We developed a lumped parameter, computer-based model of an equivalent electronic circuit for a one-atrium one-ventricle (frog) heart attached to a vascular circuit, to simulate a basic concept of cardiovascular physiology, the Frank-Starling Law of the Heart. A series of simulations was performed, to observe changes in cardiovascular variables  if either preload or afterload was increased. The simulated data agreed qualitatively, and quantitatively when experimental data are available, with data obtained on amphibian or on mammalian myocardium. In addition, the data obtained in these simulations improve our understanding of the mechanism(s) whereby the heart muscle adapts itself to increased distension (increased preload) or to impeded systolic contraction (increased afterload). The analysis of the measured valve flows suggests that the ventricle is a highly input sensitive pump because the input pressure determines the diastolic distension and, consequently, the force of ventricular systolic contraction. On the other hand, the ventricle is a relatively output insensitive pump. Therefore, not only atrium contraction, but also predominantly the preceding ventricular systolic contraction is the main mechanism of the subsequent diastolic ventricular filling. We conclude that the presented model enables the study of basic concepts of cardiovascular physiology. Originally, cardiovascular physiology was simulated by mathematical –4 or anain vitro frog heart model [In clinical practice, and in whole animal or human studies, the short-term and long-term compensatory mechanisms modify cardiac function thus impeding the study of the basic mechanical properties of the whole heart in isolation. Therefore, it would be of interest to study, by using the EECs model, the basic determinants of myocardial function(s) as it was originally attempted by using the rt model , 21. It rt model .What is the role of atrium in the filling of the ventricle, if the latter is subjected to increased preload or increased afterload?Why is the ventricle a highly input sensitive pump, but at the same time a relatively output insensitive pump?What is the change in the pressure-volume (P-V) loop diagram if the ventricle is subjected to increased preload or increased afterload?In the presented simulation of the Law of the Heart it is attempted to answer the following basic questions.In the experimental layout the one atrium-one ventricle heart  should be attached to an artificial “systemic” circuit, featuring three characteristic sections: (a) a high-pressure/low-capacitance “arterial” section, (b) a variable “peripheral” resistance section, and (c) a low-pressure/high-capacitance “venous” section including a blood reservoir. In this circular arrangement pressures, flow, and stroke volume would depend on preload and afterload. Preload is determined by the height of venous reservoir, and afterload is controlled by “resistance to flow” section . If the The equivalent electronic circuit (EEC) should have a very similar structure; the “systemic” circuit, preload control subcircuit, afterload control subcircuit, atrial contraction subcircuit, and ventricular contraction subcircuit, as shown in It should be noted that, for reasons of comparison, in the present EEC both atrium and ventricle are comparable to the adult human left atrium and left ventricle. Therefore, in the latter, in resting pressure and capacitance conditions, its volume  is about 117 mL and peak “arterial” pressure is about 70 mm Hg. For reasons of simplicity, in simulations the usual terminology is used also for both valves in this one-atrium one-ventricle heart: at the input of the ventricle the mitral and at the output the aortic valve, respectively. Analysis of the EEC simulating the one-atrium one-ventricle heart, attached to an artificial vascular circuit, is performed by using Electronics Workbench Personal version 5.12 . This soThe EEC simulating the one-atrium one-ventricle heart and the artificial systemic circuit is shown in The “systemic” circuit is made up by a chain of resistor/capacitor segments. The direction of flow (current) is indicated by arrows. Resistors are connected in series. One terminal of a single capacitor is connected to the chain of resistors and the other capacitor terminal is connected to ground. Thus, the resistor/capacitor segments simulate “resistance to flow” and capacitance of single segments of the circuit attached to the heart.Preload control subcircuit: by applying the 0.6 V, 0.7 V, and 0.8 V batteries  preload can be set as 6 mm Hg, 7 mm Hg, or 8 mm Hg. Afterload control subcircuit: by applying the 3 MΩ, 6 MΩ, and 9 MΩ resistors (in series into the “systemic” circuit) afterload can be increased. Because the series resistance of aorta is 1 U (1 MΩ) afterload can be set as 4 U, or 7 U, or 10 U.Atrial contraction subcircuit: essentially, it is a feedback loop with a nominal gain of 0.5 and a nominal time constant 0.1 s. It is activated/deactivated by the atrial pacemaker as described below.Ventricle contraction subcircuit: it is a complex feedback loop with a nominal gain of 100. Nominal time constant of ventricular contraction is 0.1 s and that of ventricular relaxation is 0.2 s. Duration of systole is 0.2 s because this value has been used in almost all previous simulations. The gain loop is activated/deactivated by the ventricular pacemaker  and two voltage-sensitive switches VS.Heart valves: the mitral and aortic valves are simulated as diodes . ThDesign of the pacemaker circuit: it consists of two parts: an atrial and a ventricular pacemaker. The atrial pacemaker is a sine-wave generator operating at 1 Hz, 60/min), but with a phase shift of 192°, driving two voltage-sensitive switches (VS). The ventricular pacemaker is a square-wave generator operating at 1 Hz  which drives two voltage-sensitive switches (VS). In this way both generators, although physically separated, act as a single pacemaker, atrial contraction  preceding the ventricular contraction . The time course of simulated variables ., 23.19, In the setting presented in Variables of interest can be recorded and measured at points as indicated : pressurThe acronyms used in text and illustrations are listed in Data are shown as the time course of different variables and as P-V loop diagrams of the ventricle. The work load of the ventricle is calculated in the usual arbitrary units (mm Hg·mL) as well as in joule (J).The effects of increasing preload on the time course of AP, CO, and AtP are shown in The effects of increasing afterload on the time course of AP, CO, and AtP are shown in The time course of cardiovascular variables during a single systole and diastole is presented in The initial conditions, preload 6 mm Hg and afterload 4 U are shown in The effects of increasing preload or afterload on the time course of AP, CO, and AtP are very similar to those shown in The time course of cardiovascular variables during a single systole and diastole is presented in The corresponding P-V loop diagram in It should be noted that in the EEC, the heart valves have a negligible “back” flow. However, valve shunts (regurgitation) could be simulated, as has been shown recently . BecauseWhen discussing the Starling heart-lung preparation it should be borne in mind that its behavior critically depends on the experimental layout; either the so-called “closed-circuit heart-lung preparation”  or the sIn the “closed-circuit heart-lung preparation” blood volume is constant. The pumping action of the heart is determined not only by preload and afterload, but also by the capacitance of the attached artificial vascular circuit . Its basTo demonstrate The Law of the Heart the so-called “open-circuit heart-lung preparation”  should bSimulations presented in this paper  are qualitatively very similar to those described earlier . quantitative differences are expected because in the simulation circuit it is not possible to exactly match the size and detailed layout of the real heart-lung preparation. As shown in [Qualitatively, however, the presented simulations of the Law of the Heart agree very well with experimental data. For example, when preload was increased, in the animal heart-lung preparation, from 20 mm H2O to 210 mm H2O, cardiac output was increased from 40 mL/10 s to 250 mL/10 s [The stroke volume of the ventricle (and consequently cardiac output and AP pulse pressure) is highly increased if preload is increased from 6 mm Hg to 8 mm Hg . The ventricle is an input-sensitive pump  is only slightly decreased if afterload is increased from 4 U to 10 U . The ventricle is an  Figures –6.In the simulation of the Law of the Heart shown in –27, the  mL/10 s  and reviTo explain the basic findings above it should be remembered that, if atrium and ventricle are contracting/relaxing, blood circulates in the attached circuit. If so, atrial pressure is not exactly equal to preload. Atrial pressure is always slightly lower than preload . Due to Afterload is determined predominantly by “peripheral” resistance; its large increase (250%) results in a relatively small decrease in cardiac output (−17%). Therefore, its effect can be neglected. If afterload is increased from 4 U to 10 U (by 250%), AtP is slightly increased while AtP pulse is decreased; the AtP max/AtP min ratio is 5.6 mm Hg to 3.9 mm Hg . HoweverSomewhat unexpected is the finding that throughout early and mid diastole the atrial-ventricular pressure difference is very small. But despite this fact the early mitral flow is relatively large. This indicates that the ventricular filling is achieved mainly by its rapid relaxation. The late mitral flow in late diastole, affected by atrial contraction, is relatively large, but very brief, only about 0.1 s. Therefore, in resting conditions, atrial contraction contributes only about 20% to the increased end-diastolic volume of the ventricle; cardiac output is about 4570 mL/min.If atrium is not contracting, cardiac output is about 4200 mL/min, which is slightly lower compared to 4570 mL/min if atrium is contracting.Late mitral flow, due to atrial contraction, is absent . HoweverIt should be noted that the early mitral flow commences as soon as atrial pressure equals the ventricular pressure, that is, when AtP = VP. If atrium is not contracting, this pressure equals 5.2 mm Hg . Peak eaThe effects of increasing preload or increasing afterload, when atrium is not contracting, are qualitatively the same as when atrium is contracting . QuantitTo summarize, if atrium is contracting, cardiac output is about 4500 mL/min and AtP, at the end of ventricular systole, is 4.5 mm Hg. Therefore, maximal early mitral flow is about 550 mL/s and is determined almost exclusively by AtP. If, however, atrium is not contracting, cardiac output is lower, about 4200 mL/min and AtP, at the end of ventricular systole, is higher, 5.2 mm Hg. Therefore, maximal early mitral flow is also higher, about 710 mL/s, and is determined almost exclusively by AtP. The increased early mitral flow is a partial compensation for the decreased total mitral flow, due to the absence of atrial contraction.In resting conditions, the role of atrium in the filling of the ventricle is relatively small since firstly, the absence of atrial contraction is partially compensated with an increased early mitral flow and secondly, the ventricular filling is achieved mainly by its rapid relaxation. If the ventricle is subjected to increased preload or increased afterload, the rapid ventricular diastolic relaxation is the main mechanism for the ventricular diastolic filling.The ventricle is a highly input sensitive pump because the input pressure determines the diastolic distension and, consequently, the force of ventricular systolic contraction. On the other hand, the ventricle is a relatively output insensitive pump. Due to mechanisms described above, increased afterload results in an increased ventricular diastolic distension. Therefore, a more vigorous ventricular systolic contraction follows, almost compensating increased aortic pressure. Therefore, in resting conditions, ventricular (cardiac) output is almost independent of afterload.In increased preload the P-V loop diagram becomes broader  and higher (with higher ventricular pressure). In increased afterload the P-V loop diagram becomes narrower  and higher.To our knowledge, the presented EEC is the first computer simulation to explicitly simulate the Frank-Starling Law of the Heart. With the presented software, the Frank-Starling Law of the Heart can be demonstrated without the need to perform a technically difficult animal preparation that requires skilled staff and access to a suitable live animal model. Also, simulated measurements of selected cardiovascular variables  are possible and do not increase the cost or the complexity of the demonstration. Finally, when live animal preparations are impractical, the presented computer-based simulation offers a technically simple and low-cost alternative for demonstrating the Frank-Starling Law of the Heart. The presented EEC could be an excellent tool in cardiovascular research, on the one hand, to study how the ventricle, during contraction, adapts itself to a resistive or capacitive load, for example, in hypertension or in greatly changed aortic elastance. On the other hand, the ventricular relaxation, the ventricular filling process, and its dependence on the heart rate can be quantitatively studied in great detail.


