Tako-tsubo syndrome (TTS) in its typical  and atypical  forms is being increasingly recognized in the West owing to early systematic coronary angiography in acute coronary syndromes (ACS).To assess the incidence, the clinical characteristics and the outcome of TTS in a single high volume cath lab in Southern Italy over the last 6 years.Among 1674 consecutive patients (pts) referred to our coronary care units in the last 6 years (2001–2006) for ACS we selected 6 (0.5%) pts  who fulfilled the following 4 criteria: 1) transient left ventricular wall motion abnormalities resulting in ballooning at contrast ventricolographic or echocardiographic evaluation; 2) normal coronary artery on coronary angiography performed 5 ± 9 hours from hospitalization; 3) new electrocardiographic ischemic-like abnormalities (either ST-segment elevation or T-wave inversion) and 4) emotional or physical trigger event.At admission all pts had presumptive diagnosis of ACS and ECG revealed ST elevation in 3 (50%) and T wave inversion with QT elongation in 3 (50%). In the acute phase cardiogenic shock occurred in 2 (33%) and heart failure in 1(16%). Presenting symptoms were chest pain in 6 (100%), dyspnoea in 2 (33%) and lipotimia in 1 (16%). At echocardiographic-ventricolographic assessment, the mechanical dysfunction  was apical in all 6 pts ("classic" TTS). In all patients wall motion abnormalities completely reversed within 4.5 ± 1.5 days. The region of initial recovery was the anterior and lateral wall in 4 cases and the lateral wall in 2 cases. Ejection fraction was 35 ± 8% in the acute phase and increased progressively at discharge (55 ± 6%) and at 41 ± 20 months follow-up . All patients remained asymptomatic with minimal  treatment.Classic TTS is a frequent serendipitous diagnosis after coronary angiography showed "surprisingly" normal findings in a clinical setting mimicking an ACS. Despite its long-term good prognosis life threatening complications in the acute phase can occur. Stress induced cardiomyopathy is described as an acute cardiomyopathy characterized by acute, but rapidly reversible, left ventricle systolic dysfunction in the absence of atherosclerotic coronary artery disease which appears to be triggered by intense psychological and physical stress . This syCharacteristic evolutionary changes that occur over 2 to 3 days include resolution of the ST-segment elevation and subsequent development of diffuse and often deep T-wave inversion that involves most leads. New pathological Q waves may occasionally be observed and, furthermore, it has been possible to observe a prolongation of the corrected QT interval , potentiDuring the last 6 years 2001–2006), among 1674 consecutive patients (pts) referred to our coronary care units for ACS, 6 patients  presenting at admission with acute onset of cardiovascular event have been retrospectively selected. All fulfilledthe following 4 predetermined criteria to define Tako-Tsubo cardiomyopathy [001–2006,All patients underwent, at admission, two-dimensional transthoracic echocardiography, 12 lead electrocardiogram, serial measurements of cardiac isoenzymes including creatine kinase, creatine kinase MB fraction, and troponin. Transthoracic echocardiography has again been repeated at discharge. All patients have been followed-up for a median period of 40 months.All patients underwent comprehensive transthoracic echocardiography examination at rest, upon discharge and at a median period of 40 months follow-up. End-systolic, end-diastolic volumes, ejection fraction and wall motion score index  were calculated following the recommendations of the American Society of Echocardiography . The lefValues are expressed as mean ± standard deviation (SD) unless indicated otherwise. Groups were compared by parametric or non-parametric tests . More than 2 groups were compared using the analysis of variance. Post-hoc tests were performed  with the help of Newman-Keuls test. A p < 0.05 was considered as statistically significant.Demographic and clinical features of the study patients are reported in Table Emergency coronary angiography showed angiographically normal coronary arteries in all with ventriculographic confirmation of apical ballooning observed by echocardiogram Figure . Due to We described 6 cases of tako-tsubo cardiomyopathy in a region of Southern Italy close to Naples. In the contemporary definition and classification of the Cardiomyopathies proposed in 2006 by the American Heart Association, stress ("Tako-Tsubo") cardiomyopathy is classified among acquired forms of cardiomyopathy . Our datClinicians should consider this syndrome in the differential diagnosis of acute coronary syndromes, especially in post-menopausal women with a recent history of acute emotional or physical stress. The non-invasive suspicion rests on the typical echocardiographic appearance apical ballooning – usually reversible within a few days or weeks. The angiographic documentation of normal coronary arteries is necessary to substantiate the diagnosis.ABS: Apical ballooning syndromeACS: Acute coronary syndromePt: patientTTS: Tako-tsubo syndrome


With a rising incidence of severe obesity in developed nations, heart failure, a well-recognised co-morbidity, is becoming more common.We describe two recent patients encountered, a 64 year old and a 42 year old, who are both severely obese and presented with fluid retention of approximately 40 kilograms. Assessment revealed that the explanation of the gross clinical features were relatively subtle cardiac abnormalities. These cases illustrate how fluid retention in severe obesity can differ from that seen in 'traditional' heart failure in terms of clinical assessment and management.Severe obesity can result in insidious fluid retention, which can be easily overlooked until large volumes of fluid have accumulated. Cardiac abnormalities are usually found in these patients, but may be relatively subtle, leading to current debate in the definition and classification of heart failure. These scenarios are increasingly being encountered in clinical practice. Recognition, assessment and treatment of the 'clinical syndrome of heart failure' in severe obesity is often difficult. The commonest causes of heart failure are ischaemic heart disease, hypertension, diabetes mellitus, and left ventricular hypertrophy . The manWe report two recent cases illustrating an increasingly common scenario.A 64 year old Caucasian lady was admitted as an emergency with worsening dyspnoea and oedema. During the three weeks prior to admission she had decreasing exercise tolerance, struggling even to transfer from her bed due to a combination of breathlessness, muscle aches and the sheer weight of her legs. During the preceding nine months, she had three admissions for cellulitis of her swollen legs. Review of the records revealed progressive weight gain of 36 kg over this time.Her past medical history included type 2 diabetes mellitus, hypertension, and atrial fibrillation, all of which had been controlled on medication for at least 12 months. She also had non-alcoholic steatohepatitis and smoked 5 cigarettes daily. She never had rheumatic fever, heart valvular problems or any cardiovascular events. Her medications were glibenclamide, metformin, co-amilofruse, enalapril, simvastatin, and digoxin.2). There was marked pitting oedema involving both legs, abdomen and chest wall with patches of cellulitis within the oedematous areas  60.5 kg/mElectrocardiogram revealed atrial fibrillation (80 beats/minute) and small QRS complexes. Blood tests were unremarkable. She had evidence of mild proteinuria but no clinical nephrotic syndrome and her renal function was normal. Chest radiography revealed cardiomegaly with bulky hila due to vascular changes. Transthoracic echocardiography showed a normal left ventricular size with an ejection fraction of 65%, bi-atrial enlargement and a dilated right ventricle with good function. Investigations gave no evidence of pulmonary embolus, ascites, sleep disordered breathing or other cause of cardiomyopathy.She was treated with intravenous furosemide initially and later with metolazone and spironolactone. Her weight reduced by 35.6 kg over 42 days and by 41.8 kg when reviewed in clinic. The patient was not on a strict diet during this period.A 42 year old Caucasian lady was admitted from an obesity clinic. She had been referred by her general practitioner because of more than 35 kg weight gain over ten months. During this period, she had developed swelling in legs and abdomen but despite furosemide (80 mg daily), the oedema had progressed