured, and conduction in the right atrium (RA) and the left atrium (LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined. Atrial tissue was analysed histologically. Results Neither systolic nor diastolic ventricular function nor atrial pressures were altered in Aldo rats. All Aldo (11/11) showed inducible atrial arrhythmias vs. two of nine controls (P = 0.03). In Aldo, the P-wave duration and the total RA activation time were longer. Prolongation of local conduction times occurred more often in Aldo, whereas the AERP did not differ between both groups. In Aldo, atrial fibroblasts and interstitial collagen were increased, active matrix metalloproteinase 13 was reduced, and atrial myocytes were hypertrophied. The connexin 43 content was unaltered. Conclusions Aldosterone causes a substrate for atrial arrhythmias characterized by atrial fibrosis, myocyte hypertrophy, and conduction disturbances. The described model imputes atrial proarrhythmia directly to aldosterone, since ventricular haemodynamics appeared unaltered in this model. This mechanism may have therapeutical impact for primary and secondary prevention of AF. [ABSTRACT FROM PUBLISHER]

Rationale: Severe increase in right ventricular pressure can compromise left ventricular (LV) function because of impaired interventricular interaction and aggravate the symptoms. Objectives: To elucidate how nonsevere idiopathic pulmonary arterial hypertension (IPAH) influences LV function because of impaired interventricular interaction. Methods: Invasive pressure-volume (PV) loop analysis obtained by conductance catheterization was performed at rest and during atrial pacing in patients with mild IPAH (n = 10) compared with patients with isolated LV diastolic dysfunction (DD) (n = 10) and control subjects without heart failure symptoms (n = 9). Measurements and Main Results: Patients with nonsevere IPAH (pulmonary artery pressure mean 29 ± 5 mm Hg) and patients with DD showed preserved systolic (ejection fraction 63 ± 12% and 62 ± 9%) and impaired LV diastolic function at rest (LV stiffness 0.027 ± 0.012 ml(-1) and 0.029 ± 0.014 ml(-1)). During pacing at 120 per minute patients with IPAH and DD decreased their stroke volume (-25% and -30%; P < 0.05) and failed to increase cardiac output significantly. Opposite to patients with DD and control subjects, temporary preload reduction during inferior vena cava occlusion initially induced an expansion of LV end-diastolic volume in IPAH (+7%; P < 0.05), whereas end-diastolic pressure continuously dropped. This resulted in an initial downward shift to the right of the PV loop indicating better LV filling, which was associated with a temporary improvement of cardiac output (+11%; P < 0.05) in the patients with IPAH, but not in patients with DD and control subjects. Conclusions: Mild idiopathic pulmonary arterial pressure impairs LV diastolic compliance even in the absence of the intrinsic LV disease and contributes to the reduced cardiac performance at stress. [ABSTRACT FROM AUTHOR]

We previously showed that human cardiomyocyte progenitor cells (hCMPCs) injected after myocardial infarction (MI) had differentiated into cardiomyocytes in vivo 3 months after MI. Here, we investigated the short-term (2 weeks) effects of hCMPCs on the infarcted mouse myocardium. MI was induced in immunocompromised (NOD/scid) mice, immediately followed by intramyocardial injection of hCMPCs labelled with enhanced green fluorescent protein (hCMPC group) or vehicle only (control group). Sham-operated mice served as reference. Cardiac performance was measured 2 and 14 days after MI by magnetic resonance imaging at 9.4 T. Left ventricular (LV) pressure-volume measurements were performed at day 15 followed by extensive immunohistological analysis. Animals injected with hCMPCs demonstrated a higher LV ejection fraction, lower LV end-systolic volume and smaller relaxation time constant than control animals 14 days after MI. hCMPCs engrafted in the infarcted myocardium, did not differentiate into cardiomyocytes, but increased vascular density and proliferation rate in the infarcted and border zone area of the hCMPC group. Injected hCMPCs engraft into murine infarcted myocardium where they improve LV systolic function and attenuate the ventricular remodelling process 2 weeks after MI. Since no cardiac differentiation of hCMPCs was evident after 2 weeks, the observed beneficial effects were most likely mediated by paracrine factors, targeting amongst others vascular homeostasis. These results demonstrate that hCMPCs can be applied to repair infarcted myocardium without the need to undergo differentiation into cardiomyocytes. [ABSTRACT FROM AUTHOR]