This is a comprehensive review of our 26-year experience with primary cardiac tumours in children with emphasis on surgical indications, strategies and long-term outcome.Between 1986 and 2012, 46 infants and children  underwent either subtotal or total resection of primary cardiac tumors  outflow tract obstruction was present in 11 children. Indications of resection were presence of hemodynamic and respiratory compromise, severe arrhythmia and risk of embolization. Approach and strategy of resection varied according to tumor location and hemodynamic status.Mean duration of follow-up is 11.6±3.5 years. Morbidity occurred in a 5-month old girl with LV fibroma underwent LVAD implantation secondary to failure from weaning off cardiopulmonary bypass and she eventually underwent heart transplantation 17 days later. Early mortality included a 5-month old boy who underwent complete resection of rhabdomyoma located in LV. Complete tumor resection was done; unfortunately, he underwent LVAD implantation for postoperative heart failure and died on the 13th postoperative day. An 8-month old girl with 3x4cm fibroma obstructing the right ventricular outflow tract compressing the right coronary artery died of severe right heart failure on the 13th postoperative day. Late mortality (7 months postoperative) occurred in a 16-year old boy with non-Hodgkin’s lymphoma. Forty-three patients are alive and well, and are in Ross functional classification 1. All survivors were free of tumor recurrence or progression, even when the resection is incomplete.Individualized approach to tumor resection allows restoration of an adequate hemodynamic function and satisfactory long-term tumor-free outcome.


We have applied a novel high temporal resolution MR imaging sequence to study diastolic function in canines with reperfused transmural infarction. Our results demonstrate abnormal diastolic strain-rates in infarct and viable risk region with corresponding abnormal filling patterns, as observed through the visualization of 2D flow pathlines 3 days post reperfusion.Coronary angioplasty limits infarct expansion post myocardial infarction (MI). However, under certain conditions such as prolonged ischemia, the procedure induces reperfusion injury (RI), linked to adverse left ventricular (LV) remodeling and heart failure (HF). The functional mechanisms involved in adverse remodeling post reperfusion are still unclear. We have developed a new high temporal resolution MR imaging technique, SPAMM-PAV  that provides regional assessment of early diastolic flow velocity and myocardial strain. This method was applied in a canine animal model with prolonged occlusion followed by reperfusion. We examine the diastolic strain-rates (index of stiffness) of infarct regions relative to remote regions and the 2D diastolic flow pathlines 3 days post reperfusion to provide insight into early diastolic function in these animals.Studies were performed in six dogs following 5-6 hours of balloon occlusion of the left anterior descending artery (LAD) followed by reperfusion creating an antero-septal transmural infarct see Fig.  with repThe average circumferential diastolic strain and strain-rate in infarct region, adjacent viable risk region and remote region are shown in Figs. In conclusion, in a canine model of reperfused transmural infarction we observe decreased diastolic strain-rates in the infarct and viable risk regions relative to remote regions and corresponding abnormalities in diastolic filling patterns at 3 days post reperfusion.


To assess left ventricular remodeling after stent angioplasty for native coarctation using serial cardiac MRI.Coarctation of the aorta in the older child and adult can be successfully treated by percutaneous stent implantation. Although afterload will be reduced by coarctation stenting, other factors including systemic blood pressure will influence left ventricular remodeling.Ethical and institutional approval was obtained. The internal cardiac database was searched for patients who had stenting for native coarctation and had MRI scans performed pre and post intervention.2 (17.9-32.0) to 20.2mls/m2 (16.2-25) causing a slightly increased cardiac output 3.5l/min/m2 (2.8-4.4) to 4.1l/min/m2 (2.9-4.6). Left ventricular mass decreased from 59.33g/m2 (50.46-87.80) to 40.54g/m2 (31.89-66.64), although there was one patient in whom LV mass increased. Figure 7 patients were identified that fell into this group. Median (range) age at stent implantation was 14.9 9.1-27.1) years and MRIs were performed 0.2 (0.09-0.9) years after implantation. There was no change in end diastolic volume, with a small decrease in end systolic volume 29.4mls/m7.1 yearsWe demonstrate that MRI at a relatively early stage after coarctation stenting can show evidence of left ventricular remodeling when there is a concomitant fall in systemic blood pressure.


Myocardial dysfunction in septic shock is common and the presentation is broad. There are conflicting data regarding the prognostic implications of low left ventricular (LV) ejection fraction and elevated E/e' ratio on mortality in this patient population. We sought to assess the impact of LV dysfunction and elevated E/e' ratio on 30-day mortality in mechanically ventilated patients with severe sepsis or septic shock.Fifty-eight mechanically ventilated patients with severe sepsis or septic shock admitted from 1 August 2007 to 31 January 2009 were prospectively evaluated with transthoracic echocardiogram within 24 hours of admission. Left ventricular ejection fraction was assessed using the modified Simpson method as recommended by the American Society of Echocardiography. Normal LV function was defined as LVEF 40%. Mitral inflow pulsed wave Doppler of peak E waves and tissue Doppler imaging (TDI) of the septal mitral annulus peak velocities were measured, the E/e' ratio was obtained. Elevated LV filling pressures was defined as E/e' >15.n = 29). Forty-six patients (79%) had normal LV function. Forty-four (76%) patients had normal LV filling pressures. Patients who survived had lower E/e' ratio,  but this was not statistically significant. However, when defined as E/e' >15, the mortality was 71%. On the contrary, patients with low LVEF had a mortality of 41% and LVEF was no different between survivors and nonsurvivors .All cause 30-day mortality was 50% (Myocardial dysfunction is a well-known entity in patients with septic shock. The clinical spectrum of this entity is broad, including LV, RV and diastolic dysfunction. Although the E/e' ratio has been a known prognostic indicator in other cardiac conditions, its role in these patients is less clear. This study demonstrated that when septal mitral annulus E/e' was >15, it was a better marker for mortality than LVEF in mechanically ventilated patients with severe sepsis or septic shock. Larger studies incorporating diastolic evaluation and TDI should be performed to further clarify this finding.


T2* Magnetic Resonance Imaging (MRI) technique allows noninvasive quantification of organ-specific iron burden, playing a key role in the management of thalassemia major (TM) patients. There are few data on the incidence of heart failure and arrhythmias in TM patients according to baseline T2* values. So, the aim of this study was to establish prospectively the risk of cardiac complications in a large cohort of well-treated TM patients.We considered 527 TM patients  for who clinical data relative to a period of 5 years after the first MRI were collected in a central data base. At time of the first scan mean ferritin levels were1653±1559 ng/l, global heart was 27±13 ms, and excellent/good level of compliance were present in the 96% of the study population.At 5 years of follow-up, we recorded 24 cardiac events: 4 episodes of cardiac failure, 15 of arrhythmia, 1 of pulmonary hypertension and 4 of other cardiac complications. The majority of these events (21/24) happened within the first 24 months subsequent to the MRI, so we considered this follow-up period.At the first MRI scan, in patients with cardiac complications the global heart T2* was 22.5 ±12.4 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of cardiac complications associated with global heart T2* values <20 ms (HR= 2.028 P=0.09).In the heart failure patients the global heart T2* was 19±12 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of heart failure associated with global heart T2* values <20 ms (HR=1.9 P=0.524) or <10 ms (HR=2.6 P=0.443).In the arrhythmic patients the global heart T2* was 25±13 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of arrhythmia associated with global heart T2* values <20 ms (HR=2.1 P=0.179) or <10 ms (HR=0.8 P=0.824).During the follow up changes in the chelation therapy (type and/or dose-frequencies) were found in > 25% of the study population.We detected very few cardiac events, almost all concentrated in the first 24 months. In a large cohort of well-treated TM patients heart T2* lost its power in predicting cardiac events probably due to a patient-specific adjustment of the chelation therapy MRI-guided.“No-profit” support by industrial sponsorships  and “Ministero della Salute, fondi ex art. 12 D.Lgs. 502/92 e s.m.i., ricerca sanitaria finalizzata anno 2006” e “Fondazione L. Giambrone”.


