To assess whether these changes were specific to the heart, we simultaneously investigated substrate levels in skeletal muscle.Metabolic dysfunction is one of the hallmarks of sepsis yet little is known about local changes in key organs such as the heart. The aim of this study was to compare myocardial metabolic changes by direct measurements of substrates, such as glucose, lactate and pyruvate, using microdialysis (MD) in n = 8, endotoxemic shock (E) n = 9 and hemorrhagic shock (H) n = 9. Interstitial myocardial pyruvate, lactate and glucose were measured using MD. Skeletal muscle MD was also performed in all three groups.Twenty-six female pigs were randomized to three groups: control (C) P <0.001; H versus E -1.1(-1.8 to -0.4), P = 0.004; C versus H -0.4(-1.1 to 0.3), P = 0.282). Up to four-fold increases in myocardial pyruvate and three-fold increases in lactate were seen in both shock groups with no differences between the two types of shock. There was no evidence of myocardial anaerobic metabolism, with normal lactate:pyruvate (L:P) ratios seen in all animals regardless of the type of shock.Marked decreases in myocardial glucose were observed in the E group but not in the H group compared to controls (mean difference (CI) in mmol/L: C versus E -1.5(-2.2 to -0.8), P = 0.007). Although skeletal muscle lactate increased in both shock groups, this was accompanied by increases in pyruvate in the E group only (mean difference: C versus E 121(46 to 195), P = 0.003; H versus E 77(7 to 147), P = 0.032; C versus H 43(-30 to 43), P = 0.229). The L:P ratio was increased in skeletal muscle in response to hemorrhagic, but not endotoxemic, shock.In skeletal muscle, decreases in glucose concentrations were observed in the E group only (mean difference: C versus E -0.8(-1.4 to -0.3), Endotoxemia, but not hemorrhage, induces a rapid decrease of myocardial glucose levels. Despite the decrease in glucose, myocardial lactate and pyruvate concentrations were elevated and not different than in hemorrhagic shock. In skeletal muscle, substrate patterns during endotoxemic shock mimicked those seen in myocardium. During hemorrhagic shock the skeletal muscle response was characterized by a lack of increase in pyruvate and higher L:P ratios.Hence, metabolic patterns in the myocardium during endotoxemic shock are different than those seen during hemorrhagic shock. Skeletal muscle and myocardium displayed similar substrate patterns during endotoxemic shock but differed during hemorrhagic shock. Further, it is not known if there is a specific pattern of changes for sepsis and if these only apply to cardiac muscle. Impairment of glucose metabolism has been demonstrated in experimental models of septic shock [+ K+ ATPase activity, mitochondrial dysfunction and pyruvate dehydrogenase inhibition. It is likely that endotoxemia, hemorrhage and other mechanisms of shock have variable effects on cardiac and skeletal muscle metabolism and this may have implications for clinical management of these conditions. This is highly relevant as approximately 15% of deaths related to septic shock have been attributed to myocardial depression [Imbalance in myocardial energy metabolism has been proposed as one of the mechanisms behind cardiac dysfunction associated with sepsis ,2. Despiic shock ,7. Emergic shock .These diic shock ,9. Possipression .Carbohydrate metabolism and its regulation in the myocardium is complex and is dependent on arterial substrate levels, coronary blood flow, hormonal levels in the blood, nutritional reserve of the heart and the inotropic state . In the The aim of this study was to compare the metabolic changes in the myocardium using MD in porcine models of shock resulting from endotoxemia and hemorrhage. To assess whether these changes were specific to the heart, we simultaneously investigated substrate levels in skeletal muscle.n = 8, endotoxemic shock (E) n = 9 and hemorrhagic shock (H) n = 9.The study was approved by the Swedish National Board for Animal Experimentation (Case number M131-09) and conforms to the guidelines laid out in the Guide for the Care and Use of Laboratory Animals from the National Research Council. Twenty-six female pigs, weighing 32 to 41 kg, were used in the study and were randomized to three groups: control (C) The porcine endotoxemic model has been previously described . After pAll animals were monitored with  invasive arterial blood pressure measurement, SpO2 and hourly urine output. Arterial blood gases were drawn every two hours for adjustment of ventilator settings.The external jugular veins were exposed bilaterally by surgical cut-down. A central venous catheter was inserted for drug and fluid infusion. The contralateral external jugular vein was used for the insertion of a pulmonary artery catheter (PAC). This was used for hourly measurements of central venous pressure (CVP), mean pulmonary arterial pressure (MPAP) and pulmonary capillary wedge pressure (PCWP).The left or right carotid artery was also exposed by surgical cut-down, and an arterial catheter was inserted for blood gas sampling.in-situ for at least one hour for stabilization before microdialysate samples were collected.The left or right femoral artery was also exposed surgically and an arterial catheter was inserted for bleed-out in the animals assigned to the hemorrhagic shock groups. A midline thoracotomy was performed and the pericardium divided, suspending the heart in a pericardial sling. A MD catheter  was inserted into the anterior surface of the myocardium, immediately adjacent and parallel to the diagonal branches of the left anterior descending artery. The catheters were perfused with Ringer's acetate at 0.3 uL/minute. MD catheters were left The pericardial cavity was filled with saline solution and ultrasound gel to provide acoustic coupling for transepicardial echocardiographic imaging.in-situ for at least one hour for stabilization before microdialysate samples were collected.Via direct surgical exposure a MD catheter  was inserted into the gluteus maximus muscle. The catheters were perfused with Ringer's acetate at 0.3 uL/minute. Microdialysis catheters were left The urinary bladder was catheterized using a suprapubic approach and urine output (UO) measured hourly.Escherichia coli lipopolysaccharide  at an infusion rate of 5 ug/kg/hour for the first hour followed by 2.5 ug/kg/hour for the remaining duration of the experiment.Endotoxemia was induced using A bleed out of 30% blood volume was made via a femoral arterial catheter assuming a blood volume of 76 ml/kg for all pigs . Bleed oThe following systemic hemodynamic measurements were recorded hourly: mean arterial pressure (MAP), MPAP, PCWP, CVP, mixed venous oxygen saturation (SmvO2), cardiac index (CI) and systemic vascular resistance index (SVRI). The following parameters were calculated: stroke volume index (SVi), oxygen delivery index (DO2i), oxygen consumption index (VO2i), left ventricular stroke work index (LVSWI), right ventricular stroke work index (RVSWI) and oxygen extraction ratio (O2ER).Urine output was recorded hourly.flex microdialysis analyzer {AU Query: Please indicate the manufacturer of the microdialysis analyzer - city, state (if applicable), country.} according to the manufacturer's instructions. This analyzer uses enzymatic reagents and colorimetric assays, with an assay imprecision of <4%.Microdialysate samples in the myocardial and skeletal muscle interstitium were collected every hour for the measurement of interstitial glucose, lactate and pyruvate and for the calculation of lactate to pyruvate ratios (L:P). Analyses of these metabolites were made on an ISCUSTransthoracic echocardiographic images of the heart were obtained from the apex using a direct epicardial approach. Four-chamber and two -chamber views are obtained. Left ventricular (LV) systolic function was evaluated using ejection fraction by eyeballing (EF), velocity time integral at the left ventricular outflow tract (VTI) and the average of septal and lateral tissue Doppler velocities (TDI). LV diastolic function was evaluated using the mitral early to late inflow velocity ratio (E/A) and mitral early inflow to tissue Doppler velocity ratio (E/é). Right ventricular function was assessed as the tricuspid annular plane systolic excursion (TAPSE) and the pressure gradient between the right atrium and ventricle (TR).P-values less than 0.05 were considered statistically significant. Skewed data were log-transformed. All analyses were conducted using R (http://www.r-project.org) and Sigma Stat version 3.5 .A mixed model analysis with a random intercept for each pig was used to control for between-pig differences. We modeled each response over time with group  as independent variables. Baseline response was included as a covariate in order to control for regression to the mean. No linear assumptions were made for the change over time. We calculated the average difference between groups over all times  and the maximum difference over hours one to six. Hemodynamic alterations in the E group were characterized by significant increases in heart rate (HR) and MPAP and decreases in MAP, SVI and LVSWI compared to the control group. RVSWI increased, reflecting increases in pulmonary arterial pressures, a finding supported by echocardiography parameters. There were trends to decreased SmvO2 but these changes were short-lived, reaching statistical significance only within the first two hours of endotoxemia. Arterial lactate concentrations increased significantly, up to three-fold compared to controls. Despite the decrease in MAP and increases in HR and arterial lactate concentration (A-lac), DO2i, VO2i and O2ER were relatively preserved. In the hemorrhage group significant increases were observed in O2ER and decreases in MAP, CVP, PCWP, DO2i, LVSWI and RVSWI compared to C and E animals. A-lac increased 2.5-fold.There were no significant changes in arterial glucose concentrations in any of the groups over time nor between the groups (data not shown).There were significant decreases in LV systolic function as assessed by EF in the E group compared to the C and H groups. EF increased slightly in the H group and decreased in the E group, with statistically significant differences between the two shock groups from four hours post endotoxemia (t4) onwards. LV diastolic function, measured as E/A and E/é remained unchanged in all three groups.P = 0.056).VTI significantly decreased in the H group and was significantly different from the C group. VTI was also decreased in the E group, but this did not reach statistical significance  whereas they remained relatively stable in the H group  and H versus E groups (P = 0.004). Post-hoc analysis revealed significant differences between C and E animals and between H and E animals from t3 onwards. No difference was seen for the C versus H group. Increases in myocardial pyruvate were seen in all animals, with four-fold increases observed in H and E shock groups  and between the C and H groups (P <0.001) but not between the H and E animals. Myocardial