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Phosphodiesterase (PDE) 4 inhibitors are potent anti-inflammatory drugs with antihypertensive properties, and their therapeutic role in bronchopulmonary dysplasia (BPD) is still controversial. We studied the role of PDE4 inhibition with piclamilast on normal lung development and its therapeutic value on pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in neonatal rats with hyperoxiainduced lung injury, a valuable model for premature infants with severe BPD. The cardiopulmonary effects of piclamilast treatment (5 mg∙kg-1∙day-1) were investigated in two models of experimental BPD: 1) daily treatment during continuous exposure to hyperoxia for 10 days; and 2) late treatment and injury-recovery in which pups were exposed to hyperoxia or room air for 9 days, followed by 9 or 42 days of recovery in room air combined with treatment started on day 6 of oxygen exposure until day 18. Prophylactic piclamilast treatment reduced pulmonary fibrin deposition, septum thickness, arteriolar wall thickness, arteriolar vascular smooth muscle cell proliferation and RVH, and prolonged survival. In the late treatment and injuryrecovery model, hyperoxia caused persistent aberrant alveolar and vascular development, PH, and RVH. Treatment with piclamilast in both models reduced arteriolar wall thickness, attenuated RVH, and improved right ventricular function in the injury recovery model, but did not restore alveolarization or angiogenesis. Treatment with piclamilast did not show adverse cardiopulmonary effects in room air controls in both models. In conclusion, PDE4 inhibition attenuated and partially reversed PH and RVH, but did not advance alveolar development in neonatal rats with hyperoxic lung injury or affect normal lung and heart development. [ABSTRACT FROM AUTHOR]

Aims Surgical ventricular restoration (SVR) aims to normalize left ventricular (LV) volume and shape in patients with ischaemic cardiomyopathy and anterior wall scar. The chronic effects on LV function may depend on alterations in myocardial collagen metabolism. The present study evaluated myocardial collagen synthesis and degradation rates at baseline and at 6 months follow-up after SVR. We hypothesize that the chronic effects of SVR on LV function and clinical outcome depend on alterations in myocardial collagen metabolism. Methods and results Serum levels of aminoterminal propeptides of type I and III collagen (PINP, PIIINP), carboxyterminal telopeptide of type I collagen (ICTP), and tenascin-C (TNC) were measured at baseline and 6 months after SVR in 24 patients. In addition, New York Heart Association (NYHA) functional class, LV volumes and function were evaluated. At follow-up, a significant improvement in NYHA class (from 3.2 ± 0.8 to 1.4 ± 0.6, P< 0.001) and LV ejection fraction (from 28 ± 9 to 35 ± 7%, P< 0.001) was found, whereas E/A ratio tended to increase (from 1.4 ± 1.1 to 1.9 ± 1.1, P= 0.064). Serum levels of PINP, PIIINP, ICTP, and TNC increased significantly (PINP: from 37 ± 15 to 67 ± 26 μg/L, P< 0.001; PIIINP: from 4.9 ± 1.7 to 7.9 ± 4.0 μg/L, P< 0.001; ICTP: from 5.9 ± 3.7 to 10.0 ± 5.3 μg/L, P< 0.001; TNC: from 30 ± 20 to 44 ± 23 μg/L, P= 0.020). At follow-up, an LV ejection fraction <34% and E/A ratio ≥2.0 were significantly associated with increased serum levels of PIIINP and ICTP. Conclusion In patients who underwent SVR, myocardial collagen metabolism was significantly enhanced 6 months after surgery. Serum levels of myocardial collagen turnover biomarkers were related to post-surgical LV systolic and diastolic function. [ABSTRACT FROM AUTHOR]

