These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for healthcare delivery systems to disseminate cardiac and vascular imaging findings related to the performance of cardiovascular magnetic resonance (CMR) examinations. These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for reporting results of cardiovascular magnetic resonance (CMR) examinations. This document builds on previously published guidelines from professional societies (ACC/AHA/ACR and others) , and is Prior to scanning, the SCMR recommends that patients be referred for CMR scans in accordance with Appropriateness Criteria developed by the SCMR, ACC, ACR, and AHA . The SCMThe SCMR recommends reporting key elements in all documents including information pertaining to a) site and equipment information, b) patient demographics, c) indications for study, d) study performance, e) cardiovascular imaging features of the examination, and f) concluding statements that synthesize the study results into a comprehensive diagnosis that can be used for planning therapy or determining prognosis.The SCMR wishes to emphasize that effective communication is an essential component of any diagnostic imaging procedures for patients with possible cardiovascular disease. Quality patient care is best achieved when study results are conveyed in a timely fashion to those ultimately responsible for treatment decisions. Accordingly, the SCMR recommends that a delivered, finalized report be available, where possible, within 1 business day of performance of the scan, but appropriate to the urgency of the examination.The following document serves as a guide to identify a) recommended and optional components of the report, b) the principles used to generate a final report, and c) suggested communications that may occur other than the final report. A final written interpretation or report shall be generated and archived following any CMR examination, procedure, or officially requested consultation to review images regardless of the setting where the CMR scan was performed . Within the document, all recommended and optional components are in bold, and summarized in Additional files 1) Administrative – 5 total elements Site ID (recommended): Site ID is a unique number assigned to each study performance site.a. Site of service (recommended): Indicate the type of facility submitting the reporting data. These would include inpatient hospital, outpatient facility, free standing imaging center, ambulatory care office, or mobile unit. b. Scanner (recommended): Indicate the type of magnet, manufacturer, model number, field strength, and software platform of the unit performing the procedure. c. Accreditation status (recommended): This should be represented as yes, pending, or no. d. Accreditation Entity (recommended): For example, . e. 2) Demographics (4 recommended elements)Unique patient ID: medical record number used by the health care delivery system where the CMR examination was performed a) Patient date of birth b) Patient Gender  c) Patient Race/Ethnicityd) 3) Study Referral Data Referral physician - National Provider Identifier (NPI) a) Referral physician specialtyb) 4) Scheduling and Performance of Study (6 recommended elements)Date of procedurea) Time of procedureb) Personnel involved in procedurec) • Nursing• House Officers• Staff physicians• TechnologistsPrimary indication for testd) Study qualitye) Listing of sequences usedf) 1 W dark blood with or without contrast• T2 W dark blood with and/or without fat saturation• T• Cine SSFP• Cine FGRE• Late gadolinium enhancement• Phase contrast CMR flow measurements1 W MRA with or without contrast• T• T2*• SPAMM (Grid Tagging)5) History and Risk Factors Height (recommended)a) Weight (recommended)b) serum creatinine level and estimated glomerular filtration rate (GFR) should be provided.c) For studies using contrast, the SCMR suggests the value and date of acquisition of the most recent 6) Non-imaging findings associated with the examination (5 recommended elements)electrocardiogram, its interpretation should be provided. This includes the presence of Q-waves, ST segment or T-wave abnormalities, or other rhythm disturbances.a) In those studies requiring 12-lead heart rates and rhythm, and systolic and diastolic blood pressure should be provided during the CMR acquisition. For tests incorporating stress testing, the heart rates and rhythm, oxygen saturation, systolic and diastolic blood pressures, and the predictive heart rate response for age should all be recorded during the following points in time:b) For studies evaluating hemodynamically important conditions , • Before study• At each level of stress• In recoveryagent, quantity, duration, and route of administration of the agents and associated medications should be provided.c) For studies utilizing cardiac active agents , the agents, the type (i.e. paramagnetic), name, route, site, and speed of administration should be provided.d) For studies utilizing contrast amount, type, route and measures of administration of these agents or support should be documented. Also, patients' cardiovascular and pulmonary responses  should be recorded accordingly to local regulations. The reason for administration required of the agent should be provided.e) For studies utilizing sedation, general anesthesia, or supported ventilatory or cardiac  assistance, the 7. Specific Conditions Assessed with CMRa) Magnetic resonance arteriography1. AortaDimensions including :Aortic annulus (recommended)a. Sinuses of Valsalva (recommended)b. Sinotubular junction (recommended)c. Ascending and descending diameters at the level of the pulmonary artery (recommended)d. e. Comment regarding whether the aorta is right or left-sided may be provided .Findings when present :sinotubular effacement (recommended)a. Comment on tortuosity (recommended)b. Comment on Aortic atherosclerosis (recommended): description of location, mobility and extent, estimate %-stenosis when advanced c. Aortic aneurysm (recommended): size (AP × LR × CC), morphology (saccular versus fusiform), location in the aorta, relation to branch vessels, presence of mural thrombus, visceral compressive effects (effacement expansion of the aorta against surrounding structures), post-contrast appearance (if these sequence were acquired), presence of periaortic, mediastinal, pericardial, or pleural fluid. d. Aortic dissection (recommended): dissection classification (either DeBakey or Stanford), presence of intimal flap, location of tear or areas of communication (if possible), description of the size and extent of the true and false lumens, presence of murmal thrombus or blood in false lumen, branch vessel involvement, presence of periaortic, mediastinal, pericardial, or pleural fluid, e. Intramural hematoma (IH): in cases of IH and penetrating aortic ulcer, the CMR practitioner should describe carefully the morphologic findings in much the same way as an aortic dissection paying careful attention to select wording to convey a diagnosis of limited ulceration or dissection.i. ii. Post-operative appearance: this should be described in accordance with (a-e) above noting additional graft insertion points and dimensions.Inflammatory diseases of the aorta (recommended): aortic wall thickness, multispectral appearance on different pulse sequences, contrast enhancement pattern, branch vessel involvement, presence of periaortic, pleural, or pericardial fluid f. g. Congenital disease involving the aorta and ventriculoarterial connections: see recommended congenital report below.Aortic flow : On CMR scans of the aorta in which PC-MR measures are obtained, the direction and magnitude of flow should be provided. h. 2. Peripheral arterial disease :Vessel location and orientation. Descriptions of each territory are required when the study is ordered to examine the respective site (recommended). When severe stenoses or vessel occlusions are identified, common collateral pathways should be described.a) • Arch vessels• Carotid bifurcation• Celiac trunk• Proximal SMA• Renal arteries and their accessory vessels• Common and external iliac• Femoral, brachial or other more peripheral arteries.b) Quantitation of luminal narrowings or stenoses (recommended)stenosis severity should be reported in 25% increments  or, in cases with high spatial resolution, finer increments of 10% may be employed. Descriptive terms may convey the wrong impression to the clinical importance of occlusive disease SCMR recommends that the CMR practitioner avoid descriptive terms such as "mild" or "moderate" stenosis, but rather adopt a semi-quantitative method that scores the severity of luminal occlusion. Accordingly, c) Optional functional measures of the vascular system may also be reported, including:flow measurements in the forms of milliliters or liters per minute, andi.) measures of vascular stiffness: aortic distensibility, or pulse wave velocity.ii.) When functional measures are provided it is recommended that the vascular territories be specified and values provided at the specific location of acquisition.b) Cardiac Size and Functionright ventricular (RV) and left and right atrial chamber sizes and volumes are optional. Reporting of left ventricular (LV) volumes is recommended when multi-slice cine short axes data are acquired from the mitral annulus to the cardiac apex. When reported, SCMR suggests that right-sided chambers measurements and the angulation from which the diameters or dimensions are acquired should be reported. For the left-sided cardiac chambers, the 3-chamber long axis view should be used for identifying LV dimensions. The SCMR encourages quantitative measures reported on their forms; however, determination of normal, enlarged, small, or not reported may be substituted.1) The reporting of LV end diastolic wall thicknesses acquired in the 3-chamber view of the left ventricle at the mitral leaflet tips; it is suggested that the end diastolic thickness be acquired at the septum and inferior lateral or posterior wall.2) Although not required, the SCMR encourages the reporting of right ventricle, the free wall end diastolic thickness  may be reported.3) When assessing the LV ejection fraction, and regional wall motion abnormalities. The method of acquisition should be reported, including:4) For those studies targeting the heart, the SCMR recommends the reporting of ▪ Visual estimation▪ Area-length formula▪ Multi-slice disk summation techniqueValues should be reported as absolute values and indexed for body surface area.