to render her bedbound.She had been obese since childhood and depressed recently, but had no other significant medical history. She never had rheumatic fever, diabetes, hypertension, valvular heart problems or any vascular events. Her medications on presentation were furosemide and sertraline. She did not smoke and drank approximately eight units of alcohol a week.2). There was pitting oedema extending up to her abdomen. Her pulse was 100 beats/minute irregularly irregular. Blood pressure was 155/85 mmHg and jugular venous pressure raised to her ear lobes. The apex beat was impalpable. Cardiac auscultation and chest examination were normal. Besides a large paraumbilical hernia, the remaining examination was unremarkable.On examination, she weighed 185.1 kg .Transthoracic echocardiography showed normal left ventricular size with mild concentric hypertrophy and good systolic function. Right ventricle and both atria were all dilated. A myocardial perfusion scan confirmed ejection fraction of 56% with no evidence of ischaemia. Further tests gave no evidence of pulmonary embolus, sleep disordered breathing or other cause of cardiomyopathy.During two months treatment with digoxin, warfarin, ramipril and furosemide 250 mg daily, her weight declined by 40.1 kg to 145.0 kg. She was not a restrictive diet during this period. She later underwent successful bariatric surgery and hernia repair.per se on heart failure. Indeed, cardiac disease remains the commonest cause of premature death in severe obesity with most deaths occurring below the age of 50 [Over 2% of the adult population in the United Kingdom is morbidly obese and this proportion is increasing. Obesity-related mortality and morbidity are rising. The association between obesity and heart failure is well recognised . Obesityge of 50 . Both thSevere obesity changes the clinical problem of fluid retention. In our cases the only abnormalities identified were cardiac. Heart failure in severe obesity can differ from 'traditional' heart failure in several aspects.Firstly, the extent of fluid retention is relatively hidden by the sheer physical mass of the patient (as seen in both our patients) and by the gradual and insidious accumulation of fluid. Most severely obese patients have some degree of oedema and display nutrition-related weight changes, so it is difficult to recognise worsening oedema.Secondly, in severe obesity there can be multiple contributors to the dyspnoea and oedema. Hypertension, diabetes, sleep disordered breathing, 'obesity-related asthma', non-alcoholic fatty liver, focal-segmental glomerulo-sclerosis, low physical fitness levels, thromboembolic disease, lymphoedema, and vitamin deficiencies are all common . Obesityper se even without heart failure and may also be elevated in non-cardiac causes of fluid retention [Thirdly, cardiac evaluation of the severely obese patient is technically difficult and interpretation controversial. Severe obesity affects cardiac mass, morphology, and histology . The noretention .Treatment of heart failure in severe obesity is poorly studied as such patients are routinely excluded from drug trials. Weight reduction reverses haemodynamic abnormalities including left ventricular hypertrophy and diastolic dysfunction in the obese . HoweverThe profile of heart failure is changing. Our patients illustrate not uncommon scenarios. Severely obese patients can insidiously gain considerable amounts of relatively hidden fluid that can be overlooked until large volumes of fluid have accumulated. Cardiac abnormalities are usually found in such patients, but may be relatively subtle and recognition, quantification, assessment and treatment can be difficult.Written informed consent was obtained from the two patients described for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.HSO was involved in management of cases, literature search, and writing of article. CS was involved in management of case and writing of article. TK was involved in literature search and writing of article, SC was involved in the idea for article, writing of article and Guarantor. All authors have read and approved the final manuscript.


We report a case of aluminium phosphide poisioning that presented to us with refractory myocardial depression. This patient developed worsening circulatory failure that did not respond to inotropic or vasopressor support and intra-aortic balloon counterpulsation. She went on to develop progressive metabolic acidosis, renal failure and died within 48 hours of admission to the intensive care unit. A 25-year-old lady was brought to the Emergency Department of our hospital half an hour after having consumed 10 tablets of aluminium phosphide (ALP) 50%. At the time of presentation, she was nauseated and had several episodes of vomiting. Her heart rate was 120/min, BP was 110/75 mmHg, she was breathing at a rate of 20 min, with oxygen saturations around 98-99% on room air. Initial blood gas analysis revealed significant metabolic acidosis with a pH: 7.33, PaCO2: of 23.3, HCO3: 12.1 and base excess: −13.8. A gastric lavage was given and she was transferred to the intensive care unit where she was put on invasive blood pressure and central venous pressure monitoring. Her initial liver function tests, blood urea nitrogen, creatinine, creatinine kinase, troponin-I and magnesium levels were within the normal range. Four hours after admission, she developed hypotension (systolic pressures less than 90 mmHg and MAP less than 60 mmHg). Fluid boluses up to 1.5 L of normal saline were given to raise the central venous pressure to 16; however her blood pressure continued to be low. She was started on a dobutamine infusion at 5 mcg/kg/min and a bicarbonate infusion at 20 mmols/hr. She was also given intravenous magnesium sulphate to keep the serum magnesium levels around the upper limit of normal. With this management she remained hemodynamically stable and maintained a urine output of 75 to 100 mls/hr. Her metabolic acidosis persisted, though it was improving with ongoing infusion of bicarbonate. The following morning (about 14 h after admission), she became more tachycardic, with heart rates up to 160/min. She was also becoming increasingly tachypnoeic and her metabolic acidosis persisted. She was intubated and put on mechanical ventilation at this time - which led to further drop in blood pressures, with high central venous pressures. She was started on adrenaline infusion at this time, initially at 0.05 mcg/kg/mt. Further magnesium supplements were given to raise her magnesium level to the upper limit of normal. She was initiated on continuous veno-venous hemodiafiltration (CVVHD) at this time in view of the persisting metabolic acidosis. After initiation of CVVHD, her acidosis improved, though she continued to remain tachycardic and hypotensive in spite of increasing doses of adrenaline. An echocardiogram revealed severe impairment of left ventricular function with an ejection fraction of 30% on high level of inotropic support with dobutamine and adrenaline. Her troponin-I level had increased at this point in time to 12.7 ng/ml . In view of her worsening cardiac function in spite of increasing doses of inotropic support, an intraaortic balloon pump was inserted to support LV function. Augmentation was commenced at 1:2 support considering her significant tachycardia. The IABP had no apparent effect on her hemodynamic status even after several hours of support. She continued to be tachycardic, hypotensive with high central venous pressures and persisting metabolic acidosis in spite of ongoing CVVHD. Despite continued supportive measures, she never showed any improvement and died about 48h after admission to the intensive care unit.Aluminium phosphide (ALP) is used as a rodenticide and is a common agent used in suicidal attempts in northern India. Refractory myocardial depression from ALP toxicity is not uncommon and carries a mortality of up to 77%.2 ALP relWe present a case of refractory myocardial depression from ALP toxicity. In spite of inotropic support with high doses of dobutamine and adrenaline, our patient went on a rapid downhill course with worsening tachycardia, hypotension, metabolic acidosis and very high troponin-I levels, possibly due to extensive myocardial necrosis. There was no improvement in her hemodynamic status with intraaortic balloon counterpulsation. To our knowledge, there is no other report in literature of IABP use to try to support the myocardium in ALP poisoning. The possible benefit of CPB would need to be explored in refractory myocardial depression due to ALP.