. (J Cardiovasc Electrophysiol, Vol. 22, pp. 677-683, June 2011) [ABSTRACT FROM AUTHOR]

We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N?-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 ± 3% vs. 37 ± 2% in Veh-treated rats, P < 0.001) and stroke volume (324 ± 33 vs. 255 ± 15 μl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 ± 1.1 mmHg) than Veh-treated rats (16.3 ± 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 ± 1.8 vs. 30.9 ± 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the accuracy and reproducibility of aortic pulse wave velocity (PWV) assessment by in-plane velocity-encoded magnetic resonance imaging (MRI). Materials and Methods In 14 patients selected for cardiac catheterization on suspicion of coronary artery disease and 15 healthy volunteers, PWV was assessed with multislice two-directional in-plane velocity-encoded MRI (PWVi.p.) and compared with conventionally assessed PWV from multisite one-directional through-plane velocity-encoded MRI (PWVt.p.). In patients, PWV was also obtained from intraarterially acquired pressure-time curves (PWVpressure), which is considered the gold standard reference method. In volunteers, PWVi.p. and PWVt.p. were obtained in duplicate in the same examination to test reproducibility. Results In patients, PWVi.p. showed stronger correlation and similar variation with PWVpressure than PWVt.p. (Pearson correlation r = 0.75 vs. r = 0.58, and coefficient of variation [COV] = 10% vs. COV = 12%, respectively). In volunteers, repeated PWVi.p. assessment showed stronger correlation and less variation than repeated PWVt.p. (proximal aorta: r = 0.97 and COV = 10% vs. r = 0.69 and COV = 17%; distal aorta: r = 0.94 and COV = 12% vs. r = 0.90 and COV = 16%; total aorta: r = 0.97 and COV = 7% vs. r = 0.90 and COV = 13%). Conclusion PWVi.p. is an improvement over conventional PWVt.p. by showing higher agreement as compared to the gold standard (PWVpressure) and higher reproducibility for repeated MRI assessment. J. Magn. Reson. Imaging 2010;32:1086-1094. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Aims Strain rate imaging provides direct information on intrinsic myocardial function and may improve the diagnostic of diastolic dysfunction in heart failure with normal ejection fraction (HFNEF). We therefore correlated global strain with pressure–volume (PV) loop analysis and compared it with flow and tissue Doppler measurements. Methods and results Longitudinal two-dimensional strain rate and flow and tissue Doppler (TDI) indices were measured simultaneously and correlated with diastolic indices of PV relationship obtained by a conductance catheter in 21 patients with HFNEF and 12 controls. HFNEF patients showed a reduced global strain rate during isovolumetric relaxation (SRIVR) [0.27 (0.12–0.39) vs. 0.44 (0.29–0.56) s−1, P = 0.028]. Global strain rate during early (SRE) and late (SRL) diastole did not defer from controls. Their ratios with early transmitral flow, E/SRIVR and E/SRE, were both elevated in HFNEF [3.68 (2.57–7.52) vs. 1.73 (1.47–2.37) m, P = 0.007 and 1.13 (0.76–1.36) vs. 0.83 (0.57–1.04) m, P = 0.030]. SRE and SRIVR correlated with left ventricular (LV) relaxation τ (r = 0.40 and 0.47, P < 0.05); E/SRIVR and E/SRE with LV end-diastolic pressure (r = 0.49 and 0.57, P < 0.01) and LV stiffness constant β (r = 0.42 and 0.43, P < 0.01). Neither of the strain rate indices were significantly more accurate than TDI (area under the curve: SRE 0.55, SRIVR 0.70, E′/A′ 0.72, E/SRE 0.75, E/SRIVR 0.80, and E/E′ 0.83). Conclusion Strain rate imaging is accurate in detecting increased LV stiffness in HFNEF, but it is not superior to already established TDI analysis including E/E′ in patients with only mild degree of disease. [ABSTRACT FROM AUTHOR]

