Hybrid PET/MRI in the assessment of cardiac viability: added value compared to PET/CT

Purpose: We evaluated the potential for hybrid PET/MRI devices to provide integrated metabolic, functional and anatomic characterisation of patients with suspected coronary artery disease.Methods and Materials: Ten patients (5 with suspected hibernating myocardium and 5 healthy volunteers) performed an imaging study using a hybrid PET/MRI (Philips). Viability assessed by 18F-FDG was performed in diseased patients along with MRI anatomic and functional study and reassessed within 30 minutes by conventional PET/CT. Non-contrast right coronary artery (RCA) targeted and whole heart 3D coronary angio-MRI using ECG-gating and respiratory navigator was performed in healthy volunteers with reconstruction performed using MPR and volume rendering. The extent of metabolic defect (MD) using PET/MRI and PET/CT was compared in patients and coronary territories (LAD, CX, RCA). Assessability of coronary lumen was judged as good, sub-optimal or non-assessable using a 16-segments coronary model.Results: Metabolic assessment was successful in all patients with MD being 19.2% vs 18.3% using PET/MRI and PET/CT, respectively (P=ns). The MD was 10.2%, 6 %, and 3 % vs 9.3%, 6 % and 3 % for LAD, CX and RCA territories, respectively (P= ns). Coronary angio-MRI was successful in all volunteers with 66 coronary segments visualised overall. The RCA was fully visualised in 4/5 volunteers and the left coronary arteries in 4/5 volunteers. Assessability in visualised segments was good, sub-optimal and non-assessable in 88 %, 2 % and 10 %, respectively.Conclusion: Hybrid PET/MRI devices may enable metabolic evaluation comparable to PET/CT with additional value owing to accurate functional and anatomical information including coronary assessment.

Small and long non-coding RNAs in cardiac homeostasis and regeneration

Cardiovascular diseases and in particular heart failure are major causes of morbidity and mortality in the Western world. Recently, the notion of promoting cardiac regeneration as a means to replace lost cardiomyocytes in the damaged heart has engendered considerable research interest. These studies envisage the utilization of both endogenous and exogenous cellular populations, which undergo highly specialized cell fate transitions to promote cardiomyocyte replenishment. Such transitions are under the control of regenerative gene regulatory networks, which are enacted by the integrated execution of specific transcriptional programs. In this context, it is emerging that the non-coding portion of the genome is dynamically transcribed generating thousands of regulatory small and long non-coding RNAs, which are central orchestrators of these networks. In this review, we discuss more particularly the biological roles of two classes of regulatory non-coding RNAs, i.e. microRNAs and long non-coding RNAs, with a particular emphasis on their known and putative roles in cardiac homeostasis and regeneration. Indeed, manipulating non-coding RNA-mediated regulatory networks could provide keys to unlock the dormant potential of the mammalian heart to regenerate. This should ultimately improve the effectiveness of current regenerative strategies and discover new avenues for repair. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

A-kinase anchoring protein-Lbc promotes pro-fibrotic signaling in cardiac fibroblasts

In response to stress or injury the heart undergoes an adverse remodeling process associated with cardiomyocyte hypertrophy and fibrosis. Transformation of cardiac fibroblasts to myofibroblasts is a crucial event initiating the fibrotic process. Cardiac myofibroblasts invade the myocardium and secrete excess amounts of extracellular matrix proteins, which cause myocardial stiffening, cardiac dysfunctions and progression to heart failure. While several studies indicate that the small GTPase RhoA can promote profibrotic responses, the exchange factors that modulate its activity in cardiac fibroblasts are yet to be identified. In the present study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor (GEF) activity, is critical for activating RhoA and transducing profibrotic signals downstream of type I angiotensin II receptors (AT1Rs) in cardiac fibroblasts. In particular, our results indicate that suppression of AKAP-Lbc expression by infecting adult rat ventricular fibroblasts with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly reduces the ability of angiotensin II to promote RhoA activation, differentiation of cardiac fibroblasts to myofibroblasts, collagen deposition as well as myofibroblast migration. Interestingly, AT1Rs promote AKAP-Lbc activation via a pathway that requires the α subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as a key Rho-guanine nucleotide exchange factor modulating profibrotic responses in cardiac fibroblasts.