Peripartum cardiomyopathy is a relatively rare disease, which can have devasting consequences and should be promptly identified and correctly treated. Overall prognosis is good in majority of the cases, although some patients may progress to irreversible heart failure. Early diagnosis is important and effective treatment reduces mortality rates and increases the chance of complete recovery of ventricular systolic function.We report of an interesting case with a favourable outcome and discuss about the clinical presentation, therapy and outcome of this condition. A month prior to delivery she started feeling weak with dyspnoea and hypertension but declined treatment for hypertension and the dyspnoea symptoms were not investigated further. The chest x-ray on admission showed acute pulmonary oedema with bilateral pleural effusion and she was commenced on diuretics, ACE-inhibitors and antibiotics. Since the patient did not show any clinical improvement over the next 2 days, she was transferred to our intensive ward. On admission she was hypotensive (90 mmHg systolic blood pressure), with sinus tachycardia at 120 bpm with a gallop and diffuse rales on lung auscultation. ECG revealed diffuse T wave inversion. Echocardiography showed the presence of a severely impaired left ventricular systolic function with EF of 30%, fractional shortening of 11% along with severe mitral regurgitation and moderate tricuspidal regurgitation. Right and left ventricles appeared severely enlarged and diffusely hypokinetic. End-diastolic volume of the left ventricle was 118 ml/m2 and end-diastolic dimension 6.5 cm with an end-diastolic dimension index of 3.96 cm/m2. Biatrial enlargement was also noted. White cell count was 6700/cubic mm, Hb 9.8 g/dl, C reactive protein 0.21 mg/dl , BNP 689 pg/ml . The thyroid hormone profile was normal. Serological tests for the usual viral agents responsible for myocarditis were negative.A 34 years old lady was referred to our cardiological intensive care unit from a peripheral hospital. She had been admitted there for cough and dyspnoea which developed on the 15Antibiotic therapy was discontinued while the diuretics were continued. To correct the hypotension and improve perfusion, saline was infused gently (1.5 l/24 hours) while closely monitoring for any further evidence of fluid overload. ACE-inhibitors were cautiously initiated since the systolic blood pressure was low at 85-90 mmHg. Beta-blocker was started on the second day of admission at a low dose (bisoprolol 1.25 mg). The patient was also commenced on enoxaparin for thrombo-prophylaxis, because of the enlarged LV with significant dysfunction. Chest x-ray on day 15 showed resolution of the pulmonary oedema and pleural effusions. Follow up echocardiography showed improvement of mitral insufficiency, which became mild by day 30 along with normalisation of dimension and function of right ventricle and disappearance of tricuspid insufficiency. While the volumes of the left ventricle decreased, EF remained severely depressed (29% at discharge). BNP levels trended down to 614 pg/ml on day 15 after having risen to a peak level of 1111 pg/ml on day 5. The patient was discharged from the hospital on day 17 on furosemide 25 mg/day, lisinopril 20 mg/day, bisoprolol 2.5 mg/day, enoxaparin 8000 UI/day. Iron supplementation was also recommended.1) and that of BNP levels in Fig. (2).During the follow up there was a continuous improvement of left ventricle dimensions and function and a decrease of BNP levels. Left ventricle EF increased to 40% by day 30 and BNP decreased to less than 100 pg/ml on day 45. The trend of left ventricle volumes and function is shown in Fig. (This case report highlights the diagnostic and therapeutic dilemma that physicians face when encountering patients with the rare, but interesting condition of peripartum cardiomyopathy which warrants prompt identification and treatment.PCM usually presents with classical symptoms and sign of systolic heart failure with ventricular enlargement and dysfunction seen on echocardiography. Often there is significant mitral and tricuspid regurgitation . UnusualThe diagnosis of PCM is challenging because most women in the last months of a normal pregnancy or soon after the delivery experience dyspnoea, fatigue and pedal oedema. Symptoms and signs which should raise the suspicion of heart failure and could help the clinicians in the diagnosis, are the presence of paroxysmal nocturnal dyspnoea, nocturnal cough, new regurgitant murmurs, pulmonary crackles, jugular venous distention and hepatomegaly .The aetiology and pathogenesis seems to be multifactorial and poorly understood with the available literature rather conflicting. Gestational hypertension, tocolytic therapy and twin pregnancy have been proposed as possible risk factors because they were commonly associated with PCM . These oThe association between PCM and twin pregnancy could support the theory of autoimmunity as a possible mechanism. This could depend on an excessive traffic of haematopoietic lineage cells from the foetus to the mother as manifest in twin pregnancy . UsuallyMultiparity could be another risk factor for the development of PCM  and agaiMolecular markers of an inflammatory process are found in most of the patients. 90% of the patients show high levels of plasma C-reactive protein that correlated positively with LV end-diastolic and end-systolic dimensions and inversely with LV ejection fractions . This coInterestingly, the possibility of developing PCM in a surrogate mother whose embryo was received from the commissioning couple of whom the mother was diagnosed with PCM following the delivery of her first child , points Overall prognosis of PCM is good in majority of the cases, although some patients may progress to irreversible heart failure. Progression of the condition requiring heart transplantation is described in 4% and death in 9% at a two years follow up ,18. PatiSudden cardiac death has been reported to account for up to 50% of the mortality  and therComplete recovery of systolic function occurs usually in the first 6 months after delivery  althoughTo get an assessment of prognosis at the time of diagnosis, a dobutamine stress echocardiography study could be performed in non-critically ill patients. Inotropic contractile reserve accurately correlated with subsequent recovery of left ventricular function and usually associated with a benign prognosis . MRI couEven if left ventricular function recovers completely, exercise tolerance may remain abnormal and this could be more objectively assessed by an abnormal response to dobutamine stress echocardiography. Management involves conventional therapy for heart failure with diuretics, ACE-inhibitors, beta-blockers and aldosterone antagonists. Angiotensin-receptor blockers should be added in case of ACE-inhibitors intolerance. Anticoagulant therapy should be considered in view of the low left ventricular EF, which predisposes to thrombus formation, especially in the peripartum period when a hypercoagulable state exists. In patients not improving on conventional therapy or in patients with critical hemodynamic state with cardiogenic shock, hemodynamic support with pressors should be considered. There have been some reports about the use of levosimendan  in non-rNon-responsive patients should be considered for heart transplantation even if there are some reports about effective use of extracorporeal membrane oxygenation , intraaoAmong patients who eventually recover, the withdrawal of heart failure medications was not associated with decompensation over a follow-up of 29 months . The durIt is important to note that the use of ACE-inhibitors should be limited to after delivery since they have teratogenic effects. Other drugs like immunosoppressive drugs are still under evaluation.A subsequent pregnancy carries a high risk of relapse, significant decrease of left ventricular function and mortality. Mortality rate is described to be approximately 55% during subsequent pregnancy  even thoPCM is a relatively rare disease, which can have devasting consequences and should be promptly identified and correctly treated. Early diagnosis is important and therefore women who develop symptoms of heart failure during pregnancy or shortly after should be investigated for this condition. Effective treatment reduces mortality rates and increases the chance of complete recovery of ventricular systolic function.