• Measurements derived from these values  should be expressed as absolute as well as indexed values and the reference heart rates used for these calculations should be provided in the report.2 for noninvasive testing  "Bullseye" plot) [As described in the non-imaging findings component of the reported list above, parameters such as vital signs, medications, and contrast agent administration should be reported. The SCMR recommends the reporting of LV myocardial information in the format of a 17-segment model through the use of a chart, table, or bipolar maps  .1. Wall motion stress:Wall function should be designated as qualitative  or quantitative  during testing. In addition, wall motion score index  should be reported at each level of stress. Inducible ischemia or contractile reserve should be identified in each study according to previously published referenced methods. Identification should be made of when global LV function does not improve or worsens during stress.st pass myocardial perfusion:2. Gadolinium, 1transmurality, and persistence of the defect. The committee recommends that stress induced (vasodilator or inotropic) perfusion defects be compared with co-registered rest perfusion or late enhancement segments in order to identify ischemic, infarcted, or non-ischemic areas. The SCMR also recognizes that observed defects may be characterized as artifacts. These should be described.Existing literature regarding the prognostic significance of qualitative perfusion defects is unavailable at this time; nevertheless, SCMR suggests that perfusion in each of the 17 segments :3. The amount of intense signal >2 SD above the average of normal myocardium should be reported for the area within each segment. Overall, LGE should be described as subepicardial, intramural, subendocardial, or transmural. Patchy or linear streaks of LGE should be identified. The transmural extent of the LGE should be defined as 0, ≤ 25%, 26% to ≤ 50%, 51% to ≤ 75%, and 76% to 100%. In addition, the total amount of infarcted tissue (volume or grams) relative to the total myocardial volume or mass (g) may be reported. It is not recommended, but measures of LV end-diastolic wall thickness for the 17 myocardial segments may also be reported. When clinically appropriate, those providing an interpretation should indicate whether the pattern of LGE is consistent with ischemic heart disease, myocarditis, etc.Microvascular obstruction (MVO) :4. If MVO is observed during LGE, its location and presence within the 17 myocardial segments should be provided.Integrative stress imaging:It is recognized by the SCMR that the procedures mentioned above can be performed in a single setting and thus must be integrated to arrive at a diagnosis. The committee recommends reporting data for all 17 myocardial segments in all modalities . Based on previously published techniques, segments should be identified as ischemic, infarcted, mixed ischemia/infarction, or normal. It is recommended that all information for baseline function be reported in patients referred for stress testing or evaluation of acute or chronic ischemic syndromes.For these clinical conditions, the following items are recommended for reporting by the SCMR.LV volumes  with and without indexing to body surface area.• Presence and extent of (T2) signal intensity• Presence and extent of irreversible injury (LGE)• Presence of pericardial effusion• T2* in ms may be reported• In the case of iron overload: early enhancement ratio† or the % injury related to LV mass• Optional: †: see Lake Louise Criteria, Consensus Group on CMR in MyocarditisCoronary Arterial Segmentse. origin and course of the coronary artery segments be reported, as well as the length of the segments visualized. If anomalous artery is intramural, it should be noted. If a study is performed for the purpose of identifying coronary artery or bypass graft anatomy, the patency of these conduits should be indicated.It is recommended that when examining the course of anomalous coronary arteries, the f. Valvular Heart DiseaseThe following lists of items should be reported for the cardiac valves.Qualitative parameters:morphology of each component of the valve complex • insufficiency or reduced valvular excursion• presence of any When quantitative flow measurements are acquired:Venc setting;• the velocity encoding peak velocity, a single value when recorded across semilunar valves or a vessel in cross-section, or both early (E) and late (A) peak velocities for atrioventricular valves;• the transvalvular gradients;• the forward stroke volume and peak and mean regurgitant volume and fraction;• the heart rate during acquisition;• the valve area (by planimetry or the continuity equation);• the method and determination of ventricular dimensions and volumes as described in III-B.• the measurement of g. Arrhythmogenic RV Cardiomyopathy (ARVC)1) It is recommended that each report identify major and minor criteria associated with ARVC. This should include a statement regarding:Global right ventricular performance (RVEF);a) RV dilation;b) Regional RV wall motion abnormalities .c) Location of When acquired:Fatty infiltration of the right ventricle, anda) fibrosis by LGE should be provided.b) Occurrence of h. Cardiac and paracardiac masses (including pericardium)The standard report should consist of the following components:Myocardial mass description:AbsentPresentLocation Size T1 signal intensity T1 fat sat images signal intensity (if performed) T2 signal intensity STIR signal intensityPerfusion pattern (if perfusion performed)Late gadolinium enhancement pattern on static/delayed images (if gadolinium administered)Relationship to myocardium/pericardium, mediastinumMargins Cine CMR appearance  Myocardial function  Pericardial abnormalities if present Pericardial description Morphology (descriptive)1. Pericardial Thickness: describe as local or circumferential and list thickness measurements2. Pericardial effusion  Ventricular parametersLV volumes  with and without indexing for body surface area.1. wall motionVentricular Systolic wall motion1. +/- abnormal septal motion during normal respiration and breath holding.2. atrial inversion4. Presence or absence of  Late Gadolinium Enhancement1. RV – site2. LV – site3. Pericardiumi. Pulmonary Vein assessmentsQualitative elements that should be included in CMR-based PV reporting include:Number of pulmonary veins;1. Atrial side of pulmonary vein return;2. Recongition of accessory or anomalous pulmonary veins; and3. stenosis in each PV, especially in reporting post-ablation CMR exams.4. Presence or absence of Quantitative elements that should be included in CMR-based PV reporting are:Maximum ostial diameter of each pulmonary vein;1. Cardiac phase  and respiratory phase (e.g. end-expiration) during acquisition of images used for ostial measurements;2. Minimum ostial diameter of each stenotic pulmonary vein; and3. Imaging technique used for measurements4. The number and position of pulmonary veins is accounted for noting common trunks, accessory veins, and evidence for stenosis or thrombosis cross sectional area of the pulmonary vein may be provided. A 3D workstation may be used to calculate major and minor axes, and cross sectional area of each pulmonary vein ostium, and compare pre- and post-ablation images side by side.SCMR recognizes the value of pictorial display of the pulmonary vein orientations, and suggests implementation of diagrams when feasible.j. Congenital Heart DiseaseMorphology (descriptive)a. Simple Lesionsb. Complex Lesionssitusi. ventriculoarterial relationshipii. artioventricular relationshipiii. pulmonary venous connectioniv. systemic veins and connectionsv. septal defectsvi. valvular lesions (including atresia)vii. pulmonary arteries viii. ix. aortax. othersRV and LV Volumes with and without indexing to body surface area PA and Aortic Dimensions (diameters)i. MPAii. LPAiii. Coarctation (minimum)iv. Shunt or conduit (minimum and maximum)Blood Flow, VelocityPulmonary/systemic flow ratioa. b. Valve (if regurgitant) forward flowi. regurgitant flowii. regurgitant fractioniii. c. Valve (if stenotic) peak velocity (gradient)i. ii. otherd. Coarctationpeak velocity (gradient)i. collateral flow estimateii. e. Pulmonary arterial flowMPAi. LPAii. RPAiii. f. Shunt or Conduit Flow (name of shunt or conduit)flowi. peak velocity (conduit)ii. optional for inclusion in the final report. Accordingly, in the case in which further data are desired, the following outline for data collection is provided:8) The SCMR recognizes that more extensive historical information may be desired by certain institutions that perform CMR. At the time of this publication, SCMR considers this information Relevant Medicationsa) • Aspirin• Warfarin• Other anti-platelet• Beta-blocker• ACE inhibitor• Angiotensin receptor blocker• Nitrate• Statin• Erectile dysfunction medication• Calcium channel blockerb) History and risk factorsHypertension1) Dyslipidemia – Indicate if the patient has a history of dyslipidemia, diagnosed or treated by a physician or documentation of a total cholesterol >200 or an LDL ≥130 or an HDL < 30.2) Is the LDL > 100 mg/dl or 2.59 mmol/l? Yes/No3) Tobacco use: Current, Former, Never4) Diabetes – Yes/No5) Peripheral arterial diseasec) 1) Claudication with exertion2) Amputation for arterial vascular insufficiency3) Aorta or iliac occlusive disease reconstruction4) Peripheral vascular bypass surgery or percutaneous intervention5) Documented AAA repair or stentOther cerebrovascular diseasesd) 1) Cerebrovascular accident2) RIND3) TIA4) Carotid test >75% occlusion5) Prior carotid surgeryArrhythmiase) 1) Atrial fibrillation2) Frequent PVC's3) History of ventricular tachycardia4) History of ventricular fibrillationHeart failuref) Previous history: Yes/No1) NYHA Class Heart failure: Class I/Class II/Class III/Class IV2) Presence of angina: None, typical angina, atypical angina, non-anginal chest paing) Characteristics of chest pain or suspected angina equivalent: Substernal chest pain, provoked by exertion, or relieved by rest &/or nitroglycerinh) Ability to exercise prior to testing (METS)i) Previous noninvasive cardiovascular imaging testsj) • Echocardiography• Nuclear myocardial scintigraphy• Cardiovascular computed tomography• Cardiovascular magnetic resonance• Cardiac catheterization• NoneSurgical riskj) • Low risk surgery• Intermediate risk surgery• High risk surgeryk) For studies incorporating CV stress, prior to the procedure, the following information should be verified:Prior MI• Prior coronary revascularization (PCI and/or CABG)• Pretest Probability of CAD • Is the ECG interpretable for ischema? Yes/No• Framingham Risk Score• Estimate of CAD risk  The final signed report is considered to be the definitive means of communicating to the referring physician or other relevant health care provider. Other methods of rapid communication are encouraged in certain situations, such as critical findings, unexpected abnormal findings, or findings that may immediately alter the patient's course of treatment.2) The report should be reviewed to minimize interpretive, descriptive, or transcription errors prior transmitting the final results.3) The final report should be completed in accordance with governmental or health care facility medical records regulations.4) The signed written report should be immediately transmitted to the referring physician or health care provider who is treating the patient once it has been finalized and in accordance with appropriate governmental requirements.5) When feasible, a copy of relevant key images should accompany the final report.6) A copy of the final report should be archived at the imaging facility as part of the patient's medical record and be retrievable for future reference. Retention and distribution of these records should be in accordance with governmental regulations and facility policies.SCMR strongly encourages the rapid dissemination of a finalized report. It is recognized however, that preliminary reports may be necessary in certain situations. Preliminary reports should be identified as such; however, it is recognized by SCMR that their accuracy may be compromised.If a change is made by a disseminated preliminary discrepant from the final interpretation, then written documentation and communication to all treating