Trimetazidine, a piperazine derivative used as an anti-anginal agent, improves myocardial glucose utilization through inhibition of fatty acid metabolism. The present study was designed to investigate whether trimetazidine has the protective effects against smoking-induced left ventricular remodeling in rats. In this study, Wistar rats were randomly divided into 3 groups: smoking group (exposed to cigarette smoke), trimetazidine group (exposed to cigarette smoke and treated with trimetazidine), and control group. The echocardiographic and morphometric data indicated that trimetazidine has protective effects against smoking-induced left ventricular remodeling. Oxidative stress was evaluated by detecting malondialdehyde, superoxide dismutase, and glutathione peroxidase in the supernatant of left ventricular tissue. Cardiomyocyte apoptotic rate was determined by flow cytometry with Annexin V/PI staining. Gene expression and serum levels of inflammatory markers, including interleukin-1β, interleukin-6, and tumor necrosis factor-α, were deteced by quantitative real-time PCR and enzyme-linked immunosorbent assay. Our results suggested that trimetazidine could significantly reduce smoking-induced oxidative stress, apoptosis, and inflammation. In conclusion, our study demonstrates that trimetazidine protects against smoking-induced left ventricular remodeling via attenuating oxidative stress, apoptosis, and inflammation. Smoking, which is a serious public health concern, contributes significantly to cardiovascular morbidity and mortality Ventricular remodeling, defined as changes in size, shape and function of the heart in response to cardiac injury or increased load, is associated with the development and progression of heart failure. The process of ventricular remodeling is largely influenced by haemodynamic load, neurohumoral activation and additional factors such as endothelin, cytokines, nitric oxide production and oxidative stress Trimetazidine, a piperazine derivative used as an anti-anginal agent, selectively inhibits long-chain 3-ketoacyl coenzyme A thiolase (the last enzyme involved in β-oxidation) activity. Previous studies have demonstrated that trimetazidine can improve left ventricular function in patients with heart failure This study was carried out in accordance with the National Institute of Health's Guide for the Care and Use of Laboratory Animals and was approved by the Animal Ethics Committee of Soochow University (Protocol number SD2011288).Male Wistar rats weighing 200–250g were housed two per plastic cage with wood chips for bedding in an animal room with an alternating 12 h light/dark cycle at 22±2°C and 55±10% relative humidity. The rats were randomly divided into 3 groups: smoking group (n = 10), exposed to cigarette smoke at the rate of 40 cigarettes/day for 4 months; trimetazidine group (n = 10), exposed to cigarette smoke (40 cigarettes/day) and meanwhile treated with trimetazidine  for 4 months; control group (n = 10), neither exposed to cigarette smoke nor treated with trimetazidine. Drugs were prepared from the tablets, suspended in 0.9% NaCl and applied by stomach tube in a volume of 2.0 ml/kg/day.The rats were exposed to cigarette smoke in a chamber (dimensions 95×80×65cm) connected to a smoking device according to the method proposed by Wang, et al. 3-LVESD3)/LVEDD3]. The transmitral diastolic flow (E and A waves) was obtained with the transducer at the apical 4-chamber view. The peak velocities in the rapid ventricular filling phase (E wave) and during atrial contraction (A wave) were measured in 5 consecutive cardiac cycles and were averaged. Tissue Doppler imaging recordings were obtained from the lateral mitral valve annulus. Early diastolic (Ea) and late diastolic (Aa) mitral annular velocities were measured in 5 consecutive cardiac cycles and the results were averaged. The E/A and Ea/Aa ratios were calculated and used as indices of left ventricular diastolic function.After 4 months, transthoracic echocardiography was carried out to evaluate cardiac structure and function in these 3 groups. All echocardiograms were performed according to the American Society of Echocardiography guidelines All animals were weighed, euthanized by carbon dioxide inhalation, then left ventricles (including the interventricular septum) were dissected, separated, and weighed. Left ventricular mass index (LVMI) was calculated as left ventricular mass divided by the rat's body weight. Left ventricular tissue was fixed in 10% buffered formalin and embedded in paraffin. Five-micron-thick sections were stained with hematoxylin-eosin (HE) and with the collagen-specific stain picrosirius red. Myocyte cross-sectional area (CSA) was determined for at least 100 myocytes per slide stained with HE. The measurements were performed using a Leica microscope (magnification lens ×400) attached to a video camera and connected to a personal computer equipped with image analyzer software . CSA was measured with a digitizing pad, and the selected cells were transversely cut with the nucleus clearly identified in the centre of the myocyte. Interstitial collagen volume fraction (ICVF) was determined for the entire picrosirius red-stained cardiac section using an automated image analyzer . Cardiac tissue components were identified according to the colour level: red for collagen fibres, yellow for myocytes, and white for interstitial space. The digitized profiles were sent to a computer that calculated collagen volume fraction as the sum of all connective tissue areas divided by the sum of all connective tissue and myocyte areas. On average, 35 microscopic fields were analyzed with a 40× lens. Perivascular collagen was excluded from this analysis.Rat left ventricular tissue was removed and homogenized in 50 mmol/L phosphate buffer (pH 7.4) kept in an ice bath. The homogenates were centrifuged for 10 min at 8,500 g (4°C), and the pellet (cellular debris) was discarded. The supernatants were harvested and stored at –20°C until biochemical assays were performed. Oxidative stress was evaluated by detecting malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the supernatant according to the instructions of detection kits from Nanjing Jiancheng Bioengineering Institute . MDA level was measured with the thiobarbituric acid reaction using Ohkawa's method 5 cells were collected and washed twice with cold PBS. 5 μl of Annexin V  and 5 μl of PI  were added to the cells, which were resuspended in 500 μl 1× binding buffer. The cells were gently vortexed and incubated for 15 min at room temperature in the dark, then they were analyzed by flow cytometry within 1 h. Annexin V labeled with a fluorophore could identify cells in the early stage of apoptosis, and PI, a fluorescent nucleic acid binding dye, was responsible for staining cells in the medium and late stages of apoptosis. Analysis was based on gating a subpopulation of cells by forward scatter versus side scatter. The intermediate to large mononuclear cell population was the gated region used to calculate the apoptotic rate. The apoptotic rate was calculated as the percentage of Annexin V-positive and PI-negative cells divided by the total number of cells in the gated region.Rat left ventricular tissue was surgically removed, minced into small pieces, and then digested for 10 min at 37°C with trypsin solution. 1×102+ and SYBR Green I , 0.3 μM of primer, 1 μL template DNA and ddH2O filled up to 25 μL. The amplification reactions were carried out according to the following cycling protocol. Initial denaturation for 5 min at 95°C was followed by 40 cycles of 94°C for 30 s, 60°C for 30 s and 72°C for 40 s. The final elongation phase was performed for 10 min at 72°C. In this study, β-actin was used as internal control. The primer sequences used were as follows: IL-1β, forward primer 5′-TACCTATGTCTTGCCCGTGGAG-3′ and reverse primer 5′-ATCATCCCACGAGTCACAGAGG-3′; IL-6, forward primer 5′-GTCAACTCCATCTGCCCTTCAG-3′ and reverse primer 5′-GGCAGTGGCTGTCAACAACAT-3′; TNF-α, forward primer 5′-ACAAGGCTGCCCCGACTAT-3′ and reverse primer 5′-CTCCTGGTATGAAGTGGCAAATC-3′; β-actin, forward primer 5′-TGTCACCAACTGGGACGATA-3′ and reverse primer 5′-AACACAGCCTGGATGGCTAC-3′. The fold change of mRNA was analyzed using the 2−ΔΔCt method The gene expression of inflammatory markers, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were deteced by quantitative real-time PCR. Total RNA was extracted from left ventricular tissue using Trizol Reagent according to the manufacturer's instructions. The concentration of RNA was quantified by measuring the absorbance at 260 nm. The reverse transcription mixture contained 1 μg of total RNA, 0.5 μg of oligo d(T) primer, 4 μl of 5×RT buffer, 0.5 mM deoxynucleotides, 50 U of RNase inhibitor and 200 U of reverse transcriptase  in a total volume of 20 μl. The reaction was carried out at 42°C for 1 h followed by heat inactivation at 95°C for 5 min. Real-time PCR was performed on the ABI 7300 Real Time PCR System following the manufacturer's instructions. The reaction mixture consisted of 12.5μl of SYBR Premix Ex Taq containing TaKaRa Ex Taq HS, dNTP mixture, MgThe serum levels of inflammatory markers, including IL-1β, IL-6, and TNF-α, were detected using the commercial enzyme-linked immunosorbent assay (ELISA) kits . All experimental procedures were performed according to the manufacturer's instructions.Data were presented as mean ± SD and differences between groups were analyzed using one-way ANOVA with the SPSS 15.0 . Scheffé post hoc test was used if the ANOVA was significant. A P value <0.05 was considered statistically significant.The echocardiographic data are presented in The morphometric data are presented in The HE-stained images of left ventricular tissue are shown in Oxidative stress was evaluated by detecting MDA, SOD and GSH-Px in the supernatant of left ventricular tissue and the results are presented in Cardiomyocyte apoptotic rate was determined by flow cytometry with Annexin V/PI staining and the results are shown in The gene expression of inflammatory markers were deteced by quantitative real-time PCR and the results are shown in The serum levels of inflammatory cytokines were detected by ELISA and the results are presented in In the present study, we demonstrated for the first time that trimetazidine has protective effects against smoking-induced left ventricular remodeling via attenuating oxidative stress, apoptosis, and inflammation.To date, there have been few studies examining the adverse effects of smoking on left ventricular remodeling. Although smoking affects the entire cardiovascular system, it has been generally accepted that the most adverse effects were on the vasculature and included endothelial dysfunction and accelerated atherosclerosis In the present study, our results demonstrate that exposure to cigarette smoke could induce myocardial hypertrophy and ventricular enlargement which play a critical role in the remodeling process. One of the most striking characteristics of cardiac remodeling is a progressive decrease in ventricular function. Initially, due to cell growth, the remodeling process may help to maintain or restore ventricular function. Chronically, however, biochemical, genetic, and structural alterations occur, resulting in progressive ventricular dysfunction. In agreement with this concept, our study indicated that cigarette smoke exposure is associated with a significant decrease in left ventricular systolic function.Trimetazidine, a piperazine derivative used as an anti-anginal agent, improves myocardial glucose utilization through inhibition of fatty acid metabolism. A previous study has reported that trimetazidine treatment was associated with a significant improvement of left ventricular function and the remodeling process in patients with ischaemic dilated cardiomyopathy Oxidative stress, defined as an excess production of reactive oxygen species (ROS), has been shown to be involved in the pathophysiology of ventricular remodeling and associated with left ventricular dysfunction Apoptosis, a highly regulated biological process, plays a critical role in the pathogenesis of ventricular remodeling Inflammation also plays an important role in the pathogenesis of ventricular remodeling. It has been demonstrated that inflammatory cytokines, including IL-1β, IL-6, and TNF-α, increase remarkably after myocardial infarction and are involved in the subsequent left ventricular remodeling In conclusion, our study demonstrates that trimetazidine protects against smoking-induced left ventricular remodeling via attenuating oxidative stress, apoptosis, and inflammation, which will provide valuable insights into the prevention and treatment of left ventricular remodeling induced by smoking.


Myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to 70%. During the sepsis-induced myocardial dysfunction, both ventricles can dilate and diminish its ejection fraction, having less response to fluid resuscitation and catecholamines, but typically is assumed to be reversible within 7-10 days. In the last 30 years, It´s being subject of substantial research; however no explanation of its etiopathogenesis or effective treatment have been proved yet. The aim of this manuscript is to review on the most relevant aspects of the sepsis-induced myocardial dysfunction, discuss its clinical presentation, pathophysiology, etiopathogenesis, diagnostic tools and therapeutic strategies proposed in recent years. Severe sepsis and septic shock are the main cause of death in non-cardiac Intensive Care Units (ICU), with unacceptably high mortality rates , 2. In 1Sepsis Occurrence in Acutelly ill Patients” (SOAP), involved 21 European countries and enrolled 3.147 septic patients for 15 days in May 2002. Mortality rates were 27% in septic patients and more than 50% of patients with septic shock [The study "ic shock -9. Encouic shock . HoweverSepsis-induced myocardial dysfunction (SIMD) is one of the major predictors of morbidity and mortality of sepsis. It is present in more than 40% of cases of sepsis  and its The aim of this paper is to review about the most important aspects of the SIMD.stunned myocardium" in 1.982. It was self-limited but could lead to decreased ventricular compliance [Reversible myocardial dysfunction (RMD) was first described in a canine experimental model by Heyndrickx and coworkers at 1.975 . The phempliance . warm shock"), which still had extremities hot but with a bounding pulse (increased cardiac output and decreased systemic vascular resistance). Later, the hypodinamyc stage ocurred ("cold shock"), in which the patient had a thready pulse, signs of peripheral hypoperfusion, organ failure and ultimately died (systemic vascular resistance increased to compensate for reduced cardiac output) [Clowes and coworkers in 1966, with a cohort of patients with diffuse visceral fulminating peritonitis , suggest output) . With the introduction of hemodynamic monitoring with pulmonary artery catheter, the existence of myocardial depression in patients with septic shock was confirmed, showing depressed cardiac response to volume infusion , 18. The1)[The concept of SIMD emerged from the study of Parker and coworkers at 1.984 . They de1). 2). In 10-20% of patients with refractory hypotension (need for dopamine >15 mg / kg per min or norepinephrine >0.25 mg / kg per min to maintain mean blood pressure above 60 mmHg or 80 mmHg if previous hypertension), exists high probability that CO was diminished by the presence of severe myocardial dysfunction , 25. DurAfter the study of Parker and coworkers , left veRecently, Zanotti-Cavazzoni group studied the impact of SIMD on the LV diameter, hemodynamic parameters and survival in a murine experimental model . In sept2). Phenomena similar to those mentioned in LV have been described in the right ventricle (RV) . In cont 3)[The LV diastolic function (compliance) can be studied using transmitral and pulmonary veins Doppler-pulsed and Doppler tissue imaging echocardiography. The transesophageal study has proven to be better than the transthoracic one due to a higher quality of images and the possibility of complete analysis of pulmonary veins flow (Image 3). Few stu 3)-42, or a 3). SIMD is 3). In the  3), diastol 3), 44. Mat 3), in a caMany pathological findings were found in the SIMD, including genetically , all posEarly theories of myocardial dysfunction in sepsis were based on global myocardial ischemia. Several canine experimental studies with endotoxemic shock so hypothesized it ,48. ThisThe microcirculation undergoes major changes during sepsis. It was thought that could be changes in the distribution of flow that conditioned localized areas of ischemia, and even that it was the reason for the appearance of elevated troponin levels that have been found occasionally, in correlation with the severity of cardiac dysfunction . Nowadayin vitro [In vivo, myocardial dysfunction in children with meningococcal septic shock has been shown, apparently caused by IL-6 [per se causes direct myocardial depression, as only a minority of septic patients have detectable levels of endotoxin [Lefer  in 1970 in vitro , 63. In  by IL-6 . Interes by IL-6 -67, and  by IL-6 , that a It has been found an accumulation of intramyocardial lipids and glycogen in non-survivors in septic patients  and in eSome authors have found apoptosis of neurons and glial cells in autonomic centers that control the cardiovascular system , 77, posIn recent years, increased attention on the cellular mechanisms that can lead to myocardial depression in sepsis and septic shock has been focused on the role of many mediators that are altered, and often by stimulation or inhibition of other mediators, may influence the appearance of the SIMD. It is still not clear, but seems possible to attribute a major role to cytokines produced by various cells of the organism , under very various stimuli , act as messengers between cells often very remote and can alter their function. in vitro [Although clear relationships were found between the appearance of these cytokines in the circulating blood of septic patients and the onset of myocardial depression in vitro , 83, it in vitro , clinicain vitro . Neitherin vitro . In isolated cardiomyocytes from animals, it has been found that both endotoxin , 87 and In animal models of sepsis with cecal ligation and puncture, a reduction of up to 46% of the rate of ATP-dependent calcium entry in hypodinámyc sepsis has been found. Since both calcium-ATPase and its main regulatory protein, the phospholamban, control the active calcium reuptake into the SR, it seems that this finding means defects in phosphorylation of proteins of the SR in myocardial dysfunction of late sepsis , 95. In Some experiments in animals have found a decrease in the density of calcium L-channels in endotoxemic animals , or a deThe occurrence of myocardial dysfunction after endotoxin action seems to depend on the presence of receptors on the cell wall type Toll-like receptor (TLR) type 4  and CD-1cathecolaminergic storm"), mainly affects the heart and can lead to impaired diastolic function, tachycardia and tachyarrhythmias, myocardial ischemia, stunning, apoptosis and necrosis [Excessive stimulation of these receptors, or for a long time, sometimes have caused myocardial damage by intracellular calcium overload and even induced cell necrosis. In murine models of sepsis, it was found decreased density of β-adrenergic receptors , while onecrosis . A large part of the extracellular stimuli recognized by mammalian cells involves a complex signaling molecules in the center of which are the so-called mitogen-activated protein kinases (MAPKs) . In cardThe matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases whose main property is to degrade extracellular matrix components. Its activity was found increased in a variety of cardiovascular diseases, including acute or chronic heart failure and atherosclerosis , 123. Thin vitro cardioinhibition at various moments of contraction and relaxation, either by production of NO as without it. In animal experiments, reversing some of the effects of LPS by administration of dexamethasone have succeeded, which appears to inhibit the induction of NOS 2, but not of NOS1 or NOS3, which suggests that NO cardiodepression is dependent of the induction and translation of a inducible protein [Nitric oxide (NO) is produced by the NO synthases (NOS). These enzymes exist in three forms, the NOS-1 and NOS-3, called constitutive, and NOS-2, called inducible, with great vasodilator power but also to generate inflammation. In humans hearts with sepsis, increased expression of inducible NOS and significant amounts of peroxynitrite have been found, producing  protein , 127. Ho protein , and tha protein , 130. Th protein , and oth protein . Mitochondrial dysfunction seems to be linked to the severity and prognosis, both in patients and experimental animals . In animThere is increasing evidence that apoptosis is involved in SIMD , probabl2) >70% and cardiac index (CI) >3.5 L/min-1. The concept of hemodynamic failure of this Consensus Conference is still not entirely correct, since it does not differentiate between sepsis-induced circulatory dysfunction and sepsis-induced cardiac dysfunction. In the 2001 International Sepsis Definitions Conference , hemodynAlthough studies based on transpulmonary thermodilution method provide key hemodynamic variables as extravascular lung water, extralung water index and intrathoracic blood volume, can detect incipient pulmonary edema and its use has been shown reduce the duration of mechanical ventilation and, therefore, admission in the ICU , 142, thThe SIMD can be accompanied by specific changes in the electrocardiogram (ECG), which can be very similar to those occurring during acute coronary syndromes , includi3). The same year that Parker described the SIMD, Ozier and coworkers showed in two-dimensional echocardiography . Annan a4). The analysis of the respiratory variation of the inferior vena cava diameters has demonstrated high and significant correlation with the increase in CO after the bolus [2/FiO2 oxygenation index [Echocardiography is a first-line technique for hemodynamic evaluation of patients with hemodynamic instability. In patients with severe sepsis or septic shock, early goal-directed optimization of CO by intensive fluid therapy has been shown to reduce morbidity and mortality , 140; hohe bolus , 148. Scon index . In severe sepsis or septic shock patients with positive-pressure mechanical ventilation, measurement of central venous pressure, pulmonary capillary wedge pressure or RV diastolic diameter can bias the analysis of the response to fluid therapy because intrathoracic pressure is increased and, therefore may decrease venous return and impair stroke volume . However5). In a descriptive study with 33 myocardial dysfunction patients without previously known cardiac disease, we [3). The improvement in the LVEF over time was accompanied by a progressive and statistically significant improvement of segmental contractility alterations (p=0.0001). The analysis of global contractility by calculating the left ventricle ejection fraction (LVEF) has several limitations. The LVEF is clearly influenced not only by LV contractility, but also by the state of preload and afterload that are frequently altered in septic patients; however, LVEF measurement has proved to be very sensitive to changes in contractility when ventricular function is decreased. As in ischemic heart disease, the Teicholtz method is not the most appropriate when there are alterations of segmental contractility. Regarding