Cardiac resynchronization therapy (CRT) improves left ventricular (LV) volumes, mitral regurgitation (MR) severity and symptoms of patients with heart failure (HF). However, ≥ 30% of patients have no significant clinical or echocardiographic improvement following CRT. Reverse remodeling after CRT correlates with improved clinical outcomes. We hypothesized that in NT-pro BNP monitoring is accurate to identify responders following CRT.42 consecutive patients  with HF undergoing CRT were prospectively enrolled. Responders at follow-up were defined by echocardiography (decrease in LV end systolic volume ≥ 15%). Echocardiography and NT-pro BNP measurement were performed at baseline and repeated 3 to 6 month after CRT.-1 vs. -61 ± 959 pg.ml-1, p = 0.002; relative: -45 ± 28% vs. 2 ± 28%, p < 0.0001). A decrease of ≥ 15% in NT-pro BNP 3–6 months after CRT identifies echocardiographic responders with a sensitivity of 90% and a specificity of 77%.There was no significant difference between responders  and non-responders  regarding baseline NT-pro BNP level. Responders had significantly higher decrease in NT-pro BNP levels during follow-up than non-responders (absolute: -1428 ± 1333 pg.mlNT-pro BNP monitoring can accurately identify echocardiographic responders after CRT. Cardiac resynchronization therapy (CRT) is established as a valuable additive treatment for patients with drug-refractory heart failure (HF) and electromechanical asynchrony. CRT improves left ventricular (LV) function and geometry, exercise capacity and outcomes of appropriately selected patients with HF -4. CRT aDeclaration of Helsinki" and all patients provided informed consent. The study protocol was approved by local ethics committee.From May 2005 to March 2008, 42 consecutive patients referred for CRT with chronic HF were prospectively enrolled. Inclusion criteria were as follow: (1) NYHA functional class ≥ III, (2) QRS duration ≥ 120 ms, (3) chronic LV systolic dysfunction defined as LV ejection fraction (LVEF) ≤ 35%, (4) LV dyssynchrony ≥ 50 ms, (5) optimal medical treatment for HF including angiotensin-converting enzyme inhibitors or AT1 receptor antagonists diuretics, beta-receptor blockers and spironolactone when tolerated, and (6) sinus rhythm. Patients with recent myocardial infarction (< 6 months), coronary revascularization procedure (< 6 months) and presenting standard contraindications to DSE were excluded. This study complies with the "Patients were submitted to clinical examination, 12-lead electrocardiography (EKG), blood sampling, transthoracic echocardiography (TTE), and dobutamine stress echocardiography (DSE) within one week before CRT. Additionally, TTE and blood sampling were also performed within the week and at 3 to 6 month following CRT.Two-dimensional and Doppler TTE examination were performed with commercially available echocardiographic systems . Doppler-echocardiographic measurements included LV end-diastolic and end-systolic diameters and LVEF determined by modified biplane Simpson method. LV outflow tract stroke volume was calculated by multiplying LV outflow tract area by LV outflow tract velocity-time integral measured by pulsed wave Doppler. Proximal isovelocity surface area (PISA) method was used to quantify both mitral regurgitation volume (RV) and effective regurgitant orifice (ERO) area as recommended by The American Society of Echocardiography guideline . QuantifA coronary sinus venogram was obtained using balloon catheter, followed by the insertion of the LV pacing lead. An SF guiding catheter was used to position the LV lead  in the coronary sinus.The preferred position was lateral or postero-lateral vein. Right atrial and ventricular leads were positioned conventionally. All leads were connected to a dual-chamber biventricular ICD .Venous blood samples were withdrawn from an antecubital vein into chilled ethylene-diamine-tetra-acetic acid Vacutainer test tubes after 20 minutes of rest with patients in a supine position. Samples were placed immediately on ice-cold water and the tubes were then centrifuged at 4000 r.p.m. at 4°C for 15 min. Supernatant plasma was then immediately aliquoted into labelled cryo-vials. NT-pro BNP was determined by a commercially available electrochemiluminescence immunoassay based on a polyclonal antibody-based sandwich chemiluminescence assay  using an autoanalyser (Elecsys 2010).Continuous variables are expressed as mean ± SD or mean ± SEM when specified. Patients were separated into 2 groups (responders and non-responders). Baseline data for responders versus non-responders groups were compared for statistical significance using t-test or chi-square test, as appropriate. Baseline and post-CRT Doppler-echocardiographic data were analyzed using a 2-way analysis of variance for repeated measurements to assess the effects of time (baseline vs. post-CRT) and group (non-responders vs. responders). Linear regression analyses were used to evaluate the relationship between changes in NT-pro BNP and changes in echocardiographic parameters. Sensitivity and specificity for identification of CRT responders were determined for various cut-off values of echocardiographic parameters using receiver-operating characteristic (ROC) curves.Forward and backward multiple stepwise regression were performed to determine the association between the change in NT-pro BNP and LV end-systolic volume after adjustment for baseline variables. Logistic regression was also performed to assess the performance of change in NT-pro BNP to identify CRT responders.Among the 42 patients included in this study , 29 (69%) were responders. There was no significant difference between responders and non-responders  and was not statistically different between responders and non-responders . The change in NT-pro BNP between pre-CRT and 3–6 months post CRT evaluations was significantly more important in responders than in non-responders . Moreover, there was a definite trend for significant difference between the 2 groups with regards to 3–6 months NT-pro BNP (p = 0.07).The decrease in NT-pro BNP following CRT was higher in responders than in non-responders (p = 0.002) Figure . BaselinBaseline LV volumes, LVEF, resting LV WMSI, MR severity  and inter and intraventricular asynchronism were not significantly different between responders and non-responders Table . HoweverCR was present in 30 patients (71%) and responders had significant higher prevalence of CR than non-responders  , patients with CR had lower ERO at follow-up  than those without CR.According to the presence of CR, there was no significant difference in baseline and post-CRT NT-pro BNP (p = 0.69 and p = 0.26). Although there was no significant difference in baseline ERO  Figure  and end-However, only the change in ERO was correlated with the peak WMSI and the change in WMSI during DSE , LV stroke volume, , LV end-diastolic volume  and RV . The best correlations were found with percent changes in LV end-systolic volume  and ERO  . ROC curve analysis, demonstrated that the absolute change in NT-pro BNP is accurate to identify response to CRT (area under curve = 0.82) and that a decrease in BNP ≥ 277 pg.ml-1 and a percent decrease of ≥ 15% were independently associated with a 9.4-fold (p = 0.0056) and 7.1-fold (p = 0.0018) increase in the likelihood of positive response to CRT, respectively. Multivariate linear regression also identified the percent change in NT-pro BNP ≥ 15%, after adjusting for baseline characteristics , as strongly associated with the percent change in ERO .Multivariate logistic regression showed, after adjustment for other baseline variables, that the percent change in NT-pro BNP is a good surrogate marker of response to CRT  per 1% of decrease in NT-pro BNP, p = 0.008). Similar results were found when adding CR in the multivariate models. When entering, the change in NT-pro BNP as a dichotomous variable in the multivariate logistic model, an absolute decrease in NT-pro BNP ≥ 277 pg.mlThe main finding of our study is that change in NT-pro BNP level between baseline and 3 to 6 months after CRT may be useful to identify (1) echocardiographic responders following CRT and (2) the magnitude of decrease in MR severity following CRT. Our results also confirm that change in MR severity after CRT implantation is related to the improvement in LV geometry. Furthermore, previous studies found that baseline LV viability is a strong predictor of LV performance following CRT -14. HencSeveral previous studies reported a significant decrease in natriuretic peptide following CRT implantation ,18-24. RMechanism underlying CRT benefit in patients with HF is related to reduction of LV dyssynchrony and corresponding stress-strain disparities and inefficient ventricle contraction. Ultimately, CRT significantly improves both LV function and geometry. This effect results in a decrease in mitral valve tethering and in a concomitant increase in mitral closing forces which, in turn, lead to significant improvement of MR severity. Furthermore, because electrical conduction and regional wall thickening are influenced by the extent of myocardial fibrosis, it has been