or referring physicians is indicated.It is recommended that any methods of such communications be included in the final report such that documentation is complete.The SCMR recognizes that some individuals may seek imaging studies as part of a self-referral or referred by a third party, such as an insurer or an employer.Imagers should recognize that performing imaging studies on self-referred patients establishes a doctor patient relationship that includes responsibility for communicating the results of imaging studies directly to the patient and arranging for appropriate followup.Patients may be referred for imaging studies by insurance companies, employers, research studies, other benefit programs, or in some instances, attorneys. In such cases, the reports of these studies are frequently communicated through their requesting entity to a clinician or directly to the third party designated clinician. The results of these examinations are then communicated to the patient directly. Regardless of the source of the referral, the diagnostic imager has an ethical responsibility to insure communication of unexpected or serious findings to the patients. It is suggested that each imaging organization that desires to scan and generate reports on self referred patients develop communication policies within their centers to address evolving issues in this arena.1 W MRA: T1 Weighted Magnetic Resonance Angiography; TIA: Transient Ischemic Attack; Venc: Velocity Encoding.AAA: Abdominal Aortic Aneurism; ACC: American College of Cardiology; AHA: American Heart Association; ARVC: Arrhythmogenic Right Ventricular Cardiomyopathy; CABG: Coronary Artery Bypass Graft; CAD: Coronary Artery Disease; CMR: Cardiovascular Magnetic Resonance; CV: Cardiovascular; ECG: Electrocardiogram; EDV: End Diastolic Volume; EF: Ejection Fraction; ESV: End Systolic Volume; FGRE: Fast Field Gradient Echo; GFR: Glomerular Filtration Rate; HDL: High Density Lipoprotein; IH: Intramural Hematoma; LDL: Low Density Lipoprotein; LGE: Late Gadolinium Enhancement; LPA: Left Pulmonary Artery; LV: Left Ventricular; MI: Myocardial Infarction; MPA: Main Pulmonary Artery; MR: Magnetic Resonance; MVO: Microvascular Obstruction; NPI: National Provider Identifier; NYHA: New York Heart Association; PA: Pulmonary Artery; PCI: Percutaneous Coronary Intervention; PC-MR: Phase-Contrast Magnetic Resonance; PV: Pulmonary Vein; PVC: Premature Ventricular Contraction; RIND: Reverse Ischemic Neurologic Deficit; RPA: Right Pulmonary Artery; RV: Right Ventricular; RVEF: Global Right Ventricular Performance; SCMR: Society for Cardiovascular Magnetic Resonance; SD: Standard Deviation; SMA: Superior Mesenteric Artery; SPAMM: Spatially Modulated Magnetization; SSFP: Steady State Free Procession; SV: Stroke Volume; TDr. Christopher Kramer serves as a consultant and receives research support from Siemens. Dr. Michael McConnell receives research support from GE Healthcare. Dr. Eike Nagel receives research support from Philips Healthcare, and Bayer Schering Pharma. Dr. Nagel is a speaker for General Electric, and Bayer Schering Pharma. Dr. Nagel also serves as a consultant for General Electric and Bayer Schering Pharma. Dr. Subha Raman receives research support from Siemens. No other authors had any competing interests.WGH, DB, JGB, MGF, MAL, MVM, SVR, CBH and ACR researched, wrote, reviewed, and revised the document. SF, CBH, CMK, EN and SN reviewed the document for content.Table S1. Recommended items for inclusion in Final Report.Click here for fileTable S2. Optional items for inclusion in the final report.Click here for file


Medline research indicates that an increasing number of manuscripts have been published in the last decade claiming, the feasibility and the potential clinical role of tissue Doppler and strain/strain rate imaging. However, despite this amount of scientific evidence, these technologies are still confined to dedicated, high-tech, research-oriented echocardiography laboratories. In this review we have critically evaluated these techniques, analysing their physical principles, the technical problems related to their current clinical application, and the future perspectives. Finally, this review explores the reasons why these technologies are still defined "new technologies" and the impact of their implementation on the current clinical activity of an echocardiography laboratory. Thus, a large volume of scientific evidence has been produced in favor of clinical use of these methods and various parameters have been proposed with the ambitious goal to contribute towards additional diagnostic value with respect to various pathologies. [In the past decade, numerous studies have been published addressing the feasibility and potential clinical applicability of tissue Doppler imaging (TDI) and its derived parameters strain and strain rate (SR) -7 Figur. The datologies. . Despitehigh-pass filter and adjustment of gain) allows the analysis of velocity signals having high amplitude and low frequency originating from tissue, which are usually not detected in traditional Doppler examination. In its various modalities , TDI renders possible on-line or off-line, the non invasive calculation of the time intervals and velocities of myocardial contraction and relaxation during the various phases of the cardiac cycle by using post-processing application software. , the most recent technique, has lately been proposed for obtaining velocities and deformation of the myocardial walls as an alternative to Doppler sampling. This method is based on the estimation of vectorial velocities instead of the analysis of the long component along the lines of the image. The algorithm identifies the vectorial velocities by 'tracking' the data obtained by the analysis of radiofrequency and black/white signals [ signals . For eveThanks to its high temporal resolution, TDI and the methods derived from it analyze phenomena that happen in such short time periods, to elude the resolution of the human eye and could not be considered during a traditional echocardiographic evaluation ,6. TheseUp to now, studies conducted "in vivo" have been undertaken on a few selected patients admitted at highly specialized centers, using specific software not always widely accessible. Furthermore, companies producing ultrasound machines have not developed their products in comparable manners for reasons related to commercialization or research. As a result, at the present time, not all machines are able to produce the same parameters with the same modality. Each company was kept busy by developing its own software, then offering it prematurely and neglecting to consider whether it would turn into a commercial gadget or a truly useful tool. In addition, only recently attempts were made to standardize the nomenclature and the parameters. Presently, no agreement has been reached on the modalities of temporal analysis, on how to identify the various waves of TDI or strain curves, or on how to perform the measurements . All of these issues are in part responsible for the difficulty of this method to enter "the real world".myocardial ischemia, an event that induces a change of the subendocardial fibers with prevalent longitudinal contraction, determining a reduction of peak systolic velocity, of peak strain and systolic SR  and of the protodiastolic velocity with Em/Am inversion only after a few seconds following occlusion of the left anterior descending coronary artery [tardokinesis' also defined as post-systolic shortening, post-systolic thickening, or post-systolic motion depending on the different technologies used to represent it, has been associated with the presence of ischemia and myocardial viability [a) One very interesting application of TDI is the diagnosis of acute y artery -15. In niability   The role and value of TDI is most clearly established in the evaluation of fraction -27 , which make up most of its subepicardial and subendocardial layers and the papillary muscles, and of circular fibers  which make up most its middle layer [m > 5,4 cm predicts a left ventricular ejection fraction of 50% with a sensitivity of 88% and a specificity of 97% [m has been reported to correlate with LVEF in patients with dilated cardiomyopathy [c) One of the new aspects introduced by TDI is the possibility to examine le layer . This sple layer ,33. Numey of 97% . Peak any of 97% . A reducmyopathy . It is i- Systolic velocity can be reduced in those parts of the mitral ring corresponding to walls with regional wall motion abnormalities. In those cases it is preferable to calculate a medium of the values obtained in at least 4 regions of the mitral ring;- The indices of longitudinal left ventricular dysfunction do not correlate linearly with the conventional indices like LVEF, because they depend on other factors such as ventricular volumes, wall thickness and cardiac rhythm;- The analysis of the mitral annulus is affected by the anatomical and functional status of the left atrium as well as by the annulus itself ;- Even in the presence of a normal LVEF the longitudinal systolic function decreases with age.contractile dyssynchrony. The development of ultrasound platforms capable of imaging at high frame rates leads to temporal resolution high enough as to allow for a meticulous analysis of the different phases of the cardiac cycle. The measurement of TDI-derived time intervals has been more easily accepted, firstly because they were related to parameters cardiologists are already confident with, secondly because they were validated in hemodynamic laboratories and thus have been confronted to a "gold standard" [d) One field of application, which in itself would guarantee the survival of TDI is the study of ventricular tandard" . The apptandard" . All thitandard" . The dectandard" . Evidenctandard" ,40-48. Ftandard" . Even intandard" ,42 othertandard" ,44, and tandard" ; measuritandard" ,40-49  It is undeniable that the potential development of TDI indices correlated to tegories -54. In etegories .diastolic myocardial dyfunction in various cardiac pathologies, like hypertensive cardiopathy [b) TDI and strain Doppler can catch preclinical signs of prevalently diopathy , diabetidiopathy , and secdiopathy . The disdiopathy . The usediopathy , thalassdiopathy , Fabry cdiopathy , Chagas diopathy  and othediopathy .atrial mechanical function. Strain indices have been shown to be capable of identifying those patients with higher probability to maintain sinus rhythm after electrical cardioversion of atrial fibrillation [c) Additionally, TDI and strain methods have been applied in the study of illation . These dFor the purpose of establishing the measuring parameters and the best modalities of acquisition, it will be necessary on the one hand to plan prospective trials directed at testing the feasibility and reproducibility of specific protocols in defined clinical settings and on the other hand to confront these echocardiographic parameters with other methods (like nuclear magnetic resonance) capable of analyzing the same phenomena with different physical principles and modalities . This kiThe authors declare that they have no competing interests.RC wrote the paper, EB drafted the manuscript, BK translated into English, GG participated in designe of the article, AS wrote and reviewed the article and participated in its designe. All authors read and approved the final manuscript.