lactate levels also increased in both shock groups  and between the C and H groups (P = 0.016). There were no differences between the E and H groups. The myocardial-A-lac gradient was significantly increased in the E compared to the H group (mean difference H versus E 0.7 (CI 0 to 1.3) mmol/L, P = 0.04) but was not significantly different from the C group (mean difference C versus E -0.3 (CI -1.0 to 0.3) mmol/L, P = 0.299). The L:P ratio over time decreased significantly in all animals, indicating no evidence of myocardial anaerobic metabolism  mmol/L, p Figure . There ws Figure . There ws Figure . Signifim Figure .P = 0.003, C versus H P = 0.229, H versus E P = 0.032) (Table P = 0.061 and a maximum difference -0.9 (-1.6 to -0.2), P = 0.014 at t4  mmol/L, skeletal muscle: nadir 0.4 (0.3 to 1.0) mmol/L; P <0.001 compared to baseline for both organs). In contrast, hemorrhagic shock did not significantly decrease myocardial or skeletal muscle glucose compared to controls Table  and 1b. 2) Table . L:P rat2) Table . In cont4 Figure .To our knowledge this is the first reported study comparing myocardial metabolism using MD in models of hemorrhagic and endotoxemic shock. The most striking finding of this study is the precipitous decrease in myocardial glucose concentrations to near-zero levels in endotoxemic, but not hemorrhagic, shock. Despite the decrease in myocardial glucose concentrations during endotoxemia, similar changes in myocardial lactate and pyruvate concentrations were measured in both hemorrhagic and endotoxemic shock. Therefore, endotoxemic and hemorrhagic shock seem to be characterized by a different myocardial glucose response but similar pyruvate and lactate responses.Next, we asked if these changes were specific to the myocardium. In skeletal muscle, endotoxemia also induced decreases in glucose, increases in lactate, pyruvate and preserved L:P ratios. In contrast hemorrhagic shock did not increase skeletal muscle pyruvate. The resultant L:P ratio in skeletal muscle was increased indicative of anaerobic metabolism. These results demonstrate that the skeletal muscle responds differently to the different types of shock. Taken together, they suggest that the heart and skeletal muscle have different metabolic signatures that are dependent on the type of shock.While FFAs are known to be the preferred energy substrate for the heart , under sAnother relevant question identified by these findings is whether the decrease in myocardial glucose concentrations may be associated with cardiac dysfunction. While we demonstrated significant impairment in both left and right ventricular function measured using echocardiography, all of the measured indices are, to different extents, preload dependent. Hence, we refrained from any further analysis of the relationship between cardiac function and metabolic parameters. A longer observation period with low concentrations of myocardial glucose may have revealed a depletion of myocardial energy stores and been associated with further decreases in cardiac function. There was a concurrent rise in myocardial pyruvate, suggesting either the conversion of glucose or lactate into pyruvate for use in the tricarboxylic acid cycle.This study supports the concept of accelerated aerobic glycolysis in the myocardium where the rate of glucose metabolism exceeds the oxidative capacity of the mitochondria. Thus, glucose is converted to pyruvate, whose concentration rises and drives the production of lactate with resultant normal L:P ratios. This was particularly observed during endotoxemic shock with about four-fold increases in pyruvate, accompanying increases in interstitial lactate and low L:P ratios. This increase in pyruvate may be an adaptive mechanism since pyruvate in supraphysiological concentrations has been shown to increase cardiac contractile performance and myocardial energy state and protect the myocardium from ischemia-reperfusion injury and oxidant stress . A key let al.'s landmark studies [There was no evidence of myocardial ischemia during shock from endotoxemia or hemorrhage despite significant hemodynamic alterations particularly in the latter group. Hence, further support is provided for Levy  studies ,20,21 whet al. demonstrated increases in myocardial lactate uptake and decreases in free fatty acid and glucose utilization measured in coronary sinus blood [Myocardial metabolism of energy substrates is altered in the setting of increased cardiac work and inflammation -7,17. Inus blood . The incus blood , switchius blood . An attrus blood .2, and greater increases in MPAP and A-lac levels. Hence, the two groups are difficult to compare and the findings here should be interpreted cautiously. The increases in myocardial pyruvate levels in the control group were unexpected and we speculated if it could have been a result of anesthesia, sternotomy and fluid resuscitation with Ringer's lactate. However, all animals were subjected to the same anesthesia and surgical procedures. Further increases in pyruvate were only seen in cardiac muscle. In a previous (unpublished) LPS dose-finding study we tested resuscitation with 0.9% saline (n = 4) and 5% albumin (n = 3), with similar results seen for pyruvate measurements in the myocardium. Hence, it is unlikely that this phenomenon is due to the administration of Ringer's acetate. It would be relevant to study the contribution of other energy substrates in the heart, such as FFAs, ketones and glycogen, which were not available using the present microdialysis technique. In line with this, it would also have been relevant to measure myocardial ATP levels. Further, while we have been able to measure substrate availability using microdialysis, we did not study their uptake or oxidation per se. Hence, any changes in substrate concentrations observed here cannot be ascribed to changes in delivery, uptake or consumption. This would be relevant in future research and requires measurement of regional flow and the use of labeled isotope which was beyond the scope of the present study. Finally, the observation time for this study was six hours post-induction of shock, and the changes here represent only the acute situation. These findings may be altered in the setting of hypodynamic, endotoxemic shock. A longer observation period may have revealed different results and allowed the investigation of prolonged interstitial metabolic changes on cardiac function. In addition, there may have been differences between the right and left heart that were beyond the scope of this study.There are a number of limitations to this study. Firstly, there are important differences between endotoxemic and septic shock and findings here may not be generalizable to patients with sepsis. However, this was a proof-of-concept study and endotoxemia is a valid model for demonstrating that myocardial concentrations of major energy substrates are affected by major inflammatory insults. The endotoxemic and hemorrhagic shock groups had different temporal hemodynamic profiles with endotoxic shock animals experiencing less severe decreases in MAP and SmvOAlthough we have used currently accepted echocardiographic indices for the measurement of systolic and diastolic function, all echo data provided in the present study are preload, afterload and HR dependent. It is, therefore, difficult, if at all possible, to differentiate between direct myocardial systolic and diastolic effects of endotoxemia from secondary effects caused by endotoxemia-induced changes in preload, afterload or heart rate.Notwithstanding the limitations above, microdialysis provides a unique possibility for studying the temporal changes in metabolism directly in tissues. We demonstrate these changes for the first time in the heart, comparing it to a different metabolically active organ, and in two different types of shock. A logical extension to this study would be to investigate changes during hypodynamic septic shock and during overt myocardial dysfunction, to monitor responses during resuscitation, as well as to extend MD studies to other organs.Endotoxemic and hemorrhagic shock induce profound changes in myocardial energy substrates, characterized by up to four-fold increases in interstitial pyruvate and three-fold increases in interstitial lactate. Endotoxemic, but not hemorrhagic, shock was characterized by a precipitous decrease in myocardial glucose. In skeletal muscle similar patterns were seen during endotoxemic shock with decreases in glucose and increases in pyruvate and lactate concentrations. However, during hemorrhagic shock, the skeletal muscle response differed and was characterized by a lack of increase in pyruvate. Taken together, these findings suggest that the heart and skeletal muscle respond in metabolically distinct fashions in different types of shock.• Endotoxemic shock causes a severe and precipitous decrease in myocardial glucose concentrations• Despite the decrease in glucose, myocardial pyruvate and lactate concentrations are simultaneously increased in both types of shock• Skeletal muscle responds differently with no increases in pyruvate seen in hemorrhagic shock• Taken together, these findings suggest that the heart responds in a metabolically distinct fashion in endotoxemic and hemorrhagic shock• The finding of increased lactate and pyruvate is consistent with Taegtmeyer's concept of the heart being a 'metabolic omnivore', switching energy substrates to maintain metabolic flexibilityA-lac: arterial lactate; CI: cardiac index; CVP: central venous pressure; DO2i: oxygen delivery index; E/A: mitral early inflow to late  inflow velocity ratio; E/é: mitral early inflow to tissue doppler velocity ratio. EF: ejection fraction; FFAs: free fatty acids; HR: heart rate; L:P: lactate to pyruvate ratio; LPS: lipopolysaccharide; LVSWI: left ventricular stroke work index; MAP: mean arterial pressure; MD: microdialysis; MPAP: mean pulmonary arterial pressure; O2ER: oxygen extraction ratio; PAC: pulmonary arterial catheter; PCWP: pulmonary capillary wedge pressure; PDH: pyruvate dehydrogenase; RVSWI: right ventricular stroke work index; SmvO2: mixed venous oxygen saturation; SVI: stroke volume index; SVRI: systemic vascular resistance index; TAPSE: tricuspid annular plane systolic excursion; TDI: tissue Doppler velocity; TR: pressure gradient between right atrium and ventricle measured using Doppler; VO2i: oxygen consumption index; VTI: velocity time integral at the left ventricular outflow tract.The authors declare that they have no competing interests.MSC designed the study, collected data, assisted in statistical analysis and drafted the manuscript. BAB was involved in study design, collected data and assisted in statistical analysis. KS assisted in statistical analysis, interpretation of the data and drafted the manuscript. CN was involved in study design, collected data and performed all MD measurements. AGB conducted all statistical analyses, interpreted the data and was involved in drafting the manuscript. All authors have read and approved the final manuscript.


Impaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE).Forty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters.2) correlated significantly with pre-op PVR , mPAP  and cardiac index . Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR , cardiac index , and E/A .Pre-op LAVI (mean 19.0 ± 7 mL/mIn CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH), the result of unresolved thrombus in the pulmonary vasculature following pulmonary embolism, carries a high rate of morbidity and mortality if left untreated -3. In adSeveral theories have been put forth to explain this LV diastolic “dysfunction”, including decreased LV volume and compliance due to leftward septal shifting, and true intrinsic dysfunction of the LV . More reThis is a retrospective analysis of forty-eight consecutive CTEPH patients undergoing PTE at a large CTEPH referral center. The study cohort was comprised of 24 men and 24 women with a mean age of 52 ± 16 years, ranging from 19 to 84. All patients had class III to IV symptoms according to the New York Heart Association (NYHA) Functional Classification. Pre- and postoperative echocardiograms and right heart catheterizations were performed in each case. All PTE surgeries were completed at UCSD Medical Center using methods outlined in previous publications , and many had depressed cardiac output (mean CO of 3.9 ± 1.2 l/min). Evidence of diastolic dysfunction was also present, with decreased mitral E/A ratio (0.95 ± 0.31) and increased deceleration time (224 ± 60 ms). Mitral lateral annular E/E’ was 6.1 ± 2.8. Of note, pre-operative left atrial volume index was relatively low (19.0 ± 7.0 cm3/m2). All baseline hemodynamic and echocardiographic findings are listed in Table Prior to PTE all patients had evidence of significantly elevated right-sided pressures [mPAP of 45.5 ± 9.6 mmHg and PVR of 765 ± 396 (dyne-sec)/cm5 (p < 0.001). This normalization of right-sided pressures coincided with an improvement in cardiac output to 5.2 ± 1.6 L/min (p < 0.001). Further, LV diastolic function improved post-operatively, with the E/A ratio rising to 1.45 ± 0.48 (p < 0.001) and the E deceleration time dropping into the normal range (189 ± 39 ms) (p < 0.001). A significant increase in left atrial volume index also occurred (from 19.0 ± 7.0 to 22.4 ± 6.8 cm3/m2) (p = 0.003). Mitral annular E/E’ increased to 7.9 ± 2.7 (p < 0.001). The changes in each variable following surgery are listed in Table Following surgery significant improvements in hemodynamics were observed. The mean pulmonary arterial pressure fell to 28.8 ± 6.7 mmHg p < 0.001) and pulmonary vascular resistance dropped to 310 ± 143 (dyne-sec)/cm and pulmPost-PTE, the change seen in LA volume index was associated with improvement in many of these same parameters. LA volume change correlated significantly with decrease in PVR  and increase in cardiac index . Similarly, increasing LA volume index correlated with improving diastolic function, such as an increase in mitral E/A ratio . Furthermore, the subsequent increase in LA volume following PTE was significantly correlated with higher mitral E/A ratio. Both of these findings support the theory of LV underfilling and suggest that LA volume is a significant component of the process.Whether LA volume in CTEPH is limited solely by decreased LA filling or by anatomic restrictions as well is not entirely clear. A recent study suggests that changes in RV outflow tract dimension may affect left atrial filling and compliance in CTEPH . A propoA limitation in our study was the timing of the preoperative transthoracic echocardiogram and right heart catheterization. They were not performed simultaneously and in some instances up to 48 hours elapsed between procedures. As this population was stable preoperatively, it is unlikely this had a significant impact on the results. Post-operatively, echocardiography was performed an average of 9 days after PTE. It is conceivable that cardiac dimensions may have varied during this period, but again these patients were overall stable following surgery. As with several previous studies from our institution, echocardiography was delayed until patients left the surgical intensive care unit and could be examined safely in the noninvasive cardiac laboratory ,6,20.This study was designed to evaluate LA volume characteristics in CTEPH patients undergoing PTE. This data suggest that LA volume is inversely associated with severity of CTEPH, and that LA volume increases after PTE. The rapid increase in LAV and correlation with improvement in E/A ratio supports the concept that left ventricular diastolic impairment is due primarily to left heart underfilling rather than inherent left ventricular diastolic dysfunction. The long-term prognostic implications of LA volume change after PTE deserves further study.CTEPH: Chronic thromboembolic pulmonary hypertension; LV: Left ventricle; LA: Left atrium; PTE: Pulmonary thromboendarterectomy; NYHA: New York Heart Association; UCSD: University of California San Diego; LAVI: Left atrial volume index; CI: Cardiac index; RHC: Right heart catheterization; mPAP: Mean pulmonary artery pressure; PVR: Peripheral vascular resistance; PCWP: Pulmonary capillary wedge pressure; CO: Cardiac output.The authors declare that they have no competing interest.All authors contributed to the study design, data collection, data analysis, and writing of the manuscript. All authors read and approved the final manuscript.This manuscript originates from the Cardiovascular Center at the University of California, San Diego Medical Center, which has the highest-volume program for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary thromboendarterectomy in the Western hemisphere. Dr. Blanchard has been senior author on a number of papers describing the interactions of the right and left ventricles in CTEPH over the last several years. Dr. Auger is a senior pulmonary specialist within the group, and Dr. Madani performs the majority of pulmonary thromboendarterectomies. Dr. Anthony DeMaria is the immediate past Editor-in-Chief of the Journal of the American College of Cardiology, and is a pre-eminent authority in echocardiography.


Heart failure prediction after acute myocardial infarction may have importantclinical implications.To analyze the functional echocardiographic variables associated with heartfailure in an infarction model in rats.The animals were divided into two groups: control and infarction.Subsequently, the infarcted animals were divided into groups: with andwithout heart failure. The predictive values were assessed by logisticregression. The cutoff values predictive of heart failure were determinedusing ROC curves.Six months after surgery, 88 infarcted animals and 43 control animals wereincluded in the study. Myocardial infarction increased left cavity diametersand the mass and wall thickness of the left ventricle. Additionally,myocardial infarction resulted in systolic and diastolic dysfunction,characterized by lower area variation fraction values, posterior wallshortening velocity, E-wave deceleration time, associated with higher valuesof E / A ratio and isovolumic relaxation time adjusted by heart rate. Amongthe infarcted animals, 54 (61%) developed heart failure. Rats with heartfailure have higher left cavity mass index and diameter, associated withworsening of functional variables. The area variation fraction, the E/Aratio, E-wave deceleration time and isovolumic relaxation time adjusted byheart rate were functional variables predictors of heart failure. The cutoffvalues of functional variables associated with heart failure were: areavariation fraction < 31.18%; E / A > 3.077; E-wave deceleration time< 42.11 and isovolumic relaxation time adjusted by heart rate <69.08.In rats followed for 6 months after myocardial infarction, the area variationfraction, E/A ratio, E-wave deceleration time and isovolumic relaxation timeadjusted by heart rate are predictors of heart failure onset. In this sense, around 50% of patients with cardiacdysfunction die within 5 years. In addition, 40% of patients die during the periodof 1 year after the first hospitalization for heart failure, with many of the deathsoccurring as sudden death.3 Thus, the association between MI and ventricular dysfunctioncannot be neglected.It is currently believed that the myocardial infarction (MI) is the main etiology ofventricular dysfunction. In this sense, epidemiological studies suggest that thesigns and symptoms of heart failure are present in 25% of MI cases. Moreover,approximately 40% of MI cases are accompanied by systolic alterations in the leftventricle (LV). Recently, it was verified that 10% of MI patients have a restrictivepattern, suggesting severe diastolic dysfunction.4One of the most often used strategies for the study of functional alterations causedby coronary occlusion is the use of the experimental infarction model in rats. Amongother factors, this is due to the low cost and simplicity of handling these animals.The most important factor, however, refers to the similarity with thephysiopathological changes that occur after an infarction in humans.18 However, there hasbeen no consensus on which functional variables are predictive of heart failure inthis model. Thus, our objective was to evaluate the functional variables associatedwith heart failure in the model. In addition, we intend to determine the criticalvalues for heart failure prediction for each variable.Echocardiography has been widely used in the study of the morphological andfunctional alterations after coronary occlusion.The experimental protocol of this study was approved by the Animal ExperimentationEthics Committee of our institution, complying with the Ethical Principies in AnimalExperimentation adopted by the Brazilian College of Animal Experimentation.20 Briefly, the rats were anesthetized with ketamine (70mg/kg) and xylazine (5 mg/kg) and submitted to a left lateral thoracotomy. Afterexteriorization of the heart, the left atrium was moved away and the leftcoronary artery was ligated with a 5-0 monofilament nylon suture between thepulmonary artery outflow tract and the left atrium. Subsequently, the heart wasreturned to the chest, the lungs were inflated with positive pressure and thethorax closed using cotton 10 sutures. Coronary occlusion was not performed in43 animals (Control Group).Male Wistar rats, weighing between 200 and 250 g were studied. Acute myocardialinfarction was produced according to the previously described method.The animals were kept in cages for recovery, fed standard commercial chow and hadfree access to water, with regular 12 hour light: dark cycles, at a temperatureof approximately 25° C and controlled humidity.21 Leftventricular cavity image was obtained by positioning the M-mode cursor betweenthe papillary muscles, right below the mitral valve plane. The LV diastolicdiameter (LVDD) and left ventricular septal thickness (LVST) were measured atthe moment corresponding to the maximum cavity diameter. The LV Systolicdiameter (LVSD) was measured at the maximum systolic excursion of the posteriorwall of the cavity. Diastolic (DA) and systolic (SA) areas of LV were measuredin two-dimensional mode, using planimetry at the parasternal plane of thesmaller axis.Echocardiography was performed 6 months after the infarction. The animals wereanesthetized intramuscularly with ketamine (50 mg/kg) and xylazine (1 mg/kg),for the echocardiographic study. After trichotomy of the anterior chest region,the animals were positioned in the supine position in a specially designedgrooves that allows slight left lateral rotation for the examination, usingPhilips equipment (HDI 5000 model) equipped with a multi-frequency electronictransducer up to 12 MH. All measurements were made in accordance with therecommendations of the American Society of Echocardiography/European Associationof Echocardiography.23LV systolic function was assessed by calculating the area variation fraction (AVF= (DA-SA)/DA) and the posterior wall shortening velocity (PWSV). Diastolicfunction was assessed by the E/A ratio, the E-wave deceleration time (EDT) andthe Isovolumic Relaxation Time Adjusted for Heart Rate (IVRT/HR).25After the echocardiographic study, the animals were euthanized and the heartswere removed and dissected. The right and left ventricles, including theinterventricular septum, were separated. Cardiac tissue samples were fixed in a10% formaldehyde solution for 48 hours, according to the previously describedmethod.The histological sections were stained on slides with hematoxylin-eosin (HE) andMasson solution for assessment of the infarcted tissue, using a Leica DM LSmicroscope coupled to a video camera, which sends digital images to a computerwith the Image Pro-Plus imaging analysis program .25 To estimate the infarctionsize through histological analysis, the epicardial and endocardialcircumferences of the infarcted and non-infarcted segments were determined. Theinfarction size is expressed as a percentage of the ventricular circumferencemeasurements.The infarction size was determined