hypothesized that long-term response to CRT could correlate with myocardial viability in patients with LV dysfunction.Using nuclear myocardial perfusion imaging (2C1Ti), magnetic resonance imaging, and DSE, several studies have demonstrated the importance of LV viability in predicting response to CRT -32. In aSeveral recent studies had underlined the crucial role of myocardial CR to allow LV reverse remodeling,16,29 anBNP is widely considered as useful marker for the diagnosis and prognosis of HF and may be helpful to guide medical management. The presence of high plasma BNP levels is associated with an increased risk of cardiac events and death in patients with chronic HF. The titration of HF treatment based on the reduction of plasma NT-pro BNP concentrations has been found to be superior to treatment with empirical trial-based therapy dictated by clinical judgment. NT-pro BNP is routinely used in patients with HF and is an accurate marker of LV and clinical status.Recently, Miller et al.  found inFurthermore, our results showed that NT-pro BNP is also a good surrogate marker to identify LV remodeling and MR reduction following CRT. More importantly, NT-pro BNP monitoring allows the clinician to accurately identify echocardiographic responders to CRT. Since LV remodeling predicts outcome with better accuracy than clinical improvement after CRT  and thatThe main limitation of this study is the relatively the small number of patients, which reduced the statistical power for multivariate analyses. In addition, the studied population had various LV dysfunction etiologies, including ischemic and non-ischemic myocardial dysfunction. Nevertheless, this also underlines that NT-pro BNP is reliable even in heterogeneous population of CRT patients. Dyssynchrony was defined by longitudinal TDI using a cut-off value of 50 ms on as inclusion criterion. Combining longitudinal and radial dyssynchrony index as inclusion criterion could have been helpful in choosing a more homogenous population prone to CRT response.Results of this study show that NT-pro BNP monitoring can accurately identify echocardiographic responders after CRT. Decrease in NT-pro BNP ≥ 15% during follow-up is a good surrogate marker of favourable LV remodeling and MR reduction following CRT. Monitoring of NT-pro BNP may be useful for the management of patients with HF and CRT.The authors declare that they have no competing interests.MS is the principal investigator, he conceived the study and participated in its design and coordination, he participated in the interpretation of the results and he drafts the manuscript; JM performed the statistical analysis, participated in the interpretation of the results and drafts the manuscript; MD participated in data collection, coordination of the study and helped to draft the manuscript; JC participated in the implantation of CRT and in the interpretation of pulmonary X rays for localization of CRT lead; JGD participated to interpreted the results and in the preparation of the manuscript, PP participate in the preparation of the manuscript; FP participated in the implantation of CRT; GO participated in the implantation of CRT; All authors read and approved the final manuscript.Movie representing an echocardiography pre CRT. This echocardiography is showing a severe mitral regurgitation (i.e. ERO = 42 mm2) in a patient with pre CRT BNP level of 1543 pg.ml-1.Click here for fileMovie representing an echocardiography post CRT. This echocardiography is showing a mild mitral regurgitation (i.e. ERO = 12 mm2) in a patient with post CRT BNP level of 1104 pg.ml-1 (decrease of 27%).Click here for file


Pulmonary regurgitation is a common and clinically important residual lesion after repair of tetralogy of Fallot. Cardiovascular magnetic resonance (CMR) phase contrast velocity mapping is widely used for measurement of pulmonary regurgitant fraction. Breath-hold acquisitions, usually acquired during held expiration, are more convenient than the non-breath-hold approach, but we hypothesized that breath-holding might affect the amount of pulmonary regurgitation.Forty-three adult patients with a previous repair of tetralogy of Fallot and residual pulmonary regurgitation were investigated with CMR. In each, pulmonary regurgitant fraction was measured from velocity maps transecting the pulmonary trunk, acquired during held expiration, held inspiration, by non-breath-hold acquisition, and also from the difference of right and left ventricular stroke volume measurements.vs. 37.0, 35.6, 35.4%, p = 0.00017, 0.0035, 0.026). The regurgitant volume was lower in held expiration than in held inspiration . Pulmonary forward flow volume was larger during held expiration than during non-breath-hold .Pulmonary regurgitant fraction was lower when measured by velocity mapping in held expiration compared with held inspiration, non-breath-hold or stroke volume difference (30.8 Pulmonary regurgitant fraction was significantly lower in held expiration compared with held inspiration, free breathing and stroke volume difference. Altered airway pressure could be a contributory factor. This information is relevant if breath-hold acquisition is to be substituted for non-breath-hold in the investigation of patients with a view to re-intervention. Over the last decades the prognosis in tetralogy of Fallot has improved dramatically. The long term survival after surgical repair is excellent ,2. ThereCardiovascular magnetic resonance (CMR) provides a valuable, arguably the best available tool for quantification of pulmonary regurgitation. Non-breath-hold velocity acquisitions during free breathing have been used as a gold standard for evaluation of pulmonary regurgitation ,8. FasteForty-three adult patients  with repaired tetralogy of Fallot were prospectively recruited from a dedicated Adult Congenital Heart Unit. Inclusion criteria were previous surgical repair of tetralogy of Fallot and clinical stability, without any significant residual shunt, pulmonary regurgitation with a regurgitant fraction > 5% and no contraindication for CMR. Patients with more than trivial regurgitation of the atrioventricular or aortic valves were excluded from the calculation of pulmonary regurgitant fraction by stroke volume difference. The mean age of the patients was 30.6 ± 9.5 and the anatomical reconstruction was performed at a mean age of 5.5 ± 5.6 years. All patients gave their written informed consent. The study was approved by the research ethics committee, Royal Brompton Hospital.All patients were investigated in a 1.5 T Siemens Sonata MR scanner . The scans included assessment of anatomy using contiguous stacks of 7 mm thickness multislice scout images in transaxial, coronal and sagittal orientations prior to acquisition of balanced steady state free precession (bSSFP) cine images and phase contrast velocity maps, as described below.A stack of bSSFP cine images was acquired in short axis planes at 10 mm intervals from the atrio-ventricular junction to the apex, located with respect to two- and four-chamber long axis cines. These cines were acquired during held expiration. End diastolic and end systolic volumes of both ventricles were measured by planimetry using Simpson's method using appropriate software . A single observer (SBN) performed all measurements as previously described .Transaxial scout images were used to locate an oblique sagittal bSSFP cine aligned with the right ventricular outflow tract as shown in Figure Velocity was encoded through a plane transecting the pulmonary trunk immediately downstream of the expected pulmonary valve level and proximal to the bifurcation Figure . This plBecause of the potential effect of branch stenosis on regurgitation, the multislice scouts were assessed for potential branch pulmonary artery stenoses, and where stenosis could not be excluded, bSSFP cines were aligned with the lumen of any suspected narrow region of the right and left pulmonary artery for qualitative assessment. Attribution of mild, moderate (or severe) degrees of branch stenosis relied on visual assessment of three factors: the degree of luminal narrowing, the formation and narrowness of a resulting jet, and the degree of damping of systolic arterial expansion distally.t-test was used. As multiple comparisons were performed, the p-value was corrected according to Bonferroni by multiplying the p-value with the number of comparisons. Only p-values less than 0.05 were regarded as significant. All calculations were performed using the SPSS 11.5 statistical software .Data are presented as means and standard deviations. To compare means a paired vs. 37.0 ± 13.6, 35.6 ± 11.4, 35.4 ± 11.0%, p < 0.00017, 0.0035, 0.026). There was no significant difference between the pulmonary regurgitant fraction in held inspiration, free breathing and stroke volume difference. A typical example of the flow patterns is shown in Figure The pulmonary regurgitant fractions calculated by the four different methods are shown in Figure vs. 48.3 ± 22.8, p = 0.0018). There was no significant difference between regurgitant volume in held inspiration, free breathing or calculated from