the analysis of ventricular contractility by echocardiography, it is known that some patients experience segmental contractility alterations, with hypokinesis mainly at the apex and basal LV segments , 155  by tissue Doppler imaging that combines the influence of transmitral driving pressure and myocardial relaxation are associated with invasive measures of diastolic LV performance, and has shown to predict the mean left ventricle diastolic pressure (M-LVDP). In shock patients preferences in the measurement site of Doppler tissue imaging E 'maximal velocity  has not been shown . A ratioThe right ventricle can also be studied by echocardiography with capacity of providing assessments of RV function similar to pulmonary artery catheter . Size, wDobutamine stress echocardiography has been used as a prognostic indicator in septic shock. Vallet's group  studied 2 and lactate). The acceleration of contractility index (ACI) measured by bioelectrical impedance was significantly lower in patients who died (71 l/s2 vs 123 l/s2), it was related to the left cardiac work index , and only predicted hospital mortality . An ACI less than 40 l/s2 was associated with a hospital mortality rate 9 times higher than the control group. The ACI was not associated with lactate levels >4 mmol/l (p = 0.24), PVC (p = 0.56) or the fluid administered (p = 0.18). In this study we can conclude that the analysis of the ACI may be a measure of contractility independent of preload and that its reduction can be attributed to segmentary contractility alterations. Larger studies would be needed in which consider whether ACI could have predictive value to guide resuscitation of sepsis based on the patient's myocardial response. The impedance cardiography (ICG) is a non-invasive method that converts changes in thoracic impedance in volume over time. It can make continuous measurements of SV, CO, systemic vascular resistance, left cardiac work, acceleration of contractility index and left ventricular ejection time among others. Napoli and coworkers , did an rd -5th day of ICU admission (n = 38) and another with LVEF <50% (n = 55), the authors analyzed the behaviour of plasma BNP with echocardiographic monitoring. They found that the lower was the LVEF higher was the plasma concentration of BNP (p <0.05), this difference was most evident after 5 days . In addition, patients with LV dysfunction and elevated plasma levels of BNP were associated with increased morbidity and mortality, indicating that the plasma concentration of BNP could be used as a prognostic marker of septic shock, at least for the short term, given that the analysis of the curves ROC of the scores APACHE II and SOFA of these patients showed that the plasma concentration of BNP had significant predictive value for survival at 30th day. . This study excluded patients with previously known cardiac disease who may have basal plasma BNP levels high. However, these patients are usually admitted to the ICU and in them, therefore, measurement of plasma BNP aren´t useful as a prognostic marker. Recently Hartemink and coworkers [The hormone B-type natriuretic peptide (BNP) is produced by ventricular myocytes. Main stimulus for BNP release is primarily increased ventricular wall stress , and sevoworkers , in a prStreptococcus pneumoniae, but it has shown no causal link at this time. Mehta and coworkers [Nowadays, it's possible to identify with more accuracy the septic patients whose myocardium has been compromise by assessing troponin (cTnI) levels, which proved to be a highly sensitive and specific marker of myocardial injury in sepsis. The mechanisms underlying cTnI release in patients with sepsis are still unknown. Several hypotheses have been developed that attempt to explain the increase in cTnI. One theory is that sepsis produces coronary hypoperfusion and ischemia; however, it has been shown that in patients with normal coronary arteries may also raise the cTnI . Anotheroworkers , in a sioworkers . In seveoworkers , 191. Jooworkers , 194. ThYucel and co-workers  did a pr2, mean arterial pressure (MAP), diuresis, CVP and hematocrit) by fluid replacement, vasoactive, transfusional therapy, inotropes, steroids or human recombinant protein C. These recommendations received a grade B recommendation (based on a single level I study), and are based on the study of Rivers [Current standard treatment for sepsis include infection control and optimization of hemodynamic parameters  inhibitors, calcium channel blockers and statins . Nor is In this section we will discuss various therapeutic strategies proposed in the treatment of SIMD, many recently published and in experimental period. We state that the treatment of SIMD remains a challenge almost 30 years after its characterization. There has been longstanding debate about whether one catecholamine vasopressor agent is superior to another. Depending on the effect of each catecholamine on its receptor  a treatment strategy that takes into account both blood pressure and tissue perfusion should be chosen . one-size-fits-all" approach to a multimodal approach in vasopressor selection [Norepinephrine or dopamine are the first choice of vasoactive drugs for hemodynamic support of septic shock after correcting any hypovolemia [Since the introduction of the protocols of the Surviving Sepsis Campaign, several observational and controlled trials have been published that reconsider the "election . Norepinovolemia . Norepinovolemia , 202. Inovolemia , with 10ovolemia , classifovolemia , which uovolemia . AccumulDopamine may be useful in patients with SIMD because increases MAP in patients who remain hypotensive after optimal fluid therapy by increasing cardiac index. Its disadvantages are that it is very tachycardic and can be very arrhythmogenic [                    hmogenic , 205, alhmogenic . Recentlhmogenic  in a muldobutamine is the preferred treatment recommended by current clinical guidelines [2I), at the expense of an often significant increase in heart rate (from 9% to 23 %) [For the above reasons, in patients with persistently low cardiac output despite adequate LV filling pressure , idelines , which hto 23 %) -211. Vasopressin (AVP) and terlipressin are increasingly used as adjunct vasopressors in the treatment of catecholamine-resistant septic shock . The def2, by baroreceptor activation, effects that can be counteracted by dobutamine. In the study by Morelli and coworkers (DOBUPRESS study) [2 at baseline. In this group of patients adverse effects is expected to happen such as increased myocardial oxygen demand, tachyarrhythmias or decrease in MAP in the presence of hypovolemia. The V2 agonistic effects of AVP may exert favourable effects on the hepatosplanchnic, renal, pulmonary and coronary circulation. Terlipressin has more activity on V1 receptors and may increase the blood pressure more potently avoiding rebound hypotension. The use of each drug is usually according to local availability . In patiS study) , the autConsidering that the SIMD is determined largely by a decrease in myofilament response to calcium, sensitization with levosimendan becomes an attractive therapeutic option. Levosimendan is a positive inotropic and vasodilator drug with demonstrated beneficial effects in acute heart failure and acute coronary syndromes -219. LevLevosimendan is a very experienced agent in animal models of induced sepsis -224, andbeta-blockers in sepsis, since Berk studies in the 60s and 70s, have been insufficient for its inclusion in universal guidelines of sepsis treatment [Over 50 years of experimentation with reatment ,231. Thereatment , patientreatment , severe reatment ,235, trareatment , or perireatment , demonstreatment , allowinreatment , the usereatment . Landiolreatment . In humareatment  observedreatment  did a rereatment , but thesimvastatin and fluvastatin have shown clear antimicrobial [Both icrobial , antiviricrobial . Other oicrobial ,248. Thricrobial . Using aicrobial . In addidihydropyridines such as manidipine, nicardipine and especially amlodipine, apart from its effect on calcium channels, could reduce levels of proinflammatory cytokines and the expression of inflammation-relevant genes TNFα and iNOS [Several experimental animal studies in rats have shown that the and iNOS ,252. XiaIntra-aortic balloon counterpulsation (IABP) is expected to be succeeded in reducing dosage of vasopressor drugs and to increase the survival time of patients with SIMD, allowing the treatment started took effect. Therefore it would be a maintenance therapy of patients with SIMD. The insertion of the IABP should be early, since it needs 3-24 hours to achieve its full operation [                    peration . Pribbleperation , in an eStreptococcus, showed that IABP could increase cardiac output and decrease pulmonary resistance. Despite the findings of Engoren and coworkers [5/kg, p=0.0001) compared with controls. Although the complications associated with use of IABP are rare, the incidence may increase in the subgroup of patients with septic shock with renal dysfunction or disseminated intravascular coagulation. The "ideal patient" to use the IABC would be the septic patient with a highly depressed myocardial function and a not severely reduced SVR, as a bridging intervention to give causal treatment time to work [Impella should not be considered a "folly" [infected with group B oworkers  in a poroworkers , more re to work . To eval "folly" . Apelin was recently identified as the putative endogenous ligand receptor coupled to G protein, which is related to the angiotensin AT1 receptor, also called receptor like-1 angiotensin II (AGTRL1) by reverse pharmacology. It has been considered the most potent positive inotropic peptide, suggesting that a decrease in the concentration of endogenous Apelin plays an important role in the development of heart failure [                     failure . Pan's g failure . mesenchymal stem cells (MSCs) is a potentially novel treatment for SIMD. Weil et al [The infusion of il et al , in a mudiazepam (Type IV phosphodiesterase inhibitor) in a murine experimental model after-LPS-induced endotoxic shock. The authors found that different functional myocardial parameters  and coronary flow were significantly improved after administration (p <0.01). Recently, Netthling and coworkers  studied Sepsis-induced myocardial dysfunction is being studied extensively. Probably, It could have greater clinical entity that is known. However, its pathogenesis as well as multiple is still unknown. Probably the best method of diagnosis is echocardiography, but this technique requires an adequate training of the modern intensivists. There is no adequate treatment, althoug it seems that might be necessary to seek a cardioprotective therapy and supportive measures, similar to those specified in cardiogenic shock, while the casual treatment of sepsis takes effect.