in 5 to 6-mm sections from the apex, as thevalues in this region correspond to the mean values obtained from sections ofthe entire heart.27The diagnosis of heart failure was made by thrombus detection in the left atrium,pleural effusion, ascites, and right ventricular hypertrophy, characterized bythe ratio of the right ventricle weight adjusted for body weight > 0.8 mg/g,as previously described.t test when data showed normal distribution. When thedata did not have normal distribution, comparisons between groups were performedusing the Mann-Whitney U test. Data were expressed as mean ± standarddeviation or median, with 25 and 75 percentiles. The predictive values wereanalyzed by logistic regression. In this analysis, the presence or absence ofheart failure was used as the dependent variable. The cutoff values predictiveof heart failure were determined using ROC curves. The significance level wasset at 5%. Statistical analyses were performed using the SigmaPlot program forWindows, v.12.0 .The comparisons between the groups after 6 months were carried out usingStudent's Six months after surgery, 88 animals with infarction (I) and 43 control animals (C)were included in the study.Echocardiographic variables are shown in Considering the infarcted animals, 54 animals (61%) developed heart failure. Animalswith heart failure had larger infarctions , higher mass index and left cavity diameters, associated withworsening of functional variables, compared with the infarcted animals without heartfailure .The aim of our study was to evaluate the functional variables associated with heartfailure in an experimental MI model in rats. Our data suggested that AVF, E/A ratio,EDT and IVRT/HR are predictors of heart failure 6 months after infarction.26 in accordance withthis concept, in this study, the animals showed, on average, large infarcts. In thissense, we can infer that the coronary occlusion model in rats is appropriate for thestudy of the heart failure syndrome.The first aspect to be considered is that in our study, most animals (61%) withinfarction developed heart failure. In a previous study, we determined thatinfarctions affecting 40% of LV are required for the development of heart failure inthis model.The second important aspect is related to the fact that, as expected, animals withheart failure had worsening of functional variables related to systolic function,when compared with animals without failure. However, in the regression analysis, theAVF, but not LVPW, was predictive of heart failure onset. It is believed that inmodels of regional LV akinesia, one-dimensional echocardiographic methods offunctional assessment may be flawed. In this situation, it is recommended to use,for instance, the Simpson's method in humans. AVF is obtained through the analysisof the SA and DA, using the two-dimensional technique. However, the LVPW is obtainedin single-dimensional mode. Therefore, our results emphasize that, in this model,similar to what occurs in humans, it is preferable to use systolic functionalanalysis with two-dimensional technique, such as AVF, for instance.Another prominent aspect is related to the diastolic function. Unlike systolicfunction, the study of diastolic function through echocardiography in the rat modelis not well standardized. Some of the main technical difficulties are the small sizeof the animal, with its implications on the transducer and heart rate of around 300beats per minute. In our study, however, all assessed diastolic function variableswere associated with heart failure onset. Thus, in this model, diastolic functionassessed by E/A ratio, EDT and IVRT/HR were predictors of heart failure 6 monthsafter coronary occlusion.2) of the LV (invasive hemodynamic method) andthe presence of clinical signs assessed after death , respectively. Therefore, our studysuggests that echocardiography is a useful non-invasive tool for the prediction ofthis syndrome, as systolic function variables, as well the diastolic functionparameters, little studied in this model, were associated with heart failure.The most important aspect of our study is that heart failure prediction in the MI ratmodel has important implications. Although there is no consensus on the definitionof cardiac dysfunction and heart failure, they are usually diagnosed by elevatedend-diastolic pressure . Therefore, we conclude that other factors rather than the infarctionsize, are important determinants of heart failure onset in this model.Finally, it is already well-established that the major determinant of ventricularfunction, of the remodeling process and, consequently, of heart failure onset inthis model, is the size of the infarction.Among the possible candidates, we can include changes in ventricular cavity diameter,wall thickness alterations, changes in the normal LV configuration, from ellipticalto the rounded shape, among others. Therefore, in some situations, changes ingeometry alone could be responsible for ventricular global function impairment, bychanging the load conditions to which the heart is submitted.In rats followed for 6 months after MI, the area variation fraction, the E/A ratio,E-wave deceleration time and the isovolumic relaxation time adjusted by heart ratewere predictors of heart failure onset.


Mechanical factors may contribute to ischemic ventricular arrhythmias. GsMtx4 peptide, a selective stretch-activated channel blocker, inhibits stretch-induced atrial arrhythmias. We aimed to assess whether GsMtx4 protects against ventricular ectopy and arrhythmias following coronary occlusion in swine. First, the effects of 170-nM GsMtx4 on the changes in the effective refractory period (ERP) induced by left ventricular (LV) dilatation were assessed in 8 isolated rat hearts. Then, 44 anesthetized, open-chest pigs subjected to 50-min left anterior descending artery occlusion and 2-h reperfusion were blindly allocated to GsMtx4  or saline, starting 5-min before occlusion and continuing until after reflow. In rat hearts, LV distension induced progressive reductions in ERP  that were prevented by GsMTx4 . Pigs receiving GsMtx4 had similar number of ventricular premature beats during the ischemic period as control pigs . There were not significant differences among treated and untreated animals in the incidence of ventricular fibrillation  or tachycardia  or in the number of ventricular tachycardia episodes during the occlusion period . Thus, GsMtx4 administered under these conditions does not suppress ventricular ectopy following coronary occlusion in swine. Whether it might protect against malignant arrhythmias should be tested in studies powered for these outcomes. Malignant ventricular arrhythmias are frequent and life-threatening complications of acute myocardial ischemia. While the mechanisms of ischemic arrhythmias are complex and not completely understood ,2, the pMechanically-induced arrhythmias have been suppressed in different experimental preparations not involving ischemia by gadolinium or other blockers of stretch-activated ion channels (SACs) –19. HoweGsMtx4, a peptide isolated from tarantula venom that selectively inhibits SACs  and thatst Century Biochemicals, Marlboro, MA) as previously described [The experimental protocol was approved by the Ethical Committee on Animal Experimentation of Vall d’Hebron Research Institute (ref. CEEA 25/05). GsMtx4 peptide was synthesized  were anesthetized with intraperitoneal sodium pentobarbital (100 mg/kg). Hearts were mounted into a non-recirculating Langendorff apparatus, and perfused at 10 ml/min with modified Krebs-Henseleit bicarbonate buffer equilibrated with 95% Oescribed . A fluidHearts were paced at a 250-ms cycle length . Programmed bipolar stimulation was performed to determine the effective refractory period (ERP). After a drive train of 20x200 ms, a ventricular extrastimulus was introduced with an initial coupling interval of 15-ms that was progressively increased at 1-ms steps until capture was observed twice in a row. The ERP was defined as the highest coupling interval failing to capture. The stimulation protocol was continued until reaching a coupling interval of 5-ms above the ERP and the number of episodes of induced ventricular tachycardia in these 5 runs was counted and their duration recorded .These measurements were performed in each heart at 3 different values of LVEDP: 0, 20 and 40 mmHg, in random order. LVEDP was modified by changing the volume of fluid in the balloon. Measurements were performed sequentially with and without GsMtx4 in the perfusate, also in a random order and in a blinded fashion. During the first set of measurements, a solution containing GsMtx4 or only the buffer was added through a lateral line, and the second set of measurements was repeated after 30-min washout by adding the complementary solution. GsMtx4 was infused at a final concentration of 170 nM, which suppressed stretch-induced atrial arrhythmias ex-vivo . The 30-Forty-six domestic hybrid pigs of either sex (33±1 kg) were premedicated with 10 mg/kg intramuscular azaperone and anesthetized with 30 mg/kg intravenous thiopental sodium followed by a continuous infusion. We previously observed in this animal model that the dilatation of the ischemic region was associated with ventricular fibrillation or tachycardia after coronary occlusion . AnimalsAfter attaining hemodynamic stability, the LAD was occluded by tightening the snare. Animals were blindly allocated to receive GsMtx4 or saline. In the former group, a saline solution containing 57.4 μg GsMtx4/kg was administered intravenously during 2 min starting 5 min before coronary occlusion . After this bolus, a maintenance infusion of 3.8 μg/kg/min was provided during the following 58 min. Fifty minutes after coronary occlusion, reperfusion was allowed for 2 hours, after which time the LAD was re-occluded. Animals were euthanized by pentobarbital overdose followed if needed by inducing ventricular fibrillation. The heart was excised and cut in slices and the mass of the ischemic region (in vivo fluorescein injection) and infarct size (triphenyltetrazolium chloride reaction) were calculated as previously described –13.Two animals were excluded, one before randomization due to major bleeding during sternotomy and one after randomization due to incessant ventricular fibrillation immediately after coronary occlusion, showing the examination of the heart severe subaortic stenosis and LV hypertrophy. Thus, this series was composed of 44 valid experiments, 22 in each treatment arm.Serial arterial blood gases were obtained to adjust the ventilator parameters. Serum pH, sodium, potassium, and bicarbonate levels and the hematocrit value were measured at baseline and at the end of the experiment. Aortic pressure was monitored. The ultrasonic signals were analyzed with an ultrasonic dimension system  and monitored with an oscilloscope . These signals, along with an electrocardiographic lead, aortic pressure, LAD blood flow and LV pressure and its first derivative (dP/dt) were continuously recorded, digitized (ML795 PowerLab) and stored . If ventIn 12 animals (6 per group), the ventricular ERP was determined by programmed stimulation, as previously described , before Segment length measurements were performed on the digital records as previously described –13. End-According to the frequency and variability  of VPBs after coronary occlusion in a previous study in the same model , the samBefore programmed stimulation, LV developed pressure averaged 109±4 mmHg and perfusion pressure 64±1 mmHg, without differences among treated and untreated conditions. The results of these experiments are illustrated in Hemodynamic data are summarized in Segment length changes are summarized in The size of the area at risk was comparable in animals receiving GsMtx4 or saline . Infarct size was also not significantly different in both groups, either considered as absolute infarct mass , as a percentage of ventricular mass  or as a percentage of the area at risk .At baseline, ventricular ERP averaged 255±10 ms in controls and 277±8 ms in animals assigned to receive GsMtx4 (P = 0.134). ERP was not modified by bolus administration of either saline or GsMtx4 . Baseline ERPs were similar in animals experiencing or not ventricular fibrillation  or ventricular tachycardia or fibrillation  during the ischemic period.The distribution of VPBs during coronary occlusion is depicted in Compared with the remaining animals, those presenting ventricular fibrillation during ischemia had similar increase in EDL in the ischemic zone 15 min after coronary occlusion , baseline potassium values , size of the ischemic region , and infarct size .The primary objective of this study was to assess the effect of intravenous administration of the selective SAC blocker GsMtx4 peptide on ischemic VPBs in swine. Compared with controls, treated animals had virtually the same number of VPBs, indicating that GsMtx4, administered under these conditions, does not suppress ventricular ectopic activity following coronary occlusion in swine. The results are compatible with some