stroke volume difference.The regurgitant volumes obtained by velocity maps and ventricular stroke volume difference are shown in Figure vs. 123.6 ± 30 ml, p = 0.0024). There was no significant difference between the forward flow volumes measured in held inspiration or during free breathing, or between either of these and the RV stroke volumes measured by planimetry.The pulmonary forward flow volumes obtained by velocity mapping and planimetric right ventricular (RV) stroke volumes are shown in Figure Evidence of no more than mild residual pulmonary stenosis was identified by analysis of velocities through the suprapulmonary plane indicated in Figure Pulmonary regurgitation is relatively common after surgery for congenital heart disease with RV outflow obstruction, as is a degree of residual pulmonary stenosis. These are patients in whom serial measurements can inform decisions on management and the consistency and comparability of measurements is important. More rapid and convenient breath-hold acquisitions are likely to be used increasingly for the investigation and follow-up of pulmonary regurgitation. As far as we know, it is common practice for held expiration to be used for breath-hold acquisitions as this has been considered to give a more reproducible and sustained diaphragm position than held inspiration in various imaging situations -12. Chilprocesses of expiration or inspiration. According to our usual clinical practice, we had instructed patients, speaking slowly, either to 'breathe in and hold' or to 'breathe in and breathe out and hold' before the respective acquisitions. Ley et al. investigated the effects of 'large volume inspiratory breath-hold and expiratory breath-hold' velocity acquisitions on pulmonary and aortic flow parameters in healthy volunteers, comparing the results to those acquired during free breathing. They found pulmonary blood flow to be reduced during (deep) inspiratory breath-hold, and less so during expiratory breath-hold, compared with free breathing [We found that a lower regurgitant fraction was measured when the breath was held at end expiration, and that increased forward flow volume and decreased regurgitant volume both appeared to contribute. The underlying mechanisms remain uncertain, but the marked effect of pulmonary airway pressure on regurgitation reported by Redington  is likelreathing . We are The differences between the regurgitant fractions measured by expiratory breath-hold velocity mapping and those by stroke volume difference, which also used expiratory breath-hold acquisitions, must have a different explanation, however. The two approaches do not necessarily measure the same thing. While the former is calculated from the pulmonary regurgitant volume expressed as a percentage of pulmonary forward flow, the latter is calculated from the stroke volume difference expressed as a percentage of the RV stroke volume. The stroke volume difference could be more than the pulmonary regurgitant volume if there were also undetected tricuspid regurgitation, and the RV stroke volume will be less than the pulmonary forward flow if there is late diastolic forward flow, which has been referred to as 'restrictive RV physiology' . As we uRegardless of the underlying mechanisms, the finding that pulmonary regurgitant fraction measurements may be lower when measured in held expiration than when measure during held inspiration, free breathing or by stroke volume difference remains important. For comparative studies, either serially or between patients, adherence to one type of acquisition and one type of breathing instruction are likely to be necessary.Measurements of flow by phase velocity mapping can be subject to errors, for example due to eddy currents and uncorrected Maxwell gradients, especially when gradients are switched rapidly to achieve short echo times for breath-hold acquisition ,17. SuchIn our centre we have used expiratory breath-hold velocity acquisitions for measurements of pulmonary regurgitation for over five years. Initially this was as an adjunct to non-breath-hold acquisitions, but subsequently as our preferred approach, given the advantages of time-saving and avoidance of respiratory motion related artefacts. However, we do not feel that a recommendation can be made for all centres or CMR systems, except that methodological consistency is important. Users should be aware of the potential affect on measurements should a transition be made from one method to another. The method used for a particular measurement of pulmonary regurgitation should be stated when the result is reported.The authors declare that they have no competing interests.BJ participated in the study, analysed the data and drafted the manuscript. SVB-N acquired the data and, with PJK, conceived, designed and coordinated the study. All authors contributed to, read and approved the final manuscript.


There has in recent years been great concern about possible cardiac side effects of thiazolidinediones (TZDs). We present a case-report of a 60 year-old male who developed significant mitral regurgitation during six months treatment with pioglitazone in parallel with laboratory indications of fluid retention. Echocardiography six months after discontinuation of medication showed regression of mitral regurgitation and the laboratory parameters were also normalized. It is noteworthy that six months treatment with pioglitazone could induce significant valve dysfunction, which was reversible, and this underlines the importance of carefully monitoring patients when placing them on treatment with TZDs. There is an ongoing discussion concerning the possible effects of thiazolidinediones (TZDs) on the heart. In a recent meta/teleo-analysis Singh et al concluded that heart failure might occur at both high and low doses, usually weeks to months after initiating TZDs and in patients without a history of heart failure .The patient is a sixty-year-old man with type 2 diabetes known since 15 years. He has proliferative retinopathy and microalbuminuria, no history or clinical signs of cardiovascular disease, stopped smoking 30 years ago. Failure to achieve optimal glycaemic control on treatment with 850 mg metformin/day (reduced dose because of elevated creatinine) and glimepiride 6 mg/day was evident with HbA1c >10%. The patient entered an ongoing study. He received add-on treatment with pioglitazone 30 mg/day that was increased after 16 weeks to 45 mg/day since HbA1c was 8.3% and no side effects were recorded. Standard transthoracic echocardiography examinations were performed with Sonos 5500  at baseline (15/12 2006), after six months pioglitazone therapy (25/6 2007), and six months after discontinuation of pioglitazone (20/12 2007). Cardiac size and volumes were quantified according to current guidelines [This case-report highlights the importance of careful monitoring of patients under treatment with TZDs. In this case, changes in haemoglobin and BNP indicated fluid retention in the absence of clinical signs or symptoms of cardiopulmonary stress or oedema. What caused the mitral regurgitation? One plausible hypothesis is that the fluid retention caused left ventricular dilatation which in turn resulted in mitral annular dilatation and to altered papillary muscle orientation, which then leads to inadequate mitral leaflet coaptation. Mitral regurgitations that are caused by left ventricular dilatation tend to have a central jet, as in our patient. It is, however, possible that there was some structural weakness in the mitral valve apparatus that was not detected on the transthoracic echocardiography examinations and that this could in part be contributing to the regurgitation. There is a need for tools to help clinicians to identify subsets of patients for whom this kind of therapy is likely to have particularly favourable/unfavourable effect, using readily identifiable clinical and laboratory factors. BNP, being a peptide hormone released from the cardiac ventricles in response to myocyte stretch have generated a lot of attention in recent years and have been proposed as potential diagnostic and prognostic marker for cardiac disease but currently there are no clear algorithms on how this should be implemented into clinical practice. However, the knowledge is increasing in this field and hopefully the results will enable clinicians to select proper therapy for individual patients in future.BNP: Brain natriuretic peptide; LVDD: Left ventricular end-diastolic diameter; LVSD: Left ventricular end-systolic diameter; IVS: End-diastolic inter-ventricular septum; Post: End-diastolic posterior wall; LA: Left atrial end-systolic diameter; LV diastolic: Left ventricular end-diastolic volume; LV systolic vol: Left ventricular end-systolic volume; EF: Ejection fraction; LA vol: Left atrial volume; E/A: Indices of left ventricular diastolic function; E/Em: estimation of left ventricular filling pressure.The authors declare that they have no competing interests.MDo and AF conceived the idea to write this manuscript. MDe performed the echocardiography examinations. All authors wrote, and edited this manuscript together.