Quality Assessment of Cardiac Magnetic Resonance Images at 1.5/3.0 T: Description and Validation of Standardized Criteria

PURPOSE: Cardiovascular magnetic resonance (CMR) has become a robust and important diagnostic imaging modality in cardiovascular medicine. However,insufficient image quality may compromise its diagnostic accuracy. No standardized criteria are available to assess the quality of CMR studies. We aimed todescribe and validate standardized criteria to evaluate the quality of CMR studies including: a) cine steady-state free precession, b) delayed gadoliniumenhancement, and c) adenosine stress first-pass perfusion. These criteria will serve for the assessment of the image quality in the setting of the Euro-CMR registry.METHOD AND MATERIALS: First, a total of 45 quality criteria were defined (35 qualitative criteria with a score from 0-3, and 10 quantitative criteria). Thequalitative score ranged from 0 to 105. The lower the qualitative score, the better the quality. The quantitative criteria were based on the absolute signal intensity (delayed enhancement) and on the signal increase (perfusion) of the anterior/posterior left ventricular wall after gadolinium injection. These criteria were then applied in 30 patients scanned with a 1.5T system and in 15 patients scanned with a 3.0T system. The examinations were jointly interpreted by 3 CMR experts and 1 study nurse. In these 45 patients the correlation between the results of the quality assessment obtained by the different readers was calculated.RESULTS: On the 1.5T machine, the mean quality score was 3.5. The mean difference between each pair of observers was 0.2 (5.7%) with a mean standarddeviation of 1.4. On the 3.0T machine, the mean quality score was 4.4. The mean difference between each pair of onservers was 0.3 (6.4%) with a meanstandard deviation of 1.6. The quantitative quality assessments between observers were well correlated for the 1.5T machine: R was between 0.78 and 0.99 (pCONCLUSION: The described criteria for the assessment of CMR image quality are robust and have a low inter-observer variability, especially on 1.5T systems.CLINICAL RELEVANCE/APPLICATION: These criteria will allow the standardization of CMR examinations. They will help to improve the overall quality ofexaminations and the comparison between clinical studies.

Association between weight perception and socioeconomic status among adults in the Seychelles.

BACKGROUND: Few studies have examined the association between weight perception and socioeconomic status (SES) in sub-Saharan Africa, and none made this association based on education, occupation and income simultaneously. METHODS: Based on a population-based survey (n = 1255) in the Seychelles, weight and height were measured and self-perception of one's own body weight, education, occupation, and income were assessed by a questionnaire. Individuals were considered to have appropriate weight perception when their self-perceived weight matched their actual body weight. RESULTS: The prevalence of overweight and obesity was 35% and 28%, respectively. Multivariate analysis among overweight/obese persons showed that appropriate weight perception was directly associated with actual weight, education, occupation and income, and that it was more frequent among women than among men. In a model using all three SES indicators together, only education (OR = 2.5; 95% CI: 1.3-4.8) and occupation (OR = 2.3; 95% CI: 1.2-4.5) were independently associated with appropriate perception of being overweight. The OR reached 6.9 [95% CI: 3.4-14.1] when comparing the highest vs. lowest categories of SES based on a score including all SES indicators and 6.1 [95% CI: 3.0-12.1] for a score based on education and occupation. CONCLUSIONS: Appropriately perceiving one's weight as too high was associated with different SES indicators, female sex and being actually overweight. These findings suggest means and targets for clinical and population-based interventions for weight control. Further studies should examine whether these differences in weight perception underlie differences in cognitive skills, healthy weight norms, or body size ideals.

How to assess prognosis after cardiac arrest and therapeutic hypothermia.

The prognosis of patients who are admitted in a comatose state following successful resuscitation after cardiac arrest remains uncertain. Although the introduction of therapeutic hypothermia (TH) and improvements in post-resuscitation care have significantly increased the number of patients who are discharged home with minimal brain damage, short-term assessment of neurological outcome remains a challenge. The need for early and accurate prognostic predictors is crucial, especially since sedation and TH may alter the neurological examination and delay the recovery of motor response for several days. The development of additional tools, including electrophysiological examinations (electroencephalography and somatosensory evoked potentials), neuroimaging and chemical biomarkers, may help to evaluate the extent of brain injury in these patients. Given the extensive literature existing on this topic and the confounding effects of TH on the strength of these tools in outcome prognostication after cardiac arrest, the aim of this narrative review is to provide a practical approach to post-anoxic brain injury when TH is used. We also discuss when and how these tools could be combined with the neurological examination in a multimodal approach to improve outcome prediction in this population.

Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo.

AIMS: High-mobility group box 1 (HMGB1) is a nuclear protein actively secreted by immune cells and passively released by necrotic cells that initiates pro-inflammatory signalling through binding to the receptor for advance glycation end-products. HMGB1 has been established as a key inflammatory mediator during myocardial infarction, but the proximal mechanisms responsible for myocardial HMGB1 expression and release in this setting remain unclear. Here, we investigated the possible involvement of peroxynitrite, a potent cytotoxic oxidant formed during myocardial infarction, on these processes. METHODS AND RESULTS: The ability of peroxynitrite to induce necrosis and HMGB1 release in vitro was evaluated in H9c2 cardiomyoblasts and in primary murine cardiac cells (myocytes and non-myocytes). In vivo, myocardial HMGB1 expression and nitrotyrosine content (a marker of peroxynitrite generation) were determined following myocardial ischaemia and reperfusion in rats, whereas peroxynitrite formation was inhibited by two different peroxynitrite decomposition catalysts: 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III) (FeTPPS) or Mn(III)-tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP). In all types of cells studied, peroxynitrite (100 μM) elicited significant necrosis, the loss of intracellular HMGB1, and its passive release into the medium. In vivo, myocardial ischaemia-reperfusion induced significant myocardial necrosis, cardiac nitrotyrosine formation, and marked overexpression of myocardial HMGB1. FeTPPS reduced nitrotyrosine, decreased infarct size, and suppressed HMGB1 overexpression, an effect that was similarly obtained with MnTBAP. CONCLUSION: These findings indicate that peroxynitrite represents a key mediator of HMGB1 overexpression and release by cardiac cells and provide a novel mechanism linking myocardial oxidative/nitrosative stress with post-infarction myocardial inflammation.

Réadaptation cardiovasculaire, un- bien sous-utilisé [Cardiac rehabilitation, a proven intervention underutilized in the French-speaking part of Switzerland].

Cardiac rehabilitation is associated with a reduced risk of recurrence and mortality after an acute coronary syndrome. Cardiac rehabilitation is a multidisciplinary approach which starts during the acute hospital phase, then followed by a four to six weeks home-based or stationary program, in order to maintain long-term lifestyle changes. Despite the important health benefits of cardiac rehabilitation and its cost-effectiveness, only half of the patients in Europe will achieve a cardiovascular prevention program after an acute coronary syndrome. In the French part of Switzerland, one explanation for this low adherence might be the lack of both stationary and home-based program facilities.

Delay of extubation in neonates and children after cardiac surgery: impact of ventilator-associated pneumonia.

OBJECTIVE: This study was undertaken to determine the delay of extubation attributable to ventilator-associated pneumonia (VAP) in comparison to other complications and complexity of surgery after repair of congenital heart lesions in neonates and children. METHODS: Cohort study in a pediatric intensive care unit of a tertiary referral center. All patients who had cardiac operations during a 22-month period and who survived surgery were eligible (n = 272, median age 1.3 years). Primary outcome was time to successful extubation. Primary variable of interest was VAP Surgical procedures were classified according to complexity. Cox proportional hazards models were calculated to adjust for confounding. Potential confounders comprised other known risk factors for delayed extubation. RESULTS: Median time to extubation was 3 days. VAP occurred in 26 patients (9.6%). The rate of VAP was not associated with complexity of surgery (P = 0.22), or cardiopulmonary bypass (P = 0.23). The adjusted analysis revealed as further factors associated with delayed extubation: other respiratory complications (n = 28, chylothorax, airway stenosis, diaphragm paresis), prolonged inotropic support (n = 48, 17.6%), and the need for secondary surgery (n = 51, 18.8%; e.g., re-operation, secondary closure of thorax). Older age promoted early extubation. The median delay of extubation attributable to VAP was 3.7 days (hazards ratio HR = 0.29, 95% CI 0.18-0.49), exceeding the effect size of secondary surgery (HR = 0.48) and other respiratory complications (HR = 0.50). CONCLUSION: VAP accounts for a major delay of extubation in pediatric cardiac surgery.

Exercise and postprandial thermogenesis in obese women before and after weight loss.