It carries a nonsynonymous single nucleotide polymorphism in its carboxyl terminal tail (Arg389Gly), which has been shown to associate with various echocardiographic parameters linked to left ventricular hypertrophy (LVH). Diabetes mellitus (DM), on the other hand, represents a risk factor for LVH. We investigated the possible association between the Arg389Gly polymorphism and LVH among non-diabetic and diabetic acute myocardial infarction (AMI) survivors.The beta-1 adrenergic receptor  when compared to the Gly389 carriers (either Gly389 homozygotes or Arg389/Gly389 heterozygotes) . In particular, the Arg389 homozygotes displayed thicker diastolic interventricular septal (IVSd) measures when compared to the Gly389 carriers . When the euglycemic and diabetic patients were analyzed separately, the latter had significantly increased LVMI and diastolic left ventricular posterior wall (LVPWd) values compared to the euglycemic patients . Furthermore, among the euglycemic patients, the Arg389 homozygotes displayed increased LVMI and IVSd values compared to the Gly389 carriers . There was no difference in the LVMI and IVSd values between the diabetic Arg389 homozygotes and Gly389 carriers.1AR Arg389Gly polymorphism and LVH, particularly the septal hypertrophy. The Arg389 variant appears to confer a higher risk of developing LVH than the corresponding Gly389 variant among patients who have suffered AMI. This association cannot be considered to be universal, however, since it does not appear to exist among diabetic AMI survivors.The data suggest an association between the β Cardiac left ventricular hypertrophy (LVH) is an important risk factor for an adverse outcome in patients both with or without coronary artery disease . Further1AR) has been considered to represent a potential candidate gene for LVH [1AR and 30% β2AR), maintaining cardiac contractility in response to endogenous catecholamines [1AR gene is localized to 10q24-26 [s coupling domain of the receptor [The beta-1 adrenergic receptor  survivors in Northern Finland. We analyzed 452 patients, 20.6% of whom had diagnosed DM.The aim of our study was to investigate the possible association of the β1AR Arg389Gly polymorphism. The patients were recruited to participate in the study during the first week after the AMI diagnosis, which was confirmed by using the contemporary guidelines at the beginning of the study. The exclusion criteria and qualifying diagnosis have been described previously [The study population was recruited in 1996-2000. This single-center, prospective study, the Multiple Risk Factor Analysis Trial, was carried out at the Institute of Clinical Medicine, Department of Internal Medicine, Division of Cardiology, University of Oulu . The aimeviously .2). Blood pressure was obtained in a supine position by a registered nurse following a five minute resting period. Blood samples were collected from the patients after an overnight fast. The fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels were measured at the Institute of Diagnostics, Department of Clinical Chemistry at Oulu University Hospital using standard enzymatic methods.Height and weight were measured for each patient by a registered nurse. Body mass index (BMI) was obtained from the ratio of weight (kg) to height squared , interventricular septal thickness (IVS) and left ventricular posterior wall thickness (LVPW) were measured at end-diastole (d) and end-systole (s). The parameters were measured with two-dimensional guided M-mode echocardiography following the American Society of Cardiology/American Heart Association guidelines. Considering each parameter, three distinct measurements were done and the averages were calculated.2.7.Left ventricular mass (LVM) was calculated from LVIDd, LVPWd and IVSd using the equation originally described by Devereux and colleagues . This me2 test. Student's two-tailed t-test was used to compare the quantitative parameters (expressed as means ± S.D) between the groups, respectively. Categorical variables were compared using the Χ2 analysis. Analysis of covariance (ANCOVA) was used for comparison of the echocardiographic variables between the genotype groups (expressed as means ± S.D). Using ANCOVA, the β1AR Arg389Gly polymorphism was set as a fixed factor. Age and BMI were added as co-variables to adjust the results. P < 0.05 was considered statistically significant. Nominal p values are presented throughout, i.e. without correction for multiple testing, as recommended by Rothman [Statistical analyses were performed with SPSS 17.0/PASW 18.0 software packages and where appropriate, power calculations were performed with SamplePower 2.0. In the power calculations, alpha was set as 0.05. The Hardy-Weinberg equilibrium was tested with the Χ Rothman .The main clinical and biochemical data of the study population are shown in Table 1AR genotype at codon 389 was determined in 452 AMI survivors. The allele frequencies were 0.75 for Arg389 and 0.25 for Gly389. These values were in accordance with frequencies observed in other Caucasian populations [2 = 0.817).The βulations . The freulations ,27. The The echocardiographic parameters according to the Arg389Gly polymorphism in the whole study population are listed in Table Table Table 1AR Arg389 homozygotes with LVH among euglycemic AMI survivors, and that this association does not appear to exist among diabetic AMI survivors. Analyzing 452 Finnish patients who had undergone AMI, 79.4% of whom were euglycemic and 20.6% diabetic, we were able to show that the β1AR Arg389 homozygotes had significantly higher LVMI when compared to the Gly389 carriers (either Gly389 homozygotes or Arg/Gly389 heterozygotes). The same applied also to IVSd, and this association was even stronger. Our result is logical based on previous reports on the functional properties of the two receptor variants. The β1AR Arg389 variant has been shown to display markedly increased coupling to Gs and stimulation of adenylyl cyclase in response to the agonist isoproterenol in vitro as compared to the Gly389 receptor form [s [1AR Arg389 variant can be considered as a "gain-of-function" receptor form.The main finding of our study is the apparent association of the βtor form . Gly389  form [s . Thus, t1AR leads to worsening of cardiac function. As a consequence, β1AR expression is down-regulated and its coupling to adenylyl cyclase is desensitized [et al., who used transgenic mice, showed that the Arg389 variant is impaired in down-regulation, which most likely represents a protective event in the failing myocardium. Furthermore, the young Arg389 mice were found to have enhanced receptor function and heart contractility compared to the Gly389 carriers, whereas the older Arg389 mice displayed a phenotypic switch with decreased signalling to adenylyl cyclase and contractility compared to the corresponding Gly389 mice [in vivo studies, Rathz et al. have shown that the β1AR Arg389 variant undergoes less agonist-promoted desensitization in vitro compared to its allelic counterpart [1AR-induced cardiac damage by showing that inactivation of the cyclic AMP response element modulator (CREM) rescued the β1AR-overexpressing mice from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction [It is well known that prolonged activation of the βnsitized . The Arg389 mice . In linenterpart . Recentlfunction . It woul1AR Arg389 homozygosity on the left ventricular structure. We cannot, however, rule out the possibility that the observed increases in LVMI and IVSd among the β1AR Arg389 homozygotes were related to hypertension because LVH partly represents an adaptive response to hypertension [1AR Arg389 homozygotes have an increased risk to develop essential hypertension among Scandinavians [Our results support the notion that there is a direct genetic impact of the βrtension . In previnavians  and Chininavians . We, nev1AR Arg389Gly polymorphism and left ventricular structure. In accordance with our study, Fu et al. described a significant association between the β1AR Arg389 variant and LVH in Chinese hypertensive individuals in two independent populations (n = 2417 and n = 327) [1AR Arg389Gly polymorphism was found in a study population consisting of 110 healthy Caucasian twin pairs (n = 220) [et al. who studied African American siblings suffering from hypertension found no significant association between the β1AR Arg389Gly polymorphism and LVMI but reported that the Gly389 allele was significantly associated with a higher mean relative wall thickness compared to the Arg389 form [To our knowledge, there are four previous studies concerning the βn = 327) . In contn = 220) . In a thn = 220) . This st389 form . This as389 form ,25, whic1AR Arg389Gly polymorphism and LVH among the diabetic patients. The negative result can be considered to arise from an independent association between DM and LVH [1AR Arg389Gly polymorphism with LVH. Therefore the assumed stronger effect of DM can be expected to mask the weaker effect of the polymorphism on the left ventricular structure. Interestingly, the association between DM and LVH seems to be stronger in women than in men [1AR expression has been shown to be markedly decreased in the hearts of diabetic patients  [When we analyzed the euglycemic and diabetic patients of our study group separately, we did not find any association between the β and LVH -6, whichn in men ,5,6. In endages) , which mEvaluating left ventricular parameters from post-AMI patients with two-dimensional guided M-mode echocardiography is not always reliable if the infarction happens to be in the area where the measures are being taken from. Determining the EF with the M-mode device has also limitations, because the systolic function is measured only from a single point of the left ventricle. Furthermore, in our study, echocardiography was performed within one week after AMI, and consequently hyperaemia may have contributed to the measurements in addition to the left ventricular dysfunction and remodeling. Additionally, the amount of diabetic patients was rather small in our study sample, which causes certain limitations to the statistic analyses.1AR Arg389 variant compared to the AMI patients carrying either one or two copies of the Gly389 allelic form of the β1AR. The β1AR Arg389 variant thus seems to confer higher risk of developing LVH. In addition, we show that the aforementioned association is not universal, since it does not exist among diabetic AMI survivors. We hypothesize that this negative finding is caused by the strong association between DM and LVH, which may mask the presumably weaker effect of the β1AR Arg389 variant on the left ventricular structure.As a conclusion, we show here that LVMI and IVSd values are significantly higher among AMI survivors who are homozygous for the β1AR: beta-1 adrenergic receptor; BMI; body mass index; DM: diabetes mellitus; EF: ejection fraction; IVSd; interventricular septal thickness at end-diastole; LVH: left ventricular hypertrophy; LVIDd: left ventricular internal dimension at end-diastole; LVM: left ventricular mass; LVMI: left ventricular mass index; LVPWd: left ventricular posterior wall thickness at end-diastoleANCOVA: analysis of covariance; AMI: acute myocardial infarction; βThe authors declare that they have no competing interests.AEH carried out the genotyping of patients, performed the statistical analyses and drafted the manuscript. JMT performed the echocardiography. JMJ, KSK and HVH critically reviewed the manuscript. UEP-R critically reviewed the manuscript and helped to draft it. All authors read and approved the final manuscript.