Cynodon dactylon are used for the treatment of heart failure in folk medicine. In the present study, we investigated the effects of hydroalcoholic extract of C. dactylon rhizomes on cardiac contractility in normal hearts and on cardiac functions in right-heart failure in rats.The rhizomes of Right-heart failure was induced by intraperitoneal injection of monocrotaline (50 mg/kg). Two weeks later, the animals were treated orally with different doses of the extract for fifteen days. At the end of the experiments cardiac functions and markers of myocardial hypertrophy were measured.C. dactylon in monocrotaline-injected rats led to profound improvement in cardiac functions as demonstrated by decreased right ventricular end diastolic pressure (RVEDP) and elevated mean arterial pressure. RVdP/dtmax, and RVdP/dt/P as indices of myocardial contractility were also markedly  increased by the extract. The extract reduced heart and lung congestion by decreasing tissue wet/dry and wet/body weight ratios (p < 0.01). In the isolated rat hearts, the extract produced a remarkable (P < 0.001) positive inotropic effect concomitant with a parallel decrease in LVEDP.The treated rats showed very less signs of fatigue, peripheral cyanosis and dyspnea. The survival rate was high in the extract treated groups (90%). Administration of C. dactylon exerted a strong protective effect on right heart failure, in part by positive inotropic action and improving cardiac functions.The results of this study indicated that  Cynodon dactylon (L.) pers. , also known as Bermuda grass, Devil's Grass, Couch Grass, Triticum repens, and Indian Doab, is a resilient and perennial grass native to the warm temperate and tropical regions [C. dactylon is claimed to have antidiabetic, antimicrobial [C. dactylon is named "chayer" and the aqueous extract obtained from its rhizomes is used as a cardiac tonic in heart failure and mostly believed that the extract has very curative effect on heart congestion diseases. The presence of glycosides and flavonoids has been shown in the alcoholic extract of the plant [C. dactylon rhizomes has a potential protective effect against ischemic/reperfusion injury and improves recovery from the reperfusion insult in isolated rat heart [C. dactylon on heart failure has not been elucidated to date. Among the most widely studied animal models of right ventricular hypertrophy and failure is the administration of monocrotaline (MCT), which produces a relatively rapid (within a few weeks) pulmonary hypertension resulting in compensatory right ventricular hypertrophy and failure [C. dactylon rhizomes on myocardial responses in right ventricular heart failure as well as on cardiac contractility in isolated normal rat hearts.Heart failure is a condition that impairs the ability of the heart to pump a sufficient amount of blood through the body. Treatment strategies have been focused mainly on the use of diuretics and cardiac glycosides. Although, such therapies relieve symptoms of the disease and stabilize patients but rarely improve survival . In addi regions ,6. It isicrobial , hypolipicrobial , anti-inicrobial  propertiicrobial . The rooicrobial . It has icrobial . In Northe plant  and its at heart . To our  failure ,16. The C. dactylon were collected from the fields of Maragheh (Iran) in November and voucher samples were preserved for reference in the Herbarium of Department of Pharmacognosy, School of Pharmacy, Tabriz University of Medical Sciences. Powdered rhizomes (400 g) were extracted by maceration in MeOH/H2O  at room temperature for 3 days. The hydroalcoholic extracts were combined and concentrated in vacuo to yield 27 g dried extract. This hydroalcoholic extract was kept in refrigerator for all experiments.Rhizomes of C. dactylon rhizomes was screened for the presence of different classes of compounds using the standard methods by some modifications [254, 0.25 mm) to confirm the results of screenings [The crude extract of ications ,18. Thinreenings . The folreenings ,20. Sincreenings .C. dactylon rhizomes was fractionated by solid-phase extraction (SPE) method. The total extract (2 g) was dissolved in minimum possible volume of 20% of MeOH/H2O mixture and adsorbed on Sep-Pak  cartridge and eluted by step gradient of MeOH/H2O mixtures . The high content fractions (20% and 40%), based on weight, were characterized by HPLC finger print. The fractions dissolved in mobile phase and 20 μl of the samples were injected into the reverse phase column (C18). The mobile phase consisted of a gradient of 0–35% (over 35 min), 35–55% (over 15 mhn), and 55-0% (over 10 min) methanol in water (V/V) and was delivered at a flow rate of 1 ml/minute. The detection was performed at three wavelengths of 220, 280, and 350 nm.The dried total extract of Male Wistar rats  were used in this study. The animals were given food and water ad libitum. They were housed in the Animal House of Tabriz University of Medical Sciences at a controlled ambient temperature of 25 ± 2°C with 50 ± 10% relative humidity and with a 12-h light/12-h dark cycle. This study was performed in accordance with the Guide for the Care and Use of Laboratory Animals of Tabriz University of Medical Sciences, Tabriz-Iran .C. dactylon rhizomes orally, twice daily continued for fifteen days. The extracts were suspended in CMC (0.5%). At the end of the experiments (4 weeks), hemodynamic measurements were taken and then the animals were sacrificed under deep anesthesia, and their hearts and lungs were removed. To assess the direct cardiac effects of the extract, in the other sets of experiments, wistar rat hearts (n = 6) were removed and mounted on a Langendorf apparatus and were exposed to different concentrations of the extract. Left ventricular developed pressure (LVDP), Left ventricular end diastolic pressure (LVEDP), and heart rate (HR) were recorded continuously during the experiment.Animals were randomized into six groups of 10 rats in each. Group 1  received an intraperitoneal (i.p) injection of physiological saline (0.5 ml) and untreated for the whole period of the experiment (4 weeks). Group 2 was injected (i.p) a single dose of monocrotaline   and two dP/dtmax and RV dP/dt/P as two indices of myocardial contractility were also calculated from RVSP. All parameters were continuously recorded using Powerlab system .Four weeks after MCT injection, the animals were anaesthetized with sodium pentobarbital . When the rats no longer responded to external stimuli, the trachea was cannulated for artificial respiration and systemic arterial blood pressure was recorded from a catheter inserted into the left carotid artery. A standard limb lead I ECG was monitored continuously throughout the experimental period. Mean Arterial Pressure (MAP) was calculated from the systolic and diastolic blood pressures trace. Heart rate (HR) was calculated from the ECG . After rFollowing the hemodynamic measurements, animals were sacrificed by an overdose of pentobarbital. The hearts, lungs, livers, and kidneys were removed and weighed. Then, the tissues were cut into small pieces for drying at 55°C until a constant weight was reached. Wet to body weight ratios and wet to dry weight ratios of the tissues were calculated to assess the degree of the congestion.3 25.0, KCl 4.8, MgSO4 1.2, KH2PO4 1.2, CaCl2 1.7 and