The magnitude of thermogenesis induced by a test meal (17% protein, 54% CHO, and 29% fat) was assessed using indirect calorimetry in six obese women before and after weight loss (mean loss: 11.2 kg) and compared with six nonobese matched controls at rest for 5 h and during and following graded moderate exercise on a bicycle ergometer at three workloads. The test meal contained 60% of the energy expended in basal state over 24 h (736-1020 kcal/meal according to the group). In obese subjects the net absolute increase in energy expenditure (delta EE) in response to the meal was similar between exercising and resting conditions (delta EE = 0.27 vs 0.32 kcal/min, respectively) but tended to be lower in obese women after weight loss (delta EE = 0.19 kcal/min while exercising and 0.25 kcal/min while resting, p less than 0.05) and in control subjects (delta EE = 0.16 vs. 0.25 kcal/min, respectively: p less than 0.05). These results show that the thermogenic response to a meal is not potentiated by moderate exercise.

Cardiac function assessed by transesophageal echocardiography during pectus excavatum repair.

BACKGROUND: We assessed end-diastolic right ventricular (RV) dimensions and left ventricular (LV) ejection fraction by use of intraoperative transesophageal echocardiography before and after surgical correction of pectus excavatum in adults. METHODS: A prospective study was conducted including 17 patients undergoing surgical correction of pectus excavatum according to the technique of Ravitch-Shamberger between 1999 and 2004. Intraoperative transesophageal echocardiography was performed under general anesthesia before and after surgery to assess end-diastolic RV dimensions and LV ejection fraction. The end-diastolic RV diameter and area were measured in four-chamber and RV inflow-outflow view, and the RV volume was calculated from these data. The LV was assessed by transgastric short-axis view, and its ejection fraction was calculated by use of the Teichholz formula. RESULTS: The end-diastolic RV diameter, area, and volume all significantly increased after surgery (mean values +/- SD, respectively: 2.4 +/- 0.8 cm versus 3.0 +/- 0.9 cm, p < 0.001; 12.5 +/- 5.2 cm(2) versus 18.4 +/- 7.5 cm(2), p < 0.001; and 21.7 +/- 11.7 mL versus 40.8 +/- 23 mL, p < 0.001). The LV ejection fraction also significantly increased after surgery (58.4% +/- 15% versus 66.2% +/- 6%, p < 0.001). CONCLUSIONS: Surgical correction of pectus excavatum according to Ravitch-Shamberger technique results in a significant increase in end-diastolic RV dimensions and a significantly increased LV ejection fraction.

The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates alpha1 adrenergic receptor-induced cardiomyocyte hypertrophy.

In response to various pathological stresses, the heart undergoes a pathological remodeling process that is associated with cardiomyocyte hypertrophy. Because cardiac hypertrophy can progress to heart failure, a major cause of lethality worldwide, the intracellular signaling pathways that control cardiomyocyte growth have been the subject of intensive investigation. It has been known for more than a decade that the small molecular weight GTPase RhoA is involved in the signaling pathways leading to cardiomyocyte hypertrophy. Although some of the hypertrophic pathways activated by RhoA have now been identified, the identity of the exchange factors that modulate its activity in cardiomyocytes is currently unknown. In this study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor activity, is critical for activating RhoA and transducing hypertrophic signals downstream of alpha1-adrenergic receptors (ARs). In particular, our results indicate that suppression of AKAP-Lbc expression by infecting rat neonatal ventricular cardiomyocytes with lentiviruses encoding AKAP-Lbc-specific short hairpin RNAs strongly reduces both alpha1-AR-mediated RhoA activation and hypertrophic responses. Interestingly, alpha1-ARs promote AKAP-Lbc activation via a pathway that requires the alpha subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as the first Rho-guanine nucleotide exchange factor (GEF) involved in the signaling pathways leading to cardiomyocytes hypertrophy.

FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes.

Recent evidence suggests that the heart possesses a greater regeneration capacity than previously thought. In the present study, we isolated undifferentiated precursors from the cardiac nonmyocyte cell population of neonatal hearts, expanded them in culture, and induced them to differentiate into functional cardiomyocytes. These cardiac precursors appear to express stem cell antigen-1 and demonstrate characteristics of multipotent precursors of mesodermal origin. Following infusion into normal recipients, these cells home to the heart and participate in physiological and pathophysiological cardiac remodeling. Cardiogenic differentiation in vitro and in vivo depends on FGF-2. Interestingly, this factor does not control the number of precursors but regulates the differentiation process. These findings suggest that, besides its angiogenic actions, FGF-2 could be used in vivo to facilitate the mobilization and differentiation of resident cardiac precursors in the treatment of cardiac diseases.