A respirophasic variation of the QRS complex was observed in a patient with bilateral pulmonary embolism and pulmonary hypertension. An analogous variation of the Sa systolic velocity of the tricuspid annular tissue Doppler imaging was also noticed. Both phaenomena persisted until the clinical and haemodynamic improvement of the patient. A mechanistic approach of the electric phaenomenon is proposed. We enjoyed the article by K. Todd and co-authors, concerning the various patterns of electrocardiogram (ECG) in pulmonary embolism (PE) . AnotherA 62 year old male, with no previous cardiocirculatory or respiratory problems, was admitted because of bilateral PE confirmed by lung scintigraphy  and spirFrom the time of admission, an S1Q3T3 pattern on the ECG attracted our attention, because of a respirophasic EV of the QRS complex. This phenomenon was mainly apparent in leads I and III, which showed an inspiratory reduction of S, Q and R waves respectively, with restitution in expiration . A respirophasic echocardiogram (ECHO) was performed, paying attention to any potential cardiac positional or internal diameter changes. No such findings were detected. Left ventricle was normal in shape and performance. Pulmonary artery systolic pressure was calculated to 50 mm Hg. Right ventricle (RV) was not dilated but its middle and apical free wall were severely hypokinetic. No signs of abnormal ventricular interdependence were noticed. There were no pericardial or pleural effusions, and inferior vena cava had a slightly dilated diameter, with normal inspiratory behaviour.When a TDI of the tricuspid annulus was reviewed, a respirophasic variation of the systolic Sa velocity appeared, in a parallel way with the EV . Thus, SEV of the QRS complex in the setting of PE is a rare phaenomenon with rather unclarified aetiology. Another case was published in 1994, where the EV acquired the form of electric alternans, without obvious respirophasic correlations. The authors of that case, attributed the EV to ischaemia of the RV when stressed by the PE .Recently, the tricuspid annular TDI came to shed a light in the study of patients with PE ,4. HowevInspiration provokes an increased venous return, which further compromises the functional status of the RV. This could result in an inspiratory reduction of the tricuspid annular Sa velocity, which is known to correlate with the RV performance, particularly the RV ejection fraction . This fuRespirophasic EV is another potential ECG pattern in cases of PE. This finding and its ECHO equivalent, from the RV free wall TDI, should be viewed as markers of considerable haemodynamic compromise. We further thank K. Todd and coauthors, for giving us the opportunity to report an intriguing ECG manifestation of PE.


Three of them, namely Nav1.5, Nav1.8, and Nav1.9, are resistant to nanomolar concentrations of tetrodotoxin . The other isoforms, which are predominantly expressed in the skeletal muscle and nervous system, are highly sensitive to TTX (IC50 ~ 10 nM). During the last two decades, it has become evident that in addition to the major cardiac isoform Nav1.5, several of those TTX sensitive isoforms are expressed in the mammalian heart. Whereas immunohistochemical and electrophysiological methods demonstrated functional expression in various heart regions, the physiological importance of those isoforms for cardiac excitation in higher mammals is still debated. This review summarizes our knowledge on the systemic cardiovascular effects of TTX in animals and humans, with a special focus on cardiac excitation and performance at lower concentrations of this marine drug. Altogether, these data strongly suggest that TTX sensitive Na+ channels, detected more recently in various heart tissues, are not involved in excitation phenomena in the healthy adult heart of higher mammals.The human genome encodes nine functional voltage-gated Na Ten different α and four β subunit isoforms have been cloned from different mammalian tissues [+ channel isoform Nav1.5, encoded by the SCN5A gene, is the predominant α subunit in the heart and plays a key role in the excitability of atrial and ventricular cardiomyocytes and in rapid impulse propagation through the specific conduction system [SCN5A can cause a broad variety of pathophysiological phenotypes, such as long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sick sinus syndrome (SSS) [Voltage-gated sodium  ,7.v1.5, as well as Nav1.8 and Nav1.9 channels, which are both expressed in dorsal root ganglion neurons, are resistant to nanomolar concentrations of the pufferfish poison tetrodotoxin (TTX). The IC50 is equal or higher than 1 μM [+ channels are highly sensitive towards TTX (IC50 ~ 10 nM) [+ channels are: (a) Nav1.1, Nav1.2 and Nav1.3, which are highly expressed in the central nervous system, (b) Nav1.4, the predominant Na+ channel in skeletal muscle, (c) Nav1.6, widely expressed in neurons of the central and peripheral nervous system, and (d) Nav1.7, which is found in the peripheral nerve system including sympathetic fibers [Cardiac Nahan 1 μM ,8. In co~ 10 nM) ,8. The T+ current, thereby providing strong evidence in support of the expression of skeletal muscle and neuronal Na+ channels in the mammalian myocardium ) is characteristically increased, which may trigger afterdepolarizations and life-threatening arrhythmias (reviewed in [Na(P) is not entirely clear [v1.5 [+ channels , subcutaneously (s.c.), intraarterially (i.a.), or intraperitoneally (i.p.). Blood or urine levels of TTX were not systematically investigated. It is known that TTX distributes nearly everywhere in the body fluid [There are some limitations regarding these previous reports that have to be mentioned: Firstly, animal models of cardiac diseases were not considered, but the presumed cardiac TTXs Naiewed in ). The moly clear . This cuar [v1.5 ,31 or byiewed in ). Notabl0 nM TTX . Furthero Nav1.5 ,32. Consnduction ,32. Secohe heart ,23,33,34he heart –40. Fourdy fluid , but sigdy fluid ,42. The in vitro approaches  and/or a reduced cardiac output. Already in 1890, Takahashi and Inoko concluded that the heart does not contribute to the TTX-mediated blood pressure reduction . The autThe mechanisms behind the TTX-mediated vasodilatation were investigated by several groups. The significance of each mechanism, however, was discussed controversially ,41. Firset al. demonstrated that the carotid blood pressure in cats can be reduced by i.v. injection of 2–3 μg/kg from 140/110 to 80/50 within two to three minutes, without affecting heart rate [Slowing of the heart rate may also contribute to hypotension. However, administration of small sub-lethal doses produced hypotension only, and apparent changes of heart rate were rarely seen. TTX in doses of 0.1–0.3 MLD, corresponding to about 16–47 nM in the whole body’s extracellular fluid, did not cause bradycardia in the cat, despite a prompt and marked fall in blood pressure –39,49. Fart rate . In someart rate . When heart rate ,40,45,46art rate . In anotart rate . Altogetvia blockade of cardiac TTXs Na+ channels: Firstly, direct application of a highly concentrated pufferfish solution or a toxin powder on the sinus node had no effect on the heart rate [2 . Fifthly, TTXs Na+ currents do not contribute to normal automaticity in isolated adult sinus node cells, as recently shown by Protas and co-workers [+ current density in the canine sinus node decreases with age and that TTXs Na+ channels are not available at physiological potentials [+ channels are present in the sinus node, but they do not exert a physiological function under normal conditions [Concerning the mechanism behind the observed bradycardic effect, one can exclude a primary chronotropic effect art rate . Secondlart rate  injectedart rate . Fourthlart rate . The aut-workers . The auttentials . Applicanditions . This conditions .The transient or permanent reduction of the heart rate is most likely the result of a complex systemic reaction to TTX intoxication. There are several parameters that interfere with a normal heart beat in intoxicated mammals, like (a) a diminished pressoreflex despite hypotension, due to blockade of respective afferent and efferent nerve fibers, (b) a reduced venous return, due to massive vasodilatation and hypotension , (c) uncvia blocking an increasingly number of Nav1.5 channels, leading to sinus bradycardia and conduction disturbances (see Section 3.4). This conclusion is supported by the following observations. Firstly, bradycardia was induced only when injecting a TTX solution of 3 μM into the canine sinus node artery (see above) [i.e., sinus bradycardia and/or sinoatrial block, are observed in familial SSS, a well-recognised loss-of-function SCN5A channelopathy [+ inward current in human sinoatrial node cells at resting potentials negative to −60 mV [v1.5 channels. And thirdly, heterozygous Scn5a+/− mice showed depressed heart rates and occasionally sinoatrial block [+ channel, Nav1.5, for pacemaker rates and sinus node conduction.At very high TTX doses of at least 1 MLD, the toxin has a direct cardiac effect ,27,43, me above) . Similare above) . Notablye above) . Secondlo −60 mV . Althougal block , implicaA reduced contractile force at low TTX concentrations has been suggested for Langendorff-perfused mouse and guinea pig hearts . ConsequHowever, unchanged stroke volumes were observed in independent studies, when sub-lethal or, depending