The atria play an important role in cardiac performance. We evaluated their function and the atrioventricular interaction in operated patients with tetralogy of Fallot (TOF). Twenty patients who had undergone surgical repair of TOF and seven controls were investigated. Patients had residual pulmonary but no major tricuspid valve insufficiency. Atrial and ventricular strain rates were obtained by echocardiographic speckle tracking. Cine MRI-derived volumetric analysis provided atrial and ventricular time volume and time volume change curves yielding emptying and filling parameters. In addition, at the atrial level, reservoir, conduit and pump function, and cyclic volume change were calculated. At the atrioventricular valve level, tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE, respectively) were measured by two-dimensional echocardiography. In the patients compared with controls, right ventricular end-diastolic volumes were increased and biventricular ejection fraction was decreased (all P < 0.05). Biventricular measures of early diastolic ventricular filling were at control levels, but in late diastole, right ventricular filling parameters and strain rates were decreased (P < 0.001). The maximal right atrial size was slightly but not significantly diminished, but cyclic volume change was significantly reduced (P < 0.0001). Pump and reservoir function were decreased (P < 0.05), and conduit function was elevated (P < 0.001). The left atrium showed reduced reservoir function and cyclic volume change (P < 0.05). TAPSE and MAPSE were also decreased (P < 0.05). There were statistically significant interdependencies between RV ejection fraction, TAPSE, and right atrial filling and emptying parameters (all P < 0.05). In TOF patients, moderate systolic and diastolic right ventricular dysfunction is associated with clearly impaired right atrial function. The left atrium is affected to a lesser extent. [ABSTRACT FROM AUTHOR]

Aims To test a method to predict the end-diastolic pressure-volume relationship (EDPVR) from a single beat in patients with heart failure. Methods and results Patients (New York Heart Association class III-IV) scheduled for mitral annuloplasty (n=9) or ventricular restoration (n=10) and patients with normal left ventricular function undergoing coronary artery bypass grafting (n=12) were instrumented with pressure-conductance catheters to measure pressure-volume loops before and after surgery. Data obtained during vena cava occlusion provided directly measured EDPVRs. Baseline end-diastolic pressure (Pm) and volume (Vm) were used for single-beat prediction of EDPVRs. Root-mean-squared error (RMSE) between measured and predicted EDPVRs, was 2.79±0.21 mm Hg. Measured versus predicted end-diastolic volumes at pressure levels 5, 10, 15 and 20 mm Hg showed tight correlations (R2=0.69-0.97). Bland-Altman analyses indicated overestimation at 5 mm Hg (bias: pre-surgery 44 ml (95% CI 29 to 58 ml); post-surgery 35 ml (23 to 47 ml)) and underestimation at 20 mm Hg (bias: pre-surgery -57 ml (-80 to -34 ml); post-surgery -13 ml (-20 to -7.0 ml)). End-diastolic volumes were significantly different between groups and between conditions, but these differences were not dependent on the method (ie, measured versus predicted). RMSEs were not different between groups or conditions, nor dependent on Vm or Pm, indicating that EDPVR prediction was equally accurate over a wide volume range. Conclusions Single-beat EDPVRs obtained from hearts spanning a wide range of sizes and conditions accurately predicted directly measured EDPVRs with low RMSE. Single-beat EDPVR indices correlated well with directly measured values, but systematic biases were present at low and high pressures. The single-beat method facilitates less invasive EDPVR estimation, particularly when coupled with emerging non-invasive techniques to measure pressures and volumes. [ABSTRACT FROM AUTHOR]

Aims: We tested the hypothesis that, in heart failure with normal ejection fraction (HFNEF), diastolic dysfunction is accentuated at increasing heart rates, and this contributes to impaired frequency-dependent augmentation of cardiac output. [ABSTRACT FROM PUBLISHER]