This study showed that the effect on the myocardium related to thyrotoxicosis was associated with the disease duration before treatment.The purpose was to evaluate the effect of the disease duration prior to treatment, thyroid hormones level, or both on the reversibility of dilated cardiomyopathy. Between January 2006 and December 2010, a longitudinal study with a 6 months follow-up was carried on. One hundred and seventy patients with hyperthyroidism were referred to the cardiologist, and 127 had a 6 months followup after antithyroid treatment and were evaluated by echocardiography. Dilated cardiomyopathy reversibility criteria were established according to echocardiographic parameters. Complete reversibility existed when all parameters were met, partial reversibility when LVEF was ≥55% plus two or three other parameters, and no reversibility when LVEF was ≤55% regardless of other parameters. The results showed that echocardiography parameters related to the regression of myocardial mass were associated with a disease duration shorter than 10.38 months. This was the main predictive variable for reversal of dilated cardiomyopathy, followed by  Hyperthyroidism's prevalence in Mexico is about 0.7%. Most patients are women between 30 and 50 years old. A hyperdynamic cardiovascular dysfunction is the result of excess thyroid hormone secretion by the thyroid gland, in these patients, manifested mainly by elevated levels of serum triiodothyronine. Thyrotoxicosis involves two sites of action of the thyroid hormone. It acts directly on the heart and on the systemic vasculature producing tachycardia, increased left ventricular mass (LVM), and unchanged systolic function at the beginning of the thyroid dysfunction. However, long-term effects are diastolic dysfunction, cardiac arrhythmias, heart dilation, and a high output heart failure , 2.It is controversial as to whether these cardiovascular alterations due to hyperthyroidism are purely functional or if there is a structural damage. An experimental study in rabbits demonstrated the presence of histological changes in myocytes, and functional damage was more important and related to the hormone levels .In follow-up studies, it has been observed that once hyperthyroidism treatment is started, cardiovascular function returns to normal. However, in a percentage of patients, the cardiac damage remains with poor myocardial function , 5.The purpose of this study is to evaluate the effect of the disease duration, serum thyroid hormones levels, or both on the myocardium of patients with overt hyperthyroidism and the implication of these factors in the reversibility of dilated cardiomyopathy once patients were euthyroid after antithyroid treatment.Between January 2006 and December 2010, a longitudinal 6 months follow-up study was carried on. A total of 2,351 patients were seen in the endocrinology clinic. Of them, 798 were diagnosed with hyperthyroidism in the presence of free triiodothyronine (T3) level >1.59 ng/mL and concomitant suppressed thyroid stimulating hormone (TSH) level <0.35 mUI/mL; [Hypertension, diabetes mellitus, and/or any cardiovascular disease  were excluded. The disease duration was established in months from the onset of the first symptoms according to the patient until euthyroid state was reached.The study included four visits to the cardiology clinic: (a) the first visit at referral time, the patients were sent by the endocrinologist because he found cardiovascular alterations, (b) the second visit was when the endocrinologist found the patients euthyroid, (c) and the third and fourth visits were three and six months later, respectively. In each visit a clinical history, physical examination, chest X-ray, electrocardiography (ECG), and echocardiographic assessment were performed, and serum thyroid hormones were determined. Echocardiographic assessment was carried out by an experienced operator (L.O.R) using the same echocardiography instrument (Philips Envisor C Philips transducer S3). All digital images were stored on X-Celera system in order to compare images. Left and right ventricular  and left and right auricular  diameters were measured, and left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVSF), pulmonary artery systolic pressure, (PASP), left ventricular mass index (LVMI), and left ventricular mass (LVM), left ventricular end-diastolic (LVEDV) and -systolic volumes (LVESV) were determined using standard M-mode echocardiography and Simpson's method according to the American Society of Echocardiography (ASE) recommendations .Dilated cardiomyopathy reversibility criteria for women and men were established according to the following echocardiographic parameter cut points: left ventricular ejection fraction (LVEF) (≤55%), left ventricular diastolic diameter (LVDD) (women ≥47 mm and men ≥49 mm), left ventricular systolic diameter (LVSD) (women ≥31 mm and men ≥35 mm), left ventricular end-diastolic volume (LVDV) (women ≥97 mL and men ≥102 mL), and left ventricular end-systolic volume (LVSD) (women ≥32 (mL) and men ≥34 mL). Complete reversibility was established when all parameters were within established cut points, partial reversibility when LVEF was equal or above 55% plus two or three of the echocardiographic parameters, and no regression when LVEF was less than 55% regardless of other parameters.Local Research Ethics Committee approved the study protocol, and all participants signed the informed consent form.P > 0.05). Data are presented as percentiles 25 and 75 and median. Relative frequencies and proportions were estimated for the nominal and categorical variables. Stata 10.0 for Windows software was used for the statistical analysis.Numerical variables showed a different distribution from normal standards (Gaussian distribution) .To estimate the effect of disease duration and/or the thyroid hormone levels on myocardium at the referral, regression coefficients were estimated for each echocardiographic parameter (the dependent variables) against disease duration or the level of thyroid hormone (the independent variables). Natural log transformed was used to normalize a skewed distribution. Because a bimodal distribution was identified, LVMI and LVM were divided into low  and high values . No interaction was identified between the disease duration and the thyroid hormone levels , and echocardiographic parameters at referral time . The Kruskal Wallis test was used for the numerical variables and ChiEchocardiographic parameters at referral time and at six months by the reversibility status were compared with the two way ANOVA . The percentage of change of the echocardiographic parameters between referral time and at 6 months was calculated:  ∗ 100. Statistical significance was set at an alpha level ≤0.05. Multivariable analysis was carried out using the classification and regression tree (CART) modeling . This meMost patients had diffuse toxic goiter (79 patients (62%)), multinodular goiter was found in 32 patients (25%), and only 16 patients (13%) had an autonomously functioning thyroid nodule. Sixty-six (52%) were treated with radioactive Iodine. In 32 patients (25%), the thyroid was removed surgically, and the remaining 29 (23%) received antithyroid drug treatment. Sixty-six patients (52%) were in sinus rhythm, 49 (39%) in atrial fibrillation, and the remaining had flutter or supraventricular tachycardia. Cardiovascular symptoms identified were tachycardia (90%), palpitations (85%), dyspnea (65%), atrial fibrillation (45%), or systolic hypertension (30%). One hundred and two were women (81%), and 25 were men (19%). Clinical data, thyroid hormones, and echocardiographic parameters at the first visit at referral time are shown in Most altered echocardiographic parameters were associated with disease duration, with a greater effect in those related to decreased myocardial mass . Free T3 levels were associated with the LVMI and the LVDD .P = 0.000). Disease duration since diagnosis was related to reversibility status; those with complete reversibility had less disease duration (13 months) than those with no regression (24 months) (P < 0.05). When disease duration was analyzed by gender, there was no difference ; however, analysis by gender showed significant differences; the male group had 50% total recovery, while in the females, complete reversibility was observed in only 26%, and most of them had a partial recovery (40%)  showed that disease duration was the main predictive variable in the recovery of dilated cardiomyopathy, followed by pharmacological treatment, and the least important were T3 serum levels.β-blocker) treatment to achieve complete recovery. Those with a long disease duration (>10.38 months), not receiving β-blocker treatment and with elevated levels of serum T3, did not recover or had a partial recovery  because of a decreased LVEF, suggesting that the heart undergoes some pathological remodeling .Thyrotoxic heart disease clinical manifestation is characterized by its rapid course and recovery after thyroid dysfunction normalization . In the Chronic exposure to thyroid hormone may trigger heart failure because of a high cardiac output associated with systolic left ventricular dysfunction with subsequent cardiovascular morbidity by volume overload due to reduced myocardial contractility, which activates sympathetic activity on the heart. In this study, the duration of thyroid dysfunction suggests that physiological compensatory and pathological hypertrophy may coexist and lead to a concentric cardiac hypertrophy, in which thyroid hormones may play very different roles from those in eccentric cardiac hypertrophy .Previous studies , 15 suggThe no reversibility may not only be related to high levels of thyroid hormones, but could also be the result of an alteration of the sympathetic nervous system with increased catecholamines. This combination could result in a tachycardiomyopathy , 21. β-blockers for heart rate control, prevention of heart remodeling, and avoidance of hemodynamic overload will lead to the resolution of heart failure.Antithyroid therapy and β-blocker administration and high T3 serum levels. Therefore, the use of β-blocker is an important factor for complete recovery.Patient's recovery is mainly dependent on the hyperthyroidism duration previous to treatment. Factors which may play a role in no recovery are no The real disease duration is unknown; it depends on the patient's recollection at the time of history taking on the first endocrinology visit. Patients included in this study were only those the endocrinologist considered to have a cardiac abnormality. The follow-up was limited to 6 months; therefore, complete reversibility in those with a partial recovery may be achieved later and could not been determined in this study.