on the application method, even lethal TTX doses were applied. For example, an unchanged blood flow in the ascending aorta of rats was observed, when injecting a sub-lethal dose of 2.5 μg/kg into the right external jugular vein. At this dose, arterial blood pressure was reduced from 120–150 to 40–55 mmHg . In a siIn some studies, a reduced contractile force was observed upon TTX intoxication –37,43. TECG alterations indicative of cardiac conduction abnormalities were observed rarely at sub-lethal doses of TTX . Only slAlready in their early reports on the systemic effect of TTX, the Japanese researchers noticed conduction abnormalities in severely intoxicated animals, particularly after the cessation of respiration ,27. Sevev1.5 channels, and (b) insufficient oxygen supply. The first conclusion is supported by the observation that conduction abnormalities were often associated with SCN5A channelopathies, like isolated CCD or LQT3 [+/− mice showed impaired AV conduction [Conduction disturbances in severely intoxicated animals were most likely due to two mechanisms: (a) blockade of a significant portion of cardiac Na or LQT3 . Moreovenduction . The secnduction ,45.v1.5 expression in different regions of the AV node [v1.5 labeling was absent in the open node, but present at a relatively low level in the pathways into the open node . This suggests that the reduced expression of Nav1.5 already diminishes the safety factor for conduction, and consequently, TTX selectively aggravates conduction in this AV nodal region.According to a previous report , one sho AV node . Nav1.5 Other ECG changes were rarely reported. Some authors noticed T-wave alterations, like a non-specific T wave reversal , the disTTX is one of the most potent, non-protein poisons known to man. It has been detected not only in many pufferfish species, but also in a wide variety of other animals, including the blue-ringed octopus, newts, gobies, frogs, worms, starfish, horseshoe crab, gastropods, and in several marine microorganisms, that produce and accumulate the toxin ,61. In tDespite, or maybe even because of its severe toxicity, pufferfish is a speciality in Japan. The fish, also known as “fugu”, is normally prepared by licensed puffer cooks, making the (expensive!) meals a culinary adventure, rather than a hazardous Russian roulette. Pufferfish poisoning or tetrodotoxication is, however, still one of the most common food poisonings along the coast of Asia. Ingestion of the toxic fish can be intentional or inadvertent. In Japan, it may happen by eating homemade liver dishes prepared from self-caught pufferfishes. In Bangladesh, several outbreaks of TTX poisoning with dozens of victims were reported, which occurred after pufferfishes  were available at local markets at a very cheap price –64. Emer2, unconsciousness, bradycardia, and hypotension. Severe cardiac manifestations, like conduction block or ventricular asystole, occurred when extremely high levels of TTX were ingested and as a late sign in fourthdegree intoxicated patients [There is a long history of TTX intoxication. The first Europeans severely intoxicated were Captain Cook and his naturalists, J.R. and G. Forster. They enjoyed a pufferfish dinner, survived, and precisely described their symptoms . Many capatients –70.Tetrodotoxication can be rapidly fatal, and antidotes do not exist. Death may occur in as little as 17 minutes after ingesting the toxin ,72. The in vitro assays (see 2) and in vivo animal experimentations (see 3), when crystalline TTX was used, human tetrodotoxication occurs by ingesting TTX-containing food. It is possible that this crude or combined TTX is more easily absorbed in the digestive tract. A respective crude TTX dose of as little as 20 μg/kg can be lethal for humans. However, feeding cats with a 10-fold higher dose of crystalline TTX (200 μg/kg) did not kill them, although an i.v. or i.p. injection of 10 μg/kg was lethal [In contrast to the s lethal . Furthers lethal .50 of about 10 nM for TTXs Na+ channels [in vitro TTX sensitivity with blood levels in patients, and to correlate the in vivo TTX concentrations with the symptoms, all currently available blood concentrations were plotted against the intoxication grade of the corresponding patients , and lowest concentrations in brain and blood [Unfortunately, a precise correlation between the biological activity of an ingested TTX bolus and the clinical symptoms is currently difficult to establish, because blood concentrations in victims were rarely determined. It is likely that the effective TTX concentration in the heart is higher than the values reported. All TTX concentrations were determined from “spot” samples taken during the first day of hospitalization. Peak concentrations were probably missed in some cases. Moreover, serum levels may not necessarily indicate the effective concentration in an organ. TTX is rapidly absorbed in the human digestive tract, but it remains in the serum compartment only for a relatively short period (less than 24 h). From day two of hospitalization, TTX serum levels were below the detection limit in severe intoxicated patients ,79, but lleagues , eliminand blood ,42. Low + channels, rather than blocking Nav1.5, could contribute to these cardiac dysrhythmias. However, cardiac excitation abnormalities may not causally depend on a direct action of TTX on cardiomyocytes, but mainly on oxygen limitation resulting from respiratory arrest. If the latter assumption is true, cardiac dysrhythmias in severely intoxicated victims should have been observed rarely during the last 25 years, because of the high standard of modern medicine and the prompt availability of a mechanical ventilation device when respiratory arrest is imminent.Cardiac dysrhythmias, like AV node conduction abnormalities, bundle-brunch block, tachycardia, or even ventricular stoppage were previously reported to occur in some severely intoxicated patients ,69. BecaTo prove this assumption, a literature screening for reports on outbreaks and cases of tetrodotoxication between 1983 and 2009 was performed . Particui.e., fourth-degree victims, presented with a stable cardiovascular status, when they were successfully resuscitated or when oxygen supply was rapidly provided by artificial ventilation [+ channel blockade on nerve and skeletal muscle excitability [The overall mortality rate during this 27-year period was about 6.6% . Hypotension was reported in 22 cases (4.2%). Blood pressure reduction was usually accompanied by rather severe other symptoms, like respiratory arrest or block of nerve conduction. Among fourth-degree cases, only 20.6% of the patients developed hypotension, as documented in . Sinus btilation ,89. In atilation . At the tilation . The auttilation , were dutilation . Higher tilation . More setilation ,83. The tability .+ channels increase the spontaneous heart rate and improve the contractile force under normal physiological conditions, their blockade by TTX would result in a decreased cardiac output. In order to maintain (or increase) the arterial blood pressure, such a cardio-depressive effect must be counteracted by an increased vasomotor tone. This scenario is very unlikely to occur when conduction in sympathetic fibers is partially or completely blocked. The TPR in TTX-poisoned patients was not yet determined. However, TTX should produce vasodilatation instead of vasoconstriction, and hypotension can be sufficiently explained by a reduced vasomotor tone (see 3).It is interesting to note that cardiovascular manifestations, like hypotension and sinus bradycardia, cannot be considered as general accompanying symptoms in severely intoxicated and mechanically ventilated patients ,88,89. Si.e., transient increases and decreases in heart rate, did not correlate with the TTX levels [The heart beat was regular, also when sinus bradycardia was noted ,87. In aX levels . As discX levels .+ channels was blocked. Except for one patient, who experienced cardiac arrest before admission to the emergency department, ECG abnormalities, indicative of cardiac arrhythmias like SA block, AV block, bundle brunch block or ventricular tachycardia/fibrillation, were not reported to occur during treatment of the patients in an emergency department or intensive care unit. This strongly suggests that cardiac excitation is not significantly impaired in intoxicated victims with relatively high TTX blood levels, as long as sufficient oxygen is provided.In conclusion, severe neurological and neuromuscular symptoms in third-degree and fourth-degree intoxicated victims strongly suggest that a significant portion of functional TTXs Nav1.5 is the only functional voltage-gated Na+ channel in the adult, non-diseased myocardium of higher mammals. The clinical data are in close agreement with results from animal experiments, a conclusion that was already drawn as early as in the 19th century [+ channels in higher mammals. This conclusion is strongly supported also by several biochemical and electrophysiological studies, demonstrating (a) Nav1.5 in all plasma membrane regions of ventricular cardiomyocytes [+ channels in the whole human heart [+ channels in the sinus node at normal membrane potentials [+ channels to excitation-contraction coupling [This review on the systemic effects of TTX is not the first account suggesting that Na century . Altogetmyocytes ,23,91,  itentials ,50, (d) tentials ,93, and coupling .