D-glucose 12.0. All solutions were gassed with 95% O2/5% CO2 with pH maintained between 7.35 and 7.45 at 37°C. Temperature was continuously monitored by a thermo-probe inserted into the pulmonary artery and maintained between 36.5 and 37.5°C. A latex, fluidfilled, isovolumic balloon was introduced into the left ventricle through the left atrial appendage and connected to a pressure transducer  and HR, LVDP, and LVEDP were recorded with a Narco Bio physiograph  [Rats were anaesthetized with sodium pentobarbital  and given heparin sodium (300 IU). Hearts were rapidly excised and placed in ice-cold buffer and mounted on a constant pressure (100 mmHg) Langendorff-perfusion apparatus. They were perfused with modified Krebs-Henseleit bicarbonate buffer containing (in mM): NaCl 118.5, NaHCOms, USA) . The heaData were presented as mean ± SD. Comparisons between groups were made with Student's paired t-test or one way ANOVA as appropriate. If ANOVA analysis indicated significant differences, a Student-Newman-Keuls post test was performed to compare mean values between treatment groups and control. Differences between groups were considered significant at p < 0.05.C. dactylon contain significant amounts of sugars, flavonoids, sterols and steroidal saponins while, the trace amount of alkaloids were also detectable. The presences of all above mentioned phytoconstituents have been reported previously [C. dactylon rhizomes demonstrated different pattern  close to the control value of 60 ± 5.5 mmHg  and lower rate of pressure change at a fixed ventricular pressue (RV dP/dt/P)  was significantly decreased from 63 ± 8 mmHg in control to 31 ± 3.5 mmHg in MCT group  was obtained by 100 μg/ml of the extract Figure . The posC. dactylon are being used traditionally for the treatment of congestive heart failures in some parts of Iran. However, little is known about its cardioprotective actions in cardiovascular diseases. In the present study, we investigated the therapeutic efficacy of the hydroalcoholic extract of rhizomes of the plant in rats with right heart failure induced by monocrotaline. Monocrotaline produces its effects primarily by injuring pulmonary vessels endothelium, resulting in pulmonary arterial pressure [C. dactylon is mainly due to the inhibition of the compensatory myocardial responses to MCT-induced pulmonary hypertension. The animals on C. dactylon treatment fared better than their untreated counterparts and exhibited an obvious improvement in their appearance and physical activity. Symptoms such as cyanosis, tachypenea, and dyspnea were almost disappeared in the most of the animals treated with the high dose of the extract. In addition, the beneficial effects were also clearly observed with respect to a variety of indices, including reduced myocardial hypertrophy, improved cardiac function, positive inotropic action, increase in myocardial contractility force, and parallel decrease in right ventricular end diastolic pressure. Furthermore, direct effect of hydroalcoholic extract of C. dactylon rhizomes on isolated rat hearts demonstrated that the extract produce a dose dependent and very significant increase of the contraction force by increasing the left ventricular developed pressure (LVDP) and parallel decrease of end diastolic pressure (LVEDP) and heart rate. In the treatment of heart failure it is very beneficial to improve the contractility of the heart and at the same time decrease the end diastolic pressure. Our preliminary phytochemical finding in this study revealed the presence of sugars, flavonoids, sterols and steroidal saponins in the hydroalcoholic extract obtained from C. dactylon rhizomes. Reactive oxygen species have been implicated in the progression of ventricular hypertrophy to congestive heart failure [Rhizomes of pressure . MCT-indpressure . In this failure . Plant f failure ,31. FurtC. dactylon in rats with compensated right heart failure. We speculate that the extract produce its protective effects at least in part by direct improvement of cardiac performance. However, the precise mechanism for the salutary effect of C. dactylon on compensatory myocardial response needs to be determined especially in view of the right ventricular heart failure nature and finding the active ingredient(s).The results of this study showed the beneficial effect of The authors declare that they have no competing interests.AG designed and coordinated the study and also drafted the manuscript. AA carried out the hemodynamic measurements and the heart failure experiments. HN collaborated in the phytochemical procedures. MN helped in the animal experiments and acquisition of data. AK carried out the isolated heart perfusion experiments. NMD has been involved in revising the manuscript and performed the statistical analysis. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Clinical data on myocardial function in HCM mutation carriers (carriers) is sparse but suggests that subtle functional abnormalities can be measured with tissue Doppler imaging before the development of overt hypertrophy. We aimed to confirm the presence of functional abnormalities using cardiovascular magnetic resonance (CMR), and to investigate if sensitive functional assessment could be employed to identify carriers.-1 was present in 45% of carriers and in none of the controls, yielding a positive predictive value of 100%. Two carriers and 18 controls had a SL ratio < 1.2 and peak DCSR >105%.s-1, yielding a negative predictive value of 90%. With multivariate analysis, HCM mutation carriership was an independent determinant of reduced peak SCS and peak DCSR.28 carriers and 28 controls were studied. Global left atrial (LA) and left ventricular (LV) dimensions, segmental peak systolic circumferential strain (SCS) and peak diastolic circumferential strain rate (DCSR), as well as the presence of late Gadolinium enhancement (LGE) were determined with CMR. Septal and lateral myocardial velocities were measured with echocardiographic tissue Doppler imaging. lv mass and volumes were comparable between groups. Maximal septal to lateral wall thickness ratio (SL ratio) was larger in carriers than in controls . Also, LA volumes were larger in carriers compared to controls (p < 0.05). Both peak SCS (p < 0.05) and peak DCSR (p < 0.01) were lower in carriers compared to controls, particularly in the basal lateral wall. Focal LGE was present in 2 carriers and not in controls. The combination of a SL ratio >1.2 and a peak DCSR <105%.sHCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers. Hypertrophic cardiomyopathy (HCM) is a relatively common cardiomyopathy with an estimated prevalence of 1:500 in the general population -4. This Limited clinical data is available on regional myocardial function in human HCM mutation carriers (carriers) when wall thickness is still within normal limits. Several studies using tissue Doppler imaging with echocardiography demonstrated that predominantly diastolic myocardial velocities were reduced prior to the development of manifest hypertrophy ,9. HowevThe high spatial and temporal resolution of cardiovascular magnetic resonance (CMR) and its well developed capabilities to assess morphology and intramural myocardial deformation, are of specific interest to evaluate the regional function of human carriers with normal wall