protective effect against ventricular tachycardia or fibrillation, but the study was not powered for these outcomes.LV dilatation decreased LV-ERP in isolated rat hearts, which concurs with previous observations in rabbit ventricles ,28 or atLV dilatation was not associated with the incidence or duration of ventricular tachycardia episodes induced by the introduction of a single extrastimulus after continuous ventricular pacing for the determination of LV-ERP, nor did it facilitate ventricular fibrillation occurrence. These results are at variance with previous observations in rabbit ventricles ,28 but cIntravenous GsMtx4 did not affect the ERP in unloaded ventricles and did not suppress ventricular ectopic activity after coronary occlusion in swine. A positive result would have been expected according to previous studies suggesting a significant role of mechanical factors in the genesis of VBPs during regional ischemia. In this respect, it was described that increasing the loading conditions may affect the action potential duration after coronary occlusion . In isolOur study was not powered to evaluate the effects of GsMtx4 on ventricular tachycardia or fibrillation, although the results are compatible with some protective effect of GsMtx4. In line with this, increasing LV wall stress has augmented the incidence of ventricular tachycardia or fibrillation in isolated, swine hearts  and regiThe paucity of events made it not possible to assess the effect of GsMtx4 on post-reperfusion ventricular fibrillation, although a significant effect was not expected.GsMtx4 appeared to be well tolerated in vivo since it did not influence hemodynamics or segment length changes and had no effect on the laboratory parameters tested. Since this peptide reduces intracellular calcium accumulation in response to stretch  and targTo the best of our knowledge, this is the first study that has tested the effects of intravenous GsMtx4 in vivo. The dose of GsMtx4 was aimed to attain a plasma concentration above that demonstrated to protect against stretch-induced arrhythmias in isolated hearts . HoweverGsMtx4 reached the ischemic area before ischemia but only the outer side of the ischemic border was infused after coronary occlusion. Given that GsMtx4 effects last approximately 20 min in isolated hearts after washout ,22, effeAs mentioned before, another limitation is that our study was not powered to detect a protective effect against ventricular tachycardia or fibrillation. For such an objective, a very large sample size  would be required. Although the incidence of arrhythmias tended to be higher in animals with greater ventricular distension or with a larger ischemic area, it also was not significantly reduced by GsMtx4 in these subgroups or after controlling for these variables in multivariable analyses in the overall sample. In addition, the incidence of ventricular fibrillation was lower than expected –12. The GsMtx4, administered under the present conditions, does not suppress ventricular ectopic activity following coronary occlusion in swine. The results cannot rule out some protective effect against ventricular tachycardia or fibrillation. Given the enormous impact of malignant ventricular arrhythmias in patients with acute myocardial infarction, this hypothesis should be tested in studies powered for these outcomes.


However, there is no data published on the potential additional value of incorporating semi-quantitative data from 3 T MRI. This study sought to determine the performance of qualitative 3 T stress magnetic resonance myocardial perfusion imaging (3 T-MRMPI) and the potential incremental benefit of using a semi-quantitative perfusion technique in patients with suspected coronary artery disease (CAD).Fifty eight patients  referred for elective diagnostic angiography underwent stress 3 T MRMPI with a 32-channel cardiac receiver coil. The MR protocol included gadolinium-enhanced stress first-pass perfusion , rest perfusion, and delayed enhancement (DE). Visual analysis was performed in two steps. Ischemia was defined as a territory with perfusion defect at stress study but no DE or a territory with DE but additional peri-infarcted perfusion defect at stress study. Semi-quantitative analysis was calculated by using the upslope of the signal intensity-time curve during the first pass of contrast medium during dipyridamole stress and at rest. ROC analysis was used to determine the MPRI threshold that maximized sensitivity. Quantitative coronary angiography served as the reference standard with significant stenosis defined as >70 % diameter stenosis. Diagnostic performance was determined on a per-patient and per-vessel basis.Qualitative assessment had an overall sensitivity and specificity for detecting significant stenoses of 77 % and 80 %, respectively. By adding MPRI analysis, in cases with negative qualitative assessment, the overall sensitivity increased to 83 %. The impact of MPRI differed depending on the territory; with the sensitivity for detection of left circumflex (LCx) stenosis improving the most after semi-quantification analysis, (66 % versus 83 %).Pure qualitative assessment of 3 T MRI had acceptable performance in detecting severe CAD. There is no overall benefit of incorporating semi-quantitative data; however a higher sensitivity can be obtained by adding MPRI, especially in the detection of LCx lesions. Magnetic resonance myocardial perfusion imaging (MRMPI) is a well-established technique for noninvasive detection of myocardial ischemia due to coronary stenosis. Compared with single-photon emission computed tomography (SPECT), the most widely used technique, MRMPI has superior spatial resolution that could facilitate differentiation of subendocardial and transmural perfusion defects. Additionally, MRMPI has fewer artifacts and is free from ionizing radiation. The vast majority of data available on MRMPI has been obtained using a 1.5-T scanner. However, with the newly available 32-channel cardiac coil and new acquisition strategies such as k-space and time sensitivity encoding (k-t SENSE), 3-T MRI system provides increased signal-to-noise ratio (SNR), reduced imaging time, and an even greater spatial resolution.Over the past decade, qualitative analysis has been the most commonly used method for MRMPI in the clinical practice. Although studies have demonstrated that both qualitative and semi-quantitative assessments of myocardial perfusion, using a 1.5-T scanner, have moderate diagnostic accuracy for the detection of coronary artery disease (CAD) , quantitThe aim of this study is to investigate the performance of 3-T stress MRMPI and the potential additional value of semi-quantification of myocardial flow for the detection of significant CAD.The study was approved by the Institutional Review Board of Mackay Memorial Hospital, Taipei, Taiwan. Sixty-four patients were recruited between September 2009 and December 2010. All patients were referred for invasive coronary angiography due to clinically suspected or known CAD. Reasons for exclusion included high-degree atrioventricular block, prior coronary artery bypass surgery, pregnancy, hypotension (systolic blood pressure < 90 mmHg), decompensated congestive heart failure , and standard contraindications to MRI imaging, dipyridamole, or gadolinium. All patients were advised not to consume caffeine within 24 h of the study. The written informed consent was obtained from all enrolled patients.All studies were performed on a 3-T MRI  equipped with 80 mT/s maximum field gradients and a 200 T/m/s slew rate using a 32-channel cardiac receiver coil  and ECG synchronization. For myocardial perfusion imaging, a saturation recovery gradient-echo T1 weighted sequence (T1-TFE) was used with prospective ECG triggering; sequence parameter included: non-selected shared 90 saturation pulse, TR/TE/flip angle: 2.2 ms/0.8 ms/10°, spatial resolution 1.8x1.8x8 mm, matrix 156x192, Sense factor 2.5–3. After the scout images for cardiac geometry and acquisition of three standard short axis views  of left ventricle, the dipyridamole infusion  was started with an infusion pump . The stress MRMPI was performed six minutes after the beginning of dipyridamole infusion with 0.05 mmol/kg gadolinium  injected intravenously with an injection rate of 4 ml/s, followed by a 25 ml saline flush at the same rate. Images were acquired for 60 cardiac phases. After stress MRMPI, aminophylline was given (3 mg/kg) intravenously and delivered over 2 min. Ten minutes later, rest MRMPI was performed using the identical protocol. Then the following 0.05 mmol/kg gadolinium was injected to achieve total dose of 0.15 mmol/kg. Approximately 10 min later, delayed-enhanced MR imaging (DE-MR) was performed by using the inversion-recovery prepared gated fast gradient-echo sequence (1.5x1.7x5mm).Two experienced readers, blinded to all data including clinical information and angiographic results, visually analyzed all MRI images. In cases of disagreement, consensus was achieved by use of a third reader.Perfusion analysis of each myocardial segment (except the apex) was performed based on the 17-segment model recommended by the AHA (American Heart Association) . IschemiAll MRI images were sent to the Harrington Heart and Vascular Institute Cardiovascular Imaging Core Laboratory  for semi-quantitative perfusion analysis. Analyses were performed using dedicated software  by examiners who were blinded to angiographic results. Perfusion analysis was performed to obtain signal intensity for each myocardial segment over time. Endocardial and epicardial contours were drawn semi-automatically and propagated through all slices on all images, then manually adjusted for breathing. Mean signal intensity was registered over time. A Signal intensity-time curve was generated from transmural myocardium for all segments on consecutive images before and during the contrast medium administration. The LV input function was determined by obtaining the signal intensity-time curve of basal level left ventricular cavity. In each signal intensity-time curve, the maximal initial slope was determined by the software.LV myocardium was divided into 6 segments per slice, and then further divided into 16 AHA segments. Myocardial perfusion reserve index (MPRI) was calculated by dividing the results of segmental upslope at stress through rest. All segments were assigned to the respective perfusion territory. The mean of the two lowest scoring segments was assigned to each perfusion territory for further analysis.In order to exam the incremental value of semi-quantitative analysis for clinical application, we selected the segments with negative results by qualitative assessment and re-stratified them according to the semi-quantitative results.Less than two months after the MRI examination, all patients underwent conventional coronary angiography by radial approach. Multiple cine angiographic projections were recorded on a hard drive and subsequently sent to the Harrington Heart and Vascular Institute Cardiovascular Imaging Core Laboratory for quantitative coronary analysis (QCA). An expert who was blinded to visual and quantitative CMR performed analysis using dedicated offline software . Quantitative coronary angiography was used as the gold standard and was performed on all vessels to characterize stenosis severity. The percentage diameter of stenosis was calculated using an automated contour detection algorithm with at least two orthogonal angiographic views. Vessels with at least one coronary lesion of >70 % diameter stenosis were considered significant. For further analysis, the coronary tree was divided into 16 segments for comparison with CMR. Territory dominance was taken into consideration . Continuous variables were expressed as mean ± SD. Categorical variables are expressed as numbers and percentages. Non-normally distributed variables were compared using the Wilcoxon two-sample test. Normally distributed variables were compared using the Student’s Receiver operating characteristics (ROC) analyses were performed using R version 2.13.1  2011). ROC was used to assess the diagnostic accuracy of visual MRI and determine the MPRI threshold that maximized sensitivity and specificity. Diagnostic performance was determined on a per-patient and per-vessel basis. The Incremental improvement of MPRI on visual MRI is presented as sensitivity, specificity, positive predictive value and negative predictive value.MRI was successfully performed without any side effects related to gadolinium or dipyridamole in 64 patients. A total of 58 patients Table  had CMR The prevalence of significant coronary artery stenosis (>70 %) was 31 % (18 of 58 patients), including ten patients with single-vessel disease, seven patients with double-vessel disease and one patient with triple-vessel disease. At the patient level, using QCA as the gold standard, qualitative MRI had a sensitivity and specificity of 77  and 80 % respectively. ROC analyses resulted in a MPRI value of 0.818, providing the optimal sensitivity and specificity to detect CAD at >70 % stenosis of 58 and 74 %, respectively, and a positive and negative predictive value of 52  and 78 % (AUC of 0.63), respectively. The additional information provided by the semi-quantitative MRI data produced some improvement in the sensitivity but a disproportional loss of specificity. At a patient level analysis, the use of MPRI resulted in an increase in sensitivity (83 vs. 77 %), but a decrease in specificity (63 vs. 80 %). Similarly, at the vessel level, the use of MPRI information produced a small increase in sensitivity (84 % vs. 76 %) but a larger loss of specificity (77 % vs.91 %)  on a per-patient basis. For coronary territories, there was agreement in 52 patients for LAD , 53 patients for LCx  and 53 patients for RCA .This study is the first to report on the diagnostic performance of 3-T MRMPI combining visual and semi-quantitative analysis in detecting significant coronary stenosis in symptomatic patients. The main findings of our study are as follows: First, qualitative 3-T MRMPI has moderate accuracy in detecting significant coronary artery stenosis defined as >70 % luminal narrowing. Second, semi-quantitative assessment of 3-T MRMPI is specific but with low sensitivity. Third, the addition of semi-quantitative methods in cases with initial negative results on visual assessment provided superior sensitivity but, with decreased specificity. Forth, the impact of adding semi-quantitative on qualitative assessment was most effective for the LCx territory. Most importantly, we demonstrated that a stepwise strategy of applying semi-quantification in an initially qualitatively negative assessment could improve the sensitivity for detection of significant CAD, highlighting the potential utility as a screening tool.SPECT myocardial perfusion imaging plays a major role in the field of cardiovascular imaging for detecting physiologically significant CAD. It also provides robust prognostic information to physicians and patients –7. HowevClinically, qualitative analysis is the most common method used in MR myocardial perfusion. There are only few studies –14 direcNevertheless, the observed increase in sensitivity by adding the semi-quantitative assessment on the initial negative results cases in visual assessment cannot translate into an improved diagnostic accuracy due to a significant decrease in specificity. This might be explained by several factors. First, semi-quantitative analysis is reported superior to visual analysis in diagnostic performance but still is a time consuming and cumbersome post-processing method, and it has rarely been performed in clinical practice. Therefore, we only applied semi-quantitative assessment on initial negative results cases from visual assessment. Secondly, previous studies have demonstrated that the diagnostic performance of stress MR myocardial perfusion depends on the severity of coronary stenosis detected on QCA , 18. CheThere were several limitations of the present study. First, coronary angiography is not a truly gold reference standard for myocardial perfusion images but remains the most established technique for decision making in interventional cardiology. In coronary lesions with stenosis over 70 % but, with normal myocardial perfusion, the diagnostic performance might not be assessed accurately. On the other hand, the stenosis grade of angiography cannot provide a reference in the setting of microvascular disease leading to CMR perfusion defect. Second, we did not compare CMR perfusion with SPECT, the most popular myocardial perfusion technique or other advanced functional studies including invasive fractional flow reserve (FFR), stress PET, stress/FFR CT. Third, the dose of dypiridamole in our study is not a high dose protocol which may fail to induce myocardial perfusion defects in some cases. Finally, we did not perform full-quantification of MR myocardial perfusion, which demonstrated close correlation to the results of FFR in hemodynamic significance of coronary artery disease.The results of our study show that performance of the pure qualitative assessment 3-T cardiac MRI in detecting significant coronary artery disease is acceptable. By adding semi-quantitative analysis, the sensitivity was increased, particularly in the detection of LCx lesions.


The use of psychostimulants labeled to treat attention deficit/hyperactivity disorder increases. Among side effects these drugs raise blood pressure and heart rate, and the safety has been scrutinised in recent years. Data from large epidemiological studies, including over a million person-years, did not report any cases of myocardial infarction in current users of methylphenidate, and the risk of serious adverse cardiac events was not found to be increased. We present a case with an 11-year-old child, treated with methylphenidate, who suffered cardiac arrest and was diagnosed with a remote myocardial infarction. This demonstrates that myocardial infarction can happen due to methylphenidate exposure in a cardiac healthy child, without cardiovascular risk factors. The risk of cardiovascular events and sudden death related to attention deficit/hyperactivity disorder (ADHD) medications has been scrutinized in the recent years –5.In adults, the initiation of methylphenidate has been found to be associated with nearly a doubling of the rate of sudden death or ventricular arrhythmia . HoweverIn children and adolescents, a low absolute number of cardiovascular events may explain why hazard ratios, even in large scale studies, come out nonsignificant. However, with the reported spreads in confidence intervals, one cannot rule out the possibility of an increase by as much as a tripling of the risk for serious cardiovascular events.Mechanisms behind cardiovascular disease and methylphenidate are not fully understood. Methylphenidate increases heart rate, increases blood pressure, and potentially causes arterial vasospasms, due to the increased levels of circulating catecholamines , 6. All We present a case with a child treated with methylphenidate that suffered from cardiac arrest during exercise and was diagnosed with a remote myocardial infarction.The patient is an 11-year-old boy with attention deficit/hyperactivity disorder and Tourette syndrome. Two years prior to the current incident he had been seen by a pediatric psychiatrist over a course of time and was finally treated with methylphenidate. He was slowly uptitrated to the maximum appropriate dose of 54 mg per day (36 + 18 mg per day/body weight 50 kg), which had been ongoing ever since.Apparently, the child had been feeling well, but a week before his admission he felt dizzy and light headed after vigorous trampoline jumping. His mother noticed he had tachycardia but thought nothing of it. The incident only lasted a few minutes and afterwards he was well.On the day of admission, the patient had been in conflict with one of his peers. To calm down, the patient was sent to the gym court, to exercise and play ball. After a few minutes he left the court and fell down with cardiac arrest due to ventricular fibrillation. He was successfully resuscitated by school staff and the prehospital service.Upon hospital arrival the child was sedated and intubated. He was circulatory stable and he was treated with hypothermia for 24 hours. A urine toxicology screening only showed traces of the anesthetics used during the resuscitation and methylphenidate according to the prescribed dose.Both the initial ECG and the ECGs after hypothermia  showed QA coronary computed tomography angiography scan showed normal coronary artery anatomy with a dominant left coronary artery and no signs of myocardial bridging. However, a subsequent cardiac magnetic resonance scan showed clear signs of an old myocardial infarction with delayed hyperenhancement and thinning of the lateral wall of the left ventricle, corresponding to the circumflex artery supply .To exclude paradox emboli, a transesophageal echocardiogram with bubble contrast was done. No atrial septal defects or mural thrombi were found. A full panel of blood coagulation tests did not reveal any coagulation disorder or hypercholesterolemia.Before discharge, a coronary angiogram was done, which confirmed the computed tomography angiography result but also excluded abnormal coronary spasm tendency by a methylergometrine test. The patient also had an invasive electrophysiology study, which showed normal atrioventricular conduction without accessory pathways and an easily inducible sustained ventricular tachycardia, deriving from the scar tissue in the left ventricle. Subsequently, an implantable cardioverter defibrillator was implanted, and the patient was put on a low dose of metoprolol succiante (25 mg), with a treatment plan to increase the dose at a later stage. The methylphenidate treatment was discontinued. A wide panel of genetic disorders related to tachyarrhythmia was examined, which all came out negative.Three weeks after discharge the child was on his own in a bouncy castle on a Friday evening. After 15 minutes of exercise, he shortly felt ill and sat down but recovered quickly without any recollection of chest pain or any other discomfort. The following Monday, the defibrillator telemetry showed that the pacemaker had defibrillated an episode of ventricular fibrillation . FollowiAcute myocardial infarction due to atherosclerotic plaque rupture is a leading cause of death and disability. However, in childhood and adolescence, myocardial infarction is extremely rare and other causes should be sought such as coronary artery anomalies, vasculitis, and coagulation defects. Due to the extremely rare occurrence in children, a myocardial infarction diagnosis may not be suspected and therefore overlooked. Likewise, myocardial infarction in children treated with methylphenidate is extremely rare. In two large epidemiological studies, including over half a million person-years of follow-up, of current users of attention deficit/hyperactivity disorder medications, not a single myocardial infarction was reported during treatment , 4. The The large epidemiological studies on methylphenidate are based on reported diagnoses, among which this boy's myocardial infarction diagnosis probably would never have appeared. Instead, he suffered from cardiac arrest and would have been classified as sudden cardiac death, had he not been resuscitated.When the boy was admitted, the first assumption was a primary arrhythmia. However the ECG clearly indicated regional myocardial necrosis and the echocardiogram showed thinning of the myocardial wall. The CMR scan clearly indicated that the myocardial infarction was of an older date (more than weeks) due to thinning of the myocardium and an adversely remodeled left ventricle.Currently there is no recommendation in Denmark or by the FDA to obtain ECG before and during methylphenidate treatment, explaining why there was no ECG prior to treatment. Theoretically, there may be more children with undiagnosed myocardial infarctions among methylphenidate users that are missed, if routine ECGs are not obtained on a regular basis. In the present case, the Q-waves in the ECG would have disclosed that the child had developed heart disease. Whether this would have altered the course is speculative.Obviously it may be questioned if the myocardial infarction actually developed prior to methylphenidate treatment and if it really was the cause. It is now two years since the index admission. The boys present clinical situation is quite concerning. Despite high dose ACE-inhibitors and beta-blockers his left ventricle has further adversely remodeled from an initial internal diastolic diameter of 5.4 cm to 7.2 cm on the latest echocardiography. His ejection fraction has deteriorated to 35%. He is in heart failure class II. He recently underwent two VT ablations due to long lasting tachycardia episodes and therapies from the ICD. Therefore it is unbelievable that this boy was started on methylphenidate after the huge myocardial infarct. He would have been in overt heart failure which would have been noticed. Children do not develop huge myocardial infarcts without a cause. This young boy has been very thoroughly examined. He did not suffer from hypertension or hypercholesterolemia, and there was no coronary artery anomaly, no myocardial bridging, no coagulation defects, no PFO, and no abnormal coronary spasm tendency to explain his myocardial infarct. Furthermore, the dosage of methylphenidate was uptitrated correctly to an appropriate dosage and there was not any suspicion of abuse. The only thing that points out is the methylphenidate treatment, which FDA recognizes can cause heart attacks in adults.Randomized trials show that ADHD drugs reduce symptoms significantly, compared to placebo , and impIn conclusion, myocardial infarction and sudden cardiac death are extremely rare among children during treatment with methylphenidate. However, the present case shows that myocardial infarction can happen due to methylphenidate exposure in a cardiac healthy child, without any other cardiovascular risk factor.