Recent developments in the field of echocardiography have allowed the cardiologist to objectively quantify regional and global myocardial function. Regional deformation (strain) and deformation rate (strain-rate) can be calculated non-invasively in both the left and right ventricle, providing information on regional (dys-)function in a variety of clinical settings. Although this promising novel technique is increasingly applied in clinical and preclinical research, knowledge about the principles, limitations and technical issues of this technique is mandatory for reliable results and for implementation both in the clinical as well as the scientific field.In this article, we aim to explain the fundamental concepts and potential clinical applicability of strain and strain-rate for both tissue Doppler imaging (TDI) derived and speckle tracking (2D-strain) derived deformation imaging. In addition, a step-by-step approach to image acquisition and post processing is proposed. Finally, clinical examples of deformation imaging in hypertrophic cardiomyopathy (HCM), cardiac resynchronization therapy (CRT) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) are presented. There is an increasing need for diagnostic modalities able to objectively quantify myocardial function. Quantification of regional myocardial function with ultrasound is challenging on its own. Visual assessment of wall motion and thickening requires extensive training and remaTissue deformation imaging is a recently introduced technique which enables the objective assessment of regional myocardial deformation assessed by ultrasound based strain and strain rate using myocardial Doppler data or B-mode images. This is a promising new technique to quantify regional left and right ventricular function and appears of added value in unmasking or unraveling cardiac pathology table . KnowledFollowing electro-mechanical activation, the myocardium deforms during systole due to sarcomere shortening. This active deformation causes a reduction in intracavitary size, resulting in the ejection of blood from the ventricle. In diastole the original ventricular geometry is restored due to active relaxation and passive filling following atrial contraction. Since myocardial tissue is virtually incompressible, the volume of the ventricular wall remains the same during the cardiac cycle and, thus, deforms in three dimensions. During systole there is three-dimensional deformation which can be expressed in three ventricular coordinates: a longitudinal shortening and a circumferential shortening and a radial thickening.Myocardial deformation is expressed as a one dimensional parameter: strain (ε). It defines the total deformation during the cardiac cycle relative to the initial length at the onset of the cardiac cycle, and is expressed in percentages figure . This im-1. SR depicts the change in strain over a period of time. Thus, when the myocardium shortens there is a negative SR and, the steeper the slope of the strain-curve, the higher the SR-values. The peak systolic strain rate correlates well to loading independent indices of contractility and hence provides valuable information on regional contractile function [The speed at which the myocardial deformation occurs is the strain-rate (SR) and is expressed in sfunction ,4. CompaTo optimally assess regional myocardial function, both strain and SR need to be calculated since they provide complementary information: end systolic strain estimates ejection fraction and peak systolic SR is a measure of contractility. By analogy, when driving a car both the total distance of the journey as well as the speed of the car during the journey provide valuable information.Currently there are two different methods to calculate myocardial deformation using ultrasound: tissue Doppler derived strain and two-dimensional strain derived from B-mode images (speckle tracking). These two techniques will be briefly explained in the following section. Notably, differences in software packages may exist between manufacturers . The exaBy color coded tissue Doppler images (TDI), the velocity relative to the transducer is recorded and can be calculated in each pixel figure . In the From this formula it is also clear that if a myocardial segment is not deforming during systole, for example due to an infarction, there is no difference in velocities and thus a SR of zero, although the segment could show a displacement and velocity due to tethering of a functional neighboring segment. This translated velocity on the non-deforming segment could give the impression of normal function when assessing it by velocity imaging only, but this is unmasked when calculating the regional SR and ε.TDI is one-dimensional, thus only deformation along the ultrasound beam can be derived from velocity. Therefore, only the longitudinal SR/ε in the apical views and radial SR/ε in the parasternal views can be calculated.Several studies have established the robustness and potential useful role of this novel echocardiographic technique.in-vitro study reported a very high degree of accuracy for velocity measurements, although there was a small overestimation of ε and SR[In-vivo invasive studies, using sonomicrometry as a reference method, have confirmed the validity to calculate strain and strain-rate from tissue velocity over a wide range of strains in animal models [The accuracy of the measurement of velocities has recently been investigated using tissue mimicking gelatin blocks in two commercially available ultrasound systems . This in ε and SR. In-vivol models ,7. Nowadl models .Thus, tissue Doppler imaging is a well validated technique to calculate strain and SR over a wide range of conditions, indicating the feasibility for the usefulness of this technique in the clinical setting.When evaluating regional myocardial function with tissue Doppler derived SR/ε, knowledge of the limitations of this technique is essential to ensure appropriate acquisition as well as correct post-processing since artifacts often mimic pathology. The most important and common artifacts will be briefly discussed in this section.1 is 4 cm/s and v2 is 3 cm/s, but due to a stationary artifact the measured v2 is 0 cm/s. This means that the calculated Δv is 4 cm/s instead of the true 1 cm/s, overestimating the SR (see formula) and strain. Drop-out interferes in a similar manner in the calculation of SR, since no velocities are measured, within the drop out zone SR is close to zero, giving the impression of hypo- or akinesia.Since all calculations are derived from the measured velocities, it is essential to work with a data set which provides the true velocities of the myocardium. Reverberations, side lobes and drop out all interfere with obtaining the true velocities and disturb the data used to calculate SR and strain. Reverberations and side lobes are stationary artifacts of extracardiac structures projecting through the myocardium. The measured velocity within such an artifact is close to zero, resulting in 1) random noise within the artifact 2) an overestimation of negative SR/ε below the artifact, 3) a reversal directly above the artifact and 4) an underestimation above the reversal region Figure . If, form) is lower than the actual myocardial velocity. This underestimation is dependent on the angle between the myocardial wall and the ultrasound beam, this implies that vm reduces if the angle increases. Angle correction however, is not an option. As explained earlier, the myocardium deforms in three dimensions, meaning that when measuring longitudinal deformation, one has to keep in mind the simultaneous radial deformation. When the ultrasound beam is parallel to the myocardial wall, the vm is the actual velocity and the vm of the transverse deformation is zero, since the movement is perpendicular to the ultrasound beam. When the angle changes, the contribution of the transverse velocity increases in the vm. For the resulting SR/ε this results in a combination of both a negative  and a positive (transverse) strain, severely disturbing the derived SR/ε patterns. For acceptable calculations, an angle deviation below the 20 to 15 degrees is mandatory.Deviation of the insonation angle is another important limitation of the technique. If the ultrasound beam deviates from the direction the investigated myocardial segment moves, the measured velocity  The myocardial wall needs to be optimally visualized with a clear delineation of myocardial tissue and extracardiac structures (e.g. suppression of the blood pool), a minimum of extracardial artifacts should be achieved and the angle of interrogation limited (deviation below 15–20 degrees). The latter is achieved by orienting the transducer parallel or perpendicular to the investigated wall.2) TDI settings need to be adjusted for optimal post-processing. The velocity scale needs to be adjusted to avoid aliasing. Although a reduction in the velocity scale will result in lower frame rates, the lowest possible velocity scale will result in the highest spatial and temporal resolution combination. Further optimization of the temporal and spatial resolution is achieved by narrowing of the image sector until it is slightly wider than the investigated wall or wall segment. Wall by wall acquisition is essential to achieve adequate frame rates, for reliable SR calculations the optimal sampling rate is >180 frames/sec.3) Three complete cardiac cycles are recorded digitally during breath hold (to minimize image translation) in the presence of a regular rhythm. This will allow filtering of average noise during post processing without losing resolution.Longitudinal ε/SR can be derived from the apical three , two  and four chamber views . Radial strain can be derived from the parasternal recordings of the posterior wall. The measurement of septal wall radial strain often produces artifacts due to the morphological and functionally bilayered architecture (LV and RV fibers) of the interventricular septal wall . CircumfKnowledge and experience in the post-processing techniques are important to interpret the ε and SR graphs and to distinguish pathological deformation from artifacts.  All commercial software programs are equipped with numerous settings to offer the possibility to optimize the calculations to derive SR from velocity. These settings are available to reduce the 'random-noise' in the SR and ε graphs. With the reduction of noise, the SR and ε graphs are smoothed with the consequence that potentially important temporal or regional information is lost. Therefore, a maximal signal to noise ratio should be achieved with a maximal spatial resolution. Averaging more than one cardiac cycle (reduction of random noise and the beat-to-beat variation), temporal (reducing the effective sampling rate) and spatial averaging and increasing the offset length , therefore the ROI needs to follow myocardial motion during the cardiac cycle. A brief explanation on tracking is described in the following segment.1) The ROI should be defined; this implies adjustment of both the offset length and ROI size. These parameters can vary and depend on the investigated parameter  or the clinical question .2) The ROI should be placed in the myocardium, typically, three ROI locations are defined in each wall .3) The ROI should be tracked throughout the cardiac cycle to follow the myocardial movement. Special attention should be made to avoid stationary artifacts (e.g. reverberations) and the blood pool  Finally the quality of the tracking should be checked. Sub-optimal tracking of the ROI will result in drift in the strain-graphs and in a noisy SR-graph. The ROI position can be corrected after the identification of the noisy frames (to eliminate frame-to-frame artifact or blood-pool noise) which are best identified in the SR graph.Numerous measurements and calculations can be performed after the tracking of the ROI. These can be divided into parameters concerning the timing and/or the magnitude of strain and SR. The most relevant measurements are presented in figure 2-dimensional strain imaging is a new technique which uses standard B-mode images for speckle tracking analysis, in which the speckled pattern (acoustic backscatter generated by the reflected ultrasound beam) is followed frame by frame. This speckle pattern is unique for each myocardial region and it is relatively stable throughout the cardiac cycle. The displacement of this speckled pattern is considered to follow myocardial movement and a change between speckles represents myocardial deformation Figure . When trValidation of early versions of 2DSE software in a tissue mimicking gelatin block revealed a good correlation compared to sonomicrometry, although values (both strain and strain-rate) were overestimated in the lower range of values . These fThe first study to determine the feasibility and accuracy of 2DSE in patients with myocardial infarction reported that of all segments, 98% in the control population and 80% in the patient group could be analyzed, findings which were reproduced in later studies . Importa2DSE is generally more smoothed and, therefore, less influenced by artifacts than TDI derived strain , which is lower compared to TDI >180 FPS): this could result in undersampling, especially in patients with tachycardia. Rapid events during the cardiac cycle (e.g. isovolumic phases) may disappear all together, and peak SR and velocity values may be reduced due to under sampling, especially in isovolumic phases and in early diastole. Higher frame rates could reduce the undersampling problem, although this will result in a reduction of spatial resolution and, consequently, less optimal ROI tracking [0 FPS: thAnother limitation of 2SDE is the fact that calculated parameters are averaged over the myocardial segment when using the "results page" of the software program  has indThe same basic principles for image acquisition as mentioned for TDI recordings apply for 2DSE: digitalized recordings of a minimum of one cardiac cycle are made during breath hold (to minimize through plane motion) with a stable ECG recording. Since the angle of interrogation does not influence strain and strain-rate calculations, the transducer can be placed off-axis to obtain the optimal gray scale image. However, misalignment in the third dimension  cannot be corrected in post-processing and should be correct. We would like to state that optimal frame rates for 2DSE are still under discussion, but in our own experience: a frame rate of 50–80 FPS seems to result in the optimal tracking quality in the left ventricle long and short axis. For single wall recordings, a frame rate between 70–110 FPS will result in proper tracking .Visualization of the myocardial wall needs to be optimal, with a clear delineation of myocardial tissue and extracardiac structures and avoidance of drop-out since this will result in unacceptable ROI tracking and drift. The optimal balance between temporal and spatial resolution is achieved when adjusting the image sector slightly wider than the interrogated wall. For small-angle acquisitions this has the advantage that frame-rate can be reduced into the 50–110 FPS range while greatly enhancing the lateral resolution and overall quality of the image. Moreover, near field clutter can be reduced with the implementation of dual-focus imaging when artifacts are prominent. For parasternal recordings  small angle recordings are not possible, all myocardial segments need to be in the image field. For any recording, it should be kept in mind that all myocardial segments need to be visualized optimal, since poor tracking of any segment often affects tracking of the adjacent segments.Comparable to TDI calculations, careful post-processing is mandatory to obtain reliable regional data, although ROI tracking is less influenced by artifacts and are easier to identify as inappropriate ROI tracking. ROI tracking in 2DSE is discussed in the following section.1) The ROI is defined by tracing the endocardium in a still frame (default at end systole).2) The ROI width is set to match the myocardial thickness. An automated software program calculates the frame-to-frame displacements of the speckle-pattern within the ROI throughout the cardiac cycle.3) The resulting tracking quality is then scored as either acceptable or non-acceptable. Since the program follows any speckle pattern, tracking of a stationary artifact during the cardiac cycle is not uncommon, and often scored as appropriate tracked. Therefore, the tracking has to be visually checked and adjusted if necessary. Even the slightest failure of ROI tracking can result in drifting of the calculated strain curve.For each myocardial segment, velocity, displacement, strain and SR are calculated in two dimensions: longitudinal and transverse parameters in the apical recordings and circumferential and radial parameters in the parasternal recordings Figure . For theBoth TDI and 2DSE derived parameters are accurate quantitative measures of local longitudinal myocardial deformation, and thus (dys)function and will general yield comparable values for local deformation and deformation rates in both the LV  and the Most of the observed differences between the two techniques are those inherent to the limitations described earlier. For example, TDI is not possible when the investigated wall is not optimally aligned, or in the presence of a stationary artifact, whereas 2DSE is less influence by these interferences. On the other hand, 2DSE has a relative low temporal resolution hindering tracking in the presence of high heart rates where also undersampling becomes an issue , this isPractical differences between the two techniques are an additional factor when choosing between one or the other. Training requirements for both image acquisition and post-processing are equal, although TDI is generally perceived as more difficult to master. This is particularly the case for post-processing. In our experience, acquisition time is comparable between the two techniques. Post-processing time, however is significantly shorter with speckle tracking  with appClinical and experimental research on the potential role of deformation imaging in various clinical settings is currently an on going topic. The additional value of deformation imaging in echocardiography has been proposed in various pathological conditions although more research is needed  In additHypertrophic (obstructive) cardiomyopathy (HCM) is a genetic disorder characterized by hypertrophy of the myocardium. The differentiation of HCM from hypertensive left ventricular hypertrophy (H-LVH) on the basis of morphological information obtained by conventional echocardiography is cumbersome. Myocardial disarray is a typical histopathological finding in HCM and provides a substrate for potential lethal ventricular arrhythmias. This disarray also induces functional abnormalities, which could be detected using tissue deformation imaging. A recent article found that this technique reliably distinguishes HCM from H-LVH with a cut-off value for peak systolic strain of -10.6% In the following example we present an asymptomatic first degree family member  of a patient with HCM. This patient had the same mutation as the index patient. On conventional echocardiography a septal thickness of 12 mm  was measured with no wall motion abnormalities. Deformation imaging (TDI) unmasked a pathologic deformation in the basal segment of the septum with prestrech, a low peak systolic strain (-3.3%) and post-systolic shortening Figure .A potential clinical role of tissue deformation imaging is for patient selection for cardiac resynchronization therapy. The maximal delay between wall segments can be visualized using different parameters. The application of regional deformation imaging in this patient group has the advantage to be able to carefully calculate timing issues of regional deformation properties of the myocardium, independent of translated displacement induced by adjacent or opposite wall segments. In addition, LV ejection fraction can be estimated using global LV end-systolic strain Figure .In the following example a patient  is presented fulfilling CRT criteria  who was implanted with a CRT-device. Prior to implantation, we found a septal-to-lateral delay to peak strain value of 425 msec using 2DSE Figure . 2DSE reAlthough clinical and preclinical research of left ventricular function is broadly being explored, little is known about normal and pathologic right ventricular (RV) function and there is an urgent need for more insight in RV function by quantitative techniques  In our oThe following case is a 36 year old woman evaluated for arrhythmogenic right ventricular dysplasia (ARVD), an inherited cardiomyopathy characterized by fibro-fatty myocardial replacement predominantly in the right ventricle. She has a first degree family member diagnosed with ARVD. No genetic defect was found in either. The RV was not dilated, no wall motion abnormalities could be detected nor any other typical ARVD findings on conventional echocardiographic examination . Tissue Several new developments are to be expected, not only to improve tracking quality, reduction noise and improve post processing time , but alsAngle dependency and the impact of artifacts in TDI derived parameters and the low temporal resolution in 2DSE are important limiting factors in the technology. A combination of the two techniques  could enhance the robustness of the technique and reduce the post-processing time.MRI-tagging is a technique to calculate deformation in three dimensions. As explained earlier, new echocardiographic techniques have "upgraded" the one-dimensional tissue Doppler to 2DSE. A next step in development is the calculation of strain in three dimensions. With the recent advances in three-dimension echocardiography, this could be possible in the near future. Currently, the low temporal resolution is a severe limitation which has to be overcome before accurate calculations of deformation parameters are feasible.Tissue deformation imaging is a rapidly evolving technique able to objectively evaluate regional myocardial function. In this review we aimed to give insight into the basic concepts, image acquisition, data analysis and potential clinical applications. Although this quantification provides both the clinician as well as the researcher with detailed information on the myocardial function during the cardiac cycle, it should be kept in mind that, like all ultrasound techniques, image acquisition and quality remain a limiting factor. Although tissue deformation imaging is a promising technique, knowledge of image acquisition, post processing techniques and interpretation of strain and strain-rate graphs are essential to reliably differentiate myocardial pathology from artifacts both in the clinical setting, and for reliable and reproducible research. Its limitations notwithstanding, tissue deformation imaging is an accurate and robust techniques that may successfully fulfill the need for quantitative assessment of myocardial function. The application of this technique in the clinical setting is currently not routine, but the potential of tissue deformation imaging and the need for quantitative measurements of ventricular function should promote its introduction in various clinical settings in the near future.The author(s) declare that they have no competing interests.AT designed the review, participated to analyzed paper collection and drafted the paper.BB and PM helped to draft the manuscript (2DSE section and Doppler section respectively).GS and PD revised the article.MC helped to draft the manuscript.All authors read and approved the final manuscript.ROI tracking in tissue Doppler imaging. The ROI is tracked (bottom left) as described in the text in the basal segment of the RV. Note the changes in the strain-graph during the tracking. After careful tracking, the ROI follows the myocardial motion.Click here for fileImpact of stationary artifact on 2DSE. Appropriate ROI in a 4-chamber view using 2DSE despite a prominent stationary artifact in the lateral wall. The ROI is color coded: yellow-red = negative SR, green = no SR and blue = positive SR. In the region of the artifact there is no reversal of SR values, all myocardial segments show identical color coding during each phase of the cardiac cycle. See figure Click here for fileDeformation imaging of the right ventricle in a patient suspected for ARVD using 2DSE. 2DSE parameter extraction in the right ventricle. A ROI is tracked along the RV free wall and follows its movement during the cardiac cycle. An overlying color map is seen on the ROI: red indicates normal deformation; pink indicates reduced deformation and blue indicates no deformation, or stretch. See figure Click here for file