CINE imaging of the mouse heart is an established technique on high-field small animal MRI systems. The current imaging protocols normally comprise two-dimensional CINE imaging in 2- and 4-chamber geometry and a stack of short axis views for full functional coverage of the heart. For SNR constraints, acquisition times are still in the minute range for a single 2D slice, yielding rather long acquisition times for a complete short axis stack. Recently introduced cryogenically cooled resonators (CCR) offer the possibility of a significant increase in SNR, and hence offer the potential for rapid cine imaging of the mouse heart. The objective of this study was to investigate the feasibility of rapid functional imaging of the mouse heart utilizing the SNR gain provided by CCRs.Five wildtype mice (B6/C57) were enrolled in this study. In each mouse a comprehensive cardiac functional examination was performed on an 11.7T small animal system (Bruker BioSpec 117/16) with a 2-element cryogenic coil . The MR protocol was performed under isoflurane anesthesia (~1.5% concentration). Functional imaging was performed applying a self-gated acquisition/reconstruction approach . In each mouse, cine data was acquired with different n=50, 100, 200, and 300 repetitions. Parallel imaging with an acceleration factor of 2 was used for all acquisitions. For further increasing the scan efficiency, all acquisitions were additionally performed with a half-scan factor of 1.6. Matrix size was 256x256, yielding 140  or 92  phase encoding steps. Overall acquisition times for a single slice resulted between 26.5s  and 241.5s . Imaging parameters were as: TE / TR = 0.95/5.75ms, flip angle = 20°, spatial resolution = 117x117x480µm3. From all data sets 20 cardiac phases were reconstructed and ejection fractions calculated semi-automatically (Segment).The scans could be completed in all mice. The resulting image quality was sufficient for identification of the end-diastolic and end-systolic frame. Even though signal to noise (SNR) and apparent flow artifacts were clearly inferior in the 50 and 100 reps scans, no differences were observed in the calculated EF. The endocardial borders were clearly delineated from the blood pool, and the resulting endocardial contours did not show any substantial differences between the investigate protocols. The delineation of the epicardial contours was substantial impaired for the 50 and 100 reps acquisitions.Applying CCRs to functional heart imaging enables significantly shorter acquisition times. If the functional analysis is limited to EF analysis, decent image quality can already be obtained by a 25s scan. In case the epicardial borders are of interest, more repetitions are required for ensuring sufficient delineation of the epicaridal border.


Classification of the overall spectrum of congenital heart defects (CHD) has always been challenging, in part because of the diversity of the cardiac phenotypes, but also because of the oft-complex associations. The purpose of our study was to establish a comprehensive and easy-to-use classification of CHD for clinical and epidemiological studies based on the long list of the International Paediatric and Congenital Cardiac Code (IPCCC).We coded each individual malformation using six-digit codes from the long list of IPCCC. We then regrouped all lesions into 10 categories and 23 subcategories according to a multi-dimensional approach encompassing anatomic, diagnostic and therapeutic criteria. This anatomic and clinical classification of congenital heart disease (ACC-CHD) was then applied to data acquired from a population-based cohort of patients with CHD in France, made up of 2867 cases .The majority of cases (79.5%) could be identified with a single IPCCC code. The category "Heterotaxy, including isomerism and mirror-imagery" was the only one that typically required more than one code for identification of cases. The two largest categories were "ventricular septal defects" (52%) and "anomalies of the outflow tracts and arterial valves" (20% of cases).Our proposed classification is not new, but rather a regrouping of the known spectrum of CHD into a manageable number of categories based on anatomic and clinical criteria. The classification is designed to use the code numbers of the long list of IPCCC but can accommodate ICD-10 codes. Its exhaustiveness, simplicity, and anatomic basis make it useful for clinical and epidemiologic studies, including those aimed at assessment of risk factors and outcomes. Because of the diversity of the cardiac phenotypes, classification of the overall spectrum of congenital cardiac defects has always been challenging, with the challenge exacerbated by the oft-complex association of intracardiac and extracardiac defects. The more complex the pathology, nonetheless, the more important is the need for specialists to speak a common language, and to unify the diagnostic process.th revised version of the International Classification of Diseases (ICD-10) [Two systems of classifications for coding and establishing medical and administrative databases for congenital heart defects (CHD) are currently used globally: the 10(ICD-10) .ICD-10 was created by the World Health Organization to "permit the systematic analysis, the interpretation and the comparison of the mortality and morbidity data harvested in different countries or regions at different periods of time" -5.http://www.ipccc.net[During the 1990's, the Society of Thoracic Surgeons (STS) and the European Association for Cardio-thoracic Surgery (EACTS), and the European Association for Paediatric Cardiology (AEPC), independently developed systems of nomenclature for evaluating the diagnosis and outcomes of patients with congenitally malformed hearts. The resulting International Congenital Heart Surgery Nomenclature and Database was published in 2000 , simultaipccc.net. The IPCipccc.net, and theipccc.net. In the The advantages of the IPCCC, particularly the long list, include its precision and exhaustiveness, since it excludes all doublets and ambiguities. At the same time, its complexity, with more than 10,000 codes, renders difficult the search for the code of an individual lesion.Our aim in preparing our anatomic and clinical classification of congenital heart defects, or ACC-CHD, was to design a comprehensive classification that is easy to use, but which is based on the long list of IPCCC. We have achieved this by regrouping the lesions in a fashion that, at least to us, makes both anatomical and clinical sense. The proposed classification can be useful for conducting epidemiological and clinical studies of risk factors and outcomes, as it aims to incorporate different but complementary approaches based on pathology and clinical practice, as well as echocardiography and criteria used for surgical management.We applied our classification to data obtained from a population-based epidemiological study of patients with congenitally malformed hearts (the EPICARD study) in France. EPICARD is an ongoing prospective cohort follow-up study of all children with a CHD born to women in the conurbation of Greater Paris between 2005 and 2008. Over that period, the total number of births in the conurbation was approximately 300,000. We included all cases of CHD, not only live births, but also stillbirths and terminations of pregnancy. The principal objectives of EPICARD are to use population-based data from a large cohort of patients with CHD to first, estimate total and live birth prevalence, pre- and postnatal diagnosis of CHD; second, assess medical and surgical management of children with CHD; third, evaluate neonatal mortality and morbidity and neuro-developmental outcomes of children with CHD; and fourth, identify the factors associated with their health outcomes, especially the role of events during the neonatal period and of the initial medical and surgical management.st 2005 and April 31st 2008, were eligible for inclusion. The total number of cases included in the study was 2867, including 2349 newborns (82%), 465 pregnancy terminations (16.2%) and 53 foetal deaths (1.8%). Diagnoses were confirmed in specialized paediatric cardiology departments, and for the majority of pregnancy terminations and foetal deaths by pathological examination. For those instances in which a pathologic study could not be achieved, the diagnoses were confirmed by consensus by a paediatric cardiologist and a specialist in echocardiography, based on the results of prenatal echocardiographic examination.The total number of births in the Greater Paris conurbation over the study period was 317,538. All cases, including live births, pregnancy terminations, and foetal deaths, therefore, if diagnosed in the prenatal period or up to one year of age in the birth cohorts between May 1We regrouped the malformations into 10 main categories and 23 subcategories, according to a multi-dimensional approach encompassing anatomy, echocardiography, and criteria for therapeutic management  The ten main categoriesThe ten main categories were listed according to flow of blood.1. Heterotaxy, including isomerism and mirror-imageryWe chose to regroup in this category all the anatomic-echocardiographic sequences known under the terms right or left isomerism, or polysplenia and asplenia syndromes, or visceral heterotaxy. The suggested definition for heterotaxy of the Nomenclature Working Group is: "an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body... heterotaxy does not include patients with either the expected usual or normal arrangement of the internal organs along the left-right axis, also known as "situs solitus", nor patients with complete mirror-imaged arrangement of the internal organs along the left-right axis also known as "situs inversus . We chos2. Anomalies of the venous returnThis group includes all the anomalies of the venous pole of the heart. Within its 2 subcategories, lesions involving anomalous pulmonary and systemic venous return, the groupings are anatomically coherent.3. Anomalies of the atria and interatrial communicationsThis group has an anatomic consistency, concerning the atrial segment of the heart. We excluded, nonetheless, the ostium primum interatrial communications, as well as common atrium, since the phenotypic feature of these entities is the commonality of the atrioventricular junction. We chose to use the term "interatrial communication" (IAC) rather than "atrial septal defect" because the sinus venosus and the coronary sinus defects, although being IAC, are not from an anatomic standpoint defects within the interatrial septum.4. Anomalies of the atrioventricular junctions and valvesAnatomically, the atrioventricular junctions include the adjacent components of atrial and ventricular musculature and the atrioventricular valves. Within this group, therefore, because of the commonality of the atrioventricular junction, we included the ostium primum defects rather than including these lesions with the other interatrial communications. Because of their wide acceptance, we decided to retain the terms "partial" and "complete" atrioventricular septal defects (AVSD) to distinguish the various forms of common atrioventricular junction, the latter indicating those forms with both atrial and ventricular shunting . These a5. Complex anomalies of the atrioventricular connectionsWe included the combination of discordant atrioventricular and ventriculo-arterial connections, congenitally corrected transposition of great arteries (TGA) or double discordance, in this group, and not in the group of anomalous ventriculo-arterial connections. This is because the discordant atrioventricular connections represent the more significant feature, clinically, anatomically and surgically, of this complex cardiac anomaly. This group does not, however, include anomalies of the atrioventricular connections in the setting of isomerism or visceral heterotaxy. We also included in this group, although they are not specific entities, criss-cross AV relations and supero-inferior ventricles, because these anomalies result from a rotational malalignment of the atrial and ventricular structures, even if the AV connections can be concordant in these patients .6. Functionally univentricular heartsHeterogeneous from an anatomic standpoint, all the malformations included in this category have as their common denominator severe hypoplasia of one ventricle. They share the same medical and surgical management, based on one-ventricle repair, and aimed eventually at creation of a total cavopulmonary connection. We chose not to include unbalanced AVSD in this category, on the basis that one of the ventricles could be inappropriately small in these cases but thought to be suitable for biventricular repair . If the 7. Ventricular septal defects (VSD)This group includes not only isolated VSD's, but also additional (multiple) VSD in the setting of another lesion, including of necessity a VSD, such as tetralogy of Fallot. Anatomically heterogeneous, this group is very important numerically. The anatomic nomenclature of VSD is still controversial. We used in our classification the unified nomenclature system proposed by the Congenital Heart Surgery Nomenclature and Database Project . In addi8. Anomalies of the ventricular outflow tractsThe anatomic definition of the ventricular outflow tracts is the area of junction between the ventricular and the arterial segments of the heart. This large category includes the anomalies of the subvalvar region, specifically the subpulmonary infundibulum or conus, the left ventricular outflow tract, the arterial valves and their supporting sinuses, and the intrapericardial segments of the great arterial trunks. Within this group we include subcategories for abnormal ventriculo-arterial connections, including TGA, double-outlet right ventricle, double-outlet left ventricle, and concordant ventriculo-arterial connections with parallel rather than spiralling arterial trunks, or anatomically corrected malposition of the great arteries ,17. We iFrom the surgical standpoint, usually the two ventricles are of normal size in these lesions, making the defects suitable for biventricular repair.9. Anomalies of the extrapericardial arterial trunksThis group includes all the anomalies of the great arteries beyond the boundaries of the pericardial cavity. Clinically heterogeneous, their diagnosis is difficult before birth, and tends to be based after birth on CT-scan, MRI, or catheterization.10. Congenital anomalies of the coronary arteriesThese anomalies are rarely isolated, but for clinical reasons pose a major concern when associated with various lesions, particularly abnormalities of the ventricular outflow tracts.b) The 23 subcategoriesWe defined 23 subcategories according to the anatomy of the heart and "clinical sense". For example, "Anomalies of atrioventricular junctions and valves" includes 3 subcategories according to the type of atrioventricular valve involved, specifically tricuspid valve, mitral valve, or common atrioventricular valve in the setting of atrioventricular septal defect. We did not include atrioventricular valvar atresia in this subcategory, but placed these patients along with those having functionally univentricular hearts, since their main characteristic is severe hypoplasia of one of the two ventricles, irrespective of the anatomy of atrioventricular junction.Rather than creating a new code number for each cardiac defect encountered in our population, we chose to attribute one six-digit code of the long list to each item of our list, facilitating in this way the interface with other databases or registries. The choice was sometimes difficult among the numerous codes proposed for one given lesion, and the final decision was made based on principles of simplicity and parsimony, combined with clinical judgement. For example, we chose to code sinus venosus type interatrial communication according to its most frequent form: "sinus venosus defect  with overriding superior caval vein (superior defect)": 05.05.01.one, and only one, of our 10 groups. Each case received one single code if the lesion was well-defined, as for example tetralogy of Fallot. On the other hand, multiple codes were used in the following situations:The hierarchy chosen for coding is fundamental, since it places the chosen lesion into - Well-defined CHD with associated anomalies . In this case, the aim was to use a hierarchy that would be logical and intuitive .- Complex CHD: Each case could receive up to five codes in order to describe accurately the major elements of the CHD. In this case, we followed the hierarchy commonly used in the clinical process of aggregation in daily practice of paediatric cardiology. For example, complex left heart disease may bring together several anomalies belonging to different main categories in our classification, such as left ventricular hypoplasia, suggesting a functionally univentricular heart, parachute mitral valve, indicating anomalies of the atrioventricular junctions and valves, coarctation of the aorta, an anomaly of the great arteries, a left superior caval vein draining to the coronary sinus, an obvious anomaly of the venous return, and a small perimembranous VSD. The chosen main code would then reflect the planned clinical and surgical management, with the other anomalies then classified randomly. The determination of the major lesion of course, is not always clear-cut, and may be prone to controversy.The proposed scheme for classification, including the 10 main categories and the 23 subcategories, together with their corresponding IPCCC and ICD-10 codes, is summarized in the Additional File Table In Table In Table Those patients classified as having heterotaxy were the only ones almost always requiring more than one IPCCC code for their identification. In addition, 37% of those categorized as having functionally univentricular hearts, and more than half of those coded with anomalies of the extrapericardial arterial trunks and complex anomalies of atrioventricular connections required two or more codes for their full classification.The classification we are proposing, rather than being new, is no more than a rearrangement of the long list of the existing IPCCC. The rearrangement is based on the cardiac anatomy, along with criteria used for therapeutic management. It is designed to avoid doublets and to reduce ambiguities. It is also intended to facilitate both the coding process and the analysis of the data in the setting of clinical and epidemiological studies.Despite its worldwide use, the shortcomings of ICD -10 are increasingly recognized. Several studies have shown that the ninth version of ICD, still in use in the United States of America for administrative databases, generates a substantial number of errors and inaccuracies when compared to the IPCCC -5. AlthoIn contrast, the IPCCC is remarkable by its exhaustiveness and its accuracy, as it was deliberately designed to be inclusive, allowing the different users to choose their preferred term for any specific congenital cardiac malformation . This maIn devising our proposed revised classification, our principal motivation was to rearrange the whole spectrum of CHD into a manageable number of categories defined on their anatomy as well as the criteria used for their clinical and surgical management. The classification is designed to use the code numbers in the long list of IPCCC but can accommodate ICD-10 codes.The categories common to the ACC-CHD and the IPCCC long list are:- anomalies of venous return or great veins,- anomalies of the atrioventricular valves and of the atrioventricular junctions- anomalies of the atria and interatrial communications- anomalies of the ventricles and of the ventricular septum (except for VSD's).We deliberately chose to group all types of ventricular hypoplasia within the large category of functionally univentricular hearts, on the basis of their common medical and surgical management. In the IPCCC, left and right ventricular hypoplasia are included in the group of abnormalities of the ventricles, while hypoplastic left heart syndrome and pulmonary atresia with intact ventricular septum, together with double-inlet ventricles, are in the group of anomalous atrioventricular and ventriculo-arterial connections.We also isolated the anomalies of the coronary arteries as a distinct category, because of their frequency as an associated anomaly and their clinical importance, instead of including them into the anomalies of great vessels, as in the long list of the IPCCC, or into a miscellaneous group as in one version of the short list. We found, nonetheless, very few cases in EPICARD, suggesting either that anomalies of the coronary arteries are frequently missed as part of the final diagnosis of the congenital malformation, or that they are, indeed, very rare.We created a large category named "anomalies of outflow tracts and arterial valves" in order to merge all the anomalies of the ventricular outflow tracts, including abnormal ventriculo-arterial connections, abnormal arterial valves, and lesions of the intrapericardial arterial trunks. In the IPCCC long and short lists, the abnormal ventriculo-arterial connections, along with the anomalies of atrioventricular connection, are placed in the large group of abnormalities of position and connection of the heart, while the anomalies of the arterial valves and the outflow tracts are included into the group of the anomalies of great vessels and ventriculo-arterial valves. For anatomic, clinical, and surgical reasons, we chose to include these in a single category, which then accounted for about one-fifth of all cases in EPICARD, and at least two-fifths of major cardiac defects when we exclude minor VSD's.We divided those with heterotaxy, and those with complex anomalies of atrioventricular connections, into two distinct groups, the latter including congenitally corrected transposition or double discordance.Because of their frequency, we considered patients with ventricular septal defects as a distinct entity. Within this group, we then incorporated the notion of size, and thus of clinical severity, as suggested in the IPCCC. The specific code for a "small" VSD does not exist in the ICD-10.The hierarchy used for coding complex CHD, although based on the clinical aggregation process reflecting the routine practice of paediatric cardiology, and clear-cut in many cases, might be questionable for some complex associations. In addition, some cardiac anomalies may exist in isolation, as well as in association with various types of CHD. For example, pulmonary atresia was considered as the main cardiac defect in only two situations, those co-existing with tetralogy of Fallot on the one hand, an anomaly of the ventricular outflow tracts, and with an intact ventricular septum on the other hand, included in the group of functionally univentricular hearts, albeit that some of the latter patients can undergo biventricular repair. In other situations, pulmonary atresia is associated with another CHD, with a specific six-digit code. Pulmonary atresia in the setting of congenitally corrected transposition, for example, was coded as double discordance, VSD, and associated pulmonary atresia.We often chose to code the associated anomalies as second, third, and fourth added codes, rather than using the different code numbers listed in the IPCCC, simply because they cannot be totally inclusive. There are, nonetheless, some exceptions to this rule, with AVSD with TOF, for example, having a specific code number.The long list of IPCCC is sufficiently detailed and precise to code satisfactorily the entire spectrum of congenital cardiac disease. It is, however, complex, including literally thousands of codes, which may hinder its use in clinical and epidemiological studies. Our suggested re-classification separates the entire spectrum of CHD into a manageable number of categories that use the code numbers of the IPCCC long list, and are based on anatomic criteria, as well as those used for clinical and surgical management. It can be useful for clinical and epidemiologic studies that aim to evaluate the outcomes of patients with CHD, and those seeking to assess the role of prognostic factors. It can also be helpful in epidemiologic studies of risk factors for CHD, and in particular those aimed at exploring specific associations that may exist between risk factors and different types of CHD. Indeed, it was found to be useful in a population-based study about the risk of CHD associated with assisted reproductive technologies . The proth version; IPCCC: international paediatric and congenital cardiac code; MRI: magnetic resonance imaging; RACHS-1: Risk Adjustment in Congenital Heart Surgery; STS/EACTS: Society of Thoracic Surgeons/European Association for Cardio-thoracic Surgery; TGA: transposition of great arteries; TOF: tetralogy of Fallot; VSD: ventricular septal defect.ACC-CHD: anatomic and clinical classification of congenital heart defects; AVSD: atrioventricular septal defect; CHD: congenital heart defects; CT-scan: computed tomography: IAC: interatrial communication; ICD-10: International classification of Diseases, 10The authors declare that they have no competing interests.LH conceived the classification and drafted the manuscript. BK and FG conceived and organized the EPICARD study, participated in the interpretation of data, helped to draft, and critically revised the manuscript. RHA made substantial contributions when critically revising the manuscript for important intellectual content. BK supervised, and NL and ACT conducted the statistical analysis of the data and interpreted the results. DB participated in designing the classification and drafting the manuscript, and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.This table displays our anatomic and clinical classification of congenital heart defects (ACC-CHD) with the corresponding IPCCC and ICD-10 codes. The list of lesions shown in the Additional File is, of course, not exhaustive, but of necessity represents only those encountered among the patients enrolled in the EPICARD study. This list is not fixed, and can easily be expanded using the six-digit codes of the comprehensive long list.Click here for file