Pressure overload in PAH leads to a complex series of changes in cardiomyocytes and the extracellular matrix of the RV2. Thus, quantitative T1 mapping of the RV to assess myocardial extracellular volume fraction (ECV) may be a valuable noninvasive marker of RV fibrosis in these patients. However, current clinically preferred T1 mapping techniques have limited spatial resolution, restricting their application to assessment of left ventricular (LV) ECV. We recently developed a novel technique, termed ANGIE3, which uses navigator gating and acceleration with compressed sensing (CS) to provide high-resolution T1 mapping for assessment of thin structures such as the wall of the RV. The aim of the present study was to use ANGIE to test the hypothesis that RV ECV is elevated in patients with PAH compared to reference subjects.Right ventricular (RV) failure is associated with increasing morbidity and mortality in pulmonary arterial hypertension (PAH)3), 3) late gadolinium enhancement (LGE) acquisitions at 10 mins after gadolinium injection (0.15mmol/kg), and 4) multiple post-contrast ANGIE acquisitions at intervals of 5 mins up to 30 mins post-contrast. Additionally, modified Look-Locker inversion recovery (MOLLI)4 scans were performed along with ANGIE in 8 out of the 10 PAH patients for validation of ANGIE LV ECV measurements. 15 patients  had enough tricuspid regurgitation by echocardiography to measure RV systolic pressure (RVSP).5Eighteen patients were recruited to undergo cardiac magnetic resonance imaging (CMR) with gadolinium on a 1.5T system (Avanto Siemens) -- 10 patients (60±16.6 yrs) with PAH and 8 patients with chronic left ventricular systolic heart failure (LHF) (60.5±7.6 yrs). The MRI protocol included: 1) SSFP cine imaging, 2) pre-contrast high-resolution ANGIE T1 mapping (1.2-1.5x1.2-1.5x4mmFigure Pre- and post-contrast ANGIE imaging provides high-resolution T1 mapping and ECV assessments for not only the LV but also the thin-walled RV, with LV ECV by ANGIE and MOLLI in close agreement. The extent of RV fibrosis in PAH, as measured by RV ECV, increases with RV pressure overload and decreasing RV systolic function. RV ECV is greater than LV ECV in PAH and similar to LV ECV in LHF.This work was funded by Siemens Medical Solutions, NIH R01 EB 001763, NHLBI K23 HL 094761, NHLBI K23 HL 112910, NIH T32 EB 003841, AHA Grant-in-Aid 12GRNT12050301, and AHA Predoctoral Award 14PRE20210008.


During the past three decades, every aspect of cardiomyopathy has undergone dramatic change. When examining the literature on the physiological aspects of the failing heart, one immediately recognises that South Africa has made a contribution: Brink, Bester and Lochner evaluated the possible therapeutic aspects of the Bowditch phenomenon and myocardial energetics in cardiomyopathy almost four decades ago, at a time when the condition even had another name, myocardiopathy. All aspects of cardiomyopathy – from our knowledge on ultra-structural and physiological alterations, to pharmacological approaches to therapy, surgical treatment modalities and later device-based therapies – have undergone dramatic changes during the last three decades. Even the terminology has changed. If one scrutinises articles from the 1950s to the 1970s one will find that the preferred term then was ‘myocardiopathy’.When analysing the progression of knowledge on the physiology of the failing heart that has made an impact on therapeutic advances over the past 30 years, I am proud to state that South Africa has made a contribution. In 1972, the following article by Brink, Bester and Lochner appeared:Thirty years later, we would see dramatic paradigm shifts regarding the importance of heart rate in cardiomyopathy. Today we understand the importance of heart rate variability and heart rate turbulence as prognostic markers in various cardiovascular disorders and we have conclusive evidence from clinical trials that reducing heart rate in cardiomyopathy confers a survival advantage.When cardiac myocytes are stimulated at faster rates, they increase their force of contraction.Henry Pickering Bowditch, famed physiologist (nephew of the well-known Boston physician Henry Ingersoll Bowditch) and later dean of Harvard Medical School,2et al.It would be many years after Bowditch’s article before it became apparent that the failing heart behaves very differently to an increase in heart rate. The failing heart does not exhibit a Bowditch phenomenon – there is no increase in the inotropic response to an increase in heart rate,et al.et al.In 1967, Brink Another important concept realised today in ‘modern’ cardiology is that the failing heart, as opposed to the normal heart, can be viewed as ‘an engine out of fuel’.in vivo human heart – they are extrapolated from global measurements using 18F-FDG PET imaging.10The human heart displays an enormous energy requirement – 6 kg of ATP every day.Already in their 1972 article, Brink, Bester and Lochner10et al.Therefore, I conclude that this historical article by Prof AJ Brink


Right Ventricular to Left Ventricular (RV/LV) diameter ratio has been shown to be a prognostic biomarker for patients suffering from acute Pulmonary Embolism (PE). While Computed Tomography Pulmonary Angiography (CTPA) images used to confirm a clinical suspicion of PE do include information of the heart, a numerical RV/LV diameter ratio is not universally reported, likely because of lack in training, inter-reader variability in the measurements, and additional effort by the radiologist. This study designs and validates a completely automated Computer Aided Detection (CAD) system to compute the axial RV/LV diameter ratio from CTPA images so that the RV/LV diameter ratio can be a more objective metric that is consistently reported in patients for whom CTPA diagnoses PE.The CAD system was designed specifically for RV/LV measurements. The system was tested in 198 consecutive CTPA patients with acute PE. Its accuracy was evaluated using reference standard RV/LV radiologist measurements and its prognostic value was established for 30-day PE-specific mortality and a composite outcome of 30-day PE-specific mortality or the need for intensive therapies. The study was Institutional Review Board (IRB) approved and HIPAA compliant.The CAD system analyzed correctly 92.4% (183/198) of CTPA studies. The mean difference between automated and manually computed axial RV/LV ratios was 0.03±0.22. The correlation between the RV/LV diameter ratio obtained by the CAD system and that obtained by the radiologist was high (r=0.81). Compared to the radiologist, the CAD system equally achieved high accuracy for the composite outcome, with areas under the receiver operating characteristic curves of 0.75 vs. 0.78. Similar results were found for 30-days PE-specific mortality, with areas under the curve of 0.72 vs. 0.75.An automated CAD system for determining the CT derived RV/LV diameter ratio in patients with acute PE has high accuracy when compared to manual measurements and similar prognostic significance for two clinical outcomes. Pulmonary embolism (PE) is a common disease with an incidence greater than 1 per 1000 in the U.S. and an overall three month mortality rate of approximately 15% . MorbidiClinical suspicion of PE is most often confirmed with Computed Tomography Pulmonary Angiography (CTPA) ,4 that aQuantification of the RV/LV ratio by CT can use chamber volumes or diameter measurements made on either four chamber reformatted views or axial images alone –14. ThesThis study describes and tests a fully automated computer aided detection (CAD) system that analyzes the ventricles from the CTPA images used for PE diagnosis, and outputs the axial RV/LV diameter ratio. While axial ventricular diameters do not represent true ventricular diameters, their prognostic value for patients suffering from acute PE has been shown not to be inferior to the prognostic value of ventricular ratios obtained in four chamber reformatted images .The CAD system produces automatically an objective and reproducible axial RV/LV diameter ratio. In this study we focus in the design and retrospective validation of the output of the CAD system and leave the evaluation of its integration in the clinical workflow and the evaluation of the effort required to correct its output as future work.The Brigham and Women’s Hospital (BWH) Institutional Review Board (IRB) approved this HIPAA-compliant retrospective cohort study; written informed consent was waived since patient data was analyzed anonymously. All consecutive CTPA examinations performed at BWH  from February 2009 to November 2009 were examined and 200 studies positive for acute PE were identified. The mean age was 60 ± 16 years (range 22–89), 113 patients were female and 87 were male. Fifty-eight patients had central PE; 13 patients had saddle emboli and 45 patients had emboli in either the main left, main right or both main pulmonary arteries. Systolic blood pressure was available for 176 patients. Massive PE, as defined in . The second reviewer estimates larger diameters than the first reviewer, by a mean value of 4.13±4.5 mm for the RV and 6.08±4.9 mm for the LV, both with p < 0.001. RV/LV diameter ratios obtained by the two reviewers are not statistically significantly different . For the nine patients were the axial RV/LV diameter ratio measurement time was documented, the mean time was 106±26 seconds.The automated RV/LV diameter ratio has similar predictive value to manually estimated diameter ratios for both clinical outcomes, as shown by the following aggregated statistics and ROC analysis.In the predictive model for 30-days PE-related mortality, RV/LV diameter ratios are significant predictors after adjusting for age and gender, with p-values of 0.0005 for the manual method and 0.008 for the CAD system. Similarly, RV/LV diameter ratios are significant predictors of 30-days PE-related death or the need of intensive therapies after adjusting for age and gender, with p < 0.0001 for both manual and automatically estimated ratios. Prognosis data from CTPA is a valuable component in the decision of whether or not to manage an acute PE patient with intensive therapies . AlthougThe proposed CAD system automatically provides an objective metric of axial RV/LV diameter ratio that has high accuracy when compared to manual measurements. There is no statistically significant difference between the reference standard measurements made manually and those that the proposed software outputs automatically. The correlation coefficient of the automated method with respect to the manual one is comparable to the correlation coefficient obtained for inter-reader variability and inter-reader variability reported in other studies . The difIt is relevant to note that the proposed methodology deals with important challenges related to the nature of the CTPA datasets. The heart in CTPA studies can present severe motion artifacts . VariabiThe goal of this study is to present software to report the RV/LV diameter ratio automatically using the standard clinical data and to retrospectively evaluate its accuracy using a cohort of patients for whom there is a comprehensive, published database of clinical outcomes. The presented CAD system reports measurements on axial images, and thus the study does not include volumetric measurements or 4-chamber reformatted images. This has been a design choice that prioritizes easy supervision, as axial RV/LV diameter can be reviewed without image reformatting and, moreover, the prognostic value of measurements derived from the axial images alone has not been shown to be inferior to such of four-chamber reformatted computed diameter ratios .We acknowledge several limitations. First, the study design did not include transthoracic echocardiography data. While such data were not available, it has been shown that echocardiography RV diameter estimations and CT RV/LV diameter ratios have a moderate Spearman correlation coefficient  and simiThis work exemplifies a revisited paradigm related to the fully automatic computation of image-based biomarkers from standard clinical imaging datasets. In the growing scenario of digital data availability, increasing radiology department burden, and initiatives to transform big data to clinical knowledge , the autWe present a new automated CAD system that inputs DICOM CTPA images and reports a measurement of the right ventricular to left ventricular diameter ratios comparable to manual assessment by a radiologist. The CAD system has high accuracy and high prognostic value with respect to two clinical outcomes: 30-days PE related death or 30-days PE related death or the need of intensive therapies. Future studies will test the integration of this software into clinical workflow.


A 73-year-old male presented to the emergency department with vomiting and diarrhoea. No abnormalities were found on physical examination, besides a blood pressure of 80/40 mmHg. The blood tests showed acute renal insufficiency and a potassium of 9.0 mmol/L (3.5–5.0). The electrocardiogram (ECG) showed atrial fibrillation and the occurrence of a left bundle branch block (LBBB) when the heart rate exceeded 76 beats per minute Fig. . When thAlthough different hyperkalaemia-induced blocks have been described , a rate-Extremely high levels of serum potassium are almost always associated with the classic ECG manifestations; reports of severe hyperkalaemia without these findings are scarce . In our In the work-up of chest pain in patients with LBBB, all non-invasive techniques fall short in diagnostic accuracy, although prognosis in case of a normal single-photon emission computed tomography (SPECT) does not seem to be altered by LBBB. However, the cardiac event rate of patients with high-risk SPECT is significantly higher than expected from data of patients without LBBB , 5.The clinician should be aware that the ECG hardly shows any changes due to hyperkalaemia when the heart rate is low, but clear changes can occur with an increasing heart rate.


Cardiomyopathy is a chronic disease of the myocardium characterized by an abnormal dilatation and thinning of the left ventricular (LV), associated with the contractile dysfunction of the muscle and loss of pump capacity, resulting in the occurrence of arrhythmias and myocardial infarction. It has many causes and can occur in the liver pathology inclusively. It has been shown that patients with liver cirrhosis show a cardiac and circulatory dysfunction mainly governed by the peripheral vasodilation . The hyperdynamic syndrome, caused by the liver dysfunction and the portal hypertension associated with the splanchnic vasodilation may contribute to the myocardial disturbances in liver cirrhosis. Central hypovolemia in association with hypotension leads to the activation of baroreceptors and the volume receptors of the vasoconstrictor systems, this aggravating the hyperdynamic circulation and cardiac contraction. For about 50 years, the deterioration of liver function was associated with the cardiovascular system functioning through hyperdynamic circulation . This term defines chronic cardiac dysfunction, characterized by a decreased contractile responsiveness to stress and impaired diastolic relaxation associated with electrophysiological abnormalities such as QT prolongation, in the absence of any heart disease [6]. Biochemical and physiological abnormalities of liver cirrhosis can affect heart rate, contractility, management and cardiac repolarization.The results of the clinical and experimental studies have shown that the impaired myocardial contractility and electrophysiological abnormalities in cirrhosis define the notion of “cirrhotic cardiomyopathy” [Cardiac consequences of the hyperdynamic syndrome are the following:5].1. Systolic dysfunction - is a consequence of excessive release of nitric oxide (NO) and TNF that causes a reduced vascular reactivity to adrenaline and angiotensin II, respectively, altered beta-adrenergic signal. This hypothesis is supported by cardiovascular reflex tests in patients with cirrhosis, who are affected . The systolic function is directly proportional with the heart rate and cardiac output (CO). At rest, cardiac pressures are normal and CO is increased in patients with liver cirrhosis [6]. In some patients, it was found that exercise increases the pressure in the left ventricle (LV), ejection fraction and heart rate due to SNS tone. In contrast, the cardiac performance is reduced due to a lower cardiovascular reactivity [7]. The administration of vasoconstrictor substances  increases peripheral vascular resistance and LV afterload. The exercise or the pharmacological point of view may reveal a latent left ventricular dysfunction in patients with cirrhosis, expressed by increased LV end-diastolic volume and decreased ejection fraction (EF). The increase in the value of atrial natriuretic peptide (ANP) in some cirrhotic patients can express an atrial distension associated with hypovolemia . Ventricular mass is increased in some cirrhotic patients, associated with septal hypertrophy, which can be reflected by the level of troponin I, which may reveal this damage. This marker is increased in patients with cardiac ischemia but also in cirrhosis. BNP and pro-BNP are sensitive markers of myocardial alteration and are significantly increased in patients with compensated liver cirrhosis [10]. Levels of these peptides are correlated with the severity of cirrhosis, the degree of cardiac dysfunction and myocardial hypertrophy, and hyperdynamic circulation. Therefore, the determination of BNP and pro-BNP is useful in screening patients with cirrhotic cardiomyopathy.The criteria for the positive diagnosis of cirrhotic cardiomyopathy target systolic dysfunction and diastolic dysfunction and the supportive criteria are summarized in 6].Systolic dysfunction is the latency in patients with liver cirrhosis but is evidenced by exercise or pharmacologically. Reducing systolic function can cause complications in patients with liver cirrhosis [11]. Sodium retention in patients with cirrhosis may lead to myocardial hypertrophy and diastolic dysfunction . Doppler echocardiography showed impaired ventricular relaxation, decreased E / A ratio and a decreased diastolic filling in patients with liver cirrhosis [12]. The renin-angiotensin-aldosterone system (RAAS) and ANP are associated with diastolic dysfunction in cirrhosis [13]. Thus, there is evidence that the diastolic function is impaired in patients with cirrhosis and the diastolic dysfunction indicators can provide prognostic information that may affect the ventricular filling during the procedure.Diastolic dysfunction is caused by a decreased LV compliance and relaxation, causing an abnormal LV filling. The pathophysiological background of the diastolic dysfunction is increased myocardial wall stiffness, consequently myocardial hypertrophy, fibrosis and subendothelial edema [11]. In the advanced forms of liver cirrhosis characterized by vasodilation, hypovolemia and hypotension RAAS which increases DC, contributes to the stimulation of hydro-saline retention and development of hepato-renal syndrome, also with poor prognosis.The prognosis of patients with cirrhotic cardiomyopathy is reserved due to undiagnosed cardiac dysfunction, which may increase the risk of death. Recent studies have shown that approximately 50% of the patients with liver cirrhosis performing signs of cardiac dysfunction before liver transplantation and 7-21% die by heart attack after transplantation [14].The management in cirrhotic cardiomyopathy is not well structured. Diuretics increase the elimination of sodium and improve cardiac function. Beta-adrenergic blockers are commonly used in patients with liver cirrhosis with portal hypertension, because of the lowering and prevention of bleeding by the rupture of esophageal varices. Beta-blockers lower heart rate and reduce QT prolongation. However, there are no studies to support the benefits of these therapies in cirrhotic cardiomyopathy. Currently, liver transplantation is the only therapeutic solution for associated cirrhosis and cardiomyopathy [There is overwhelming evidence on the presence of cardiomyopathy in patients with cirrhosis. Further studies are needed to deepen the mechanisms involved in the development of cirrhotic cardiomyopathy and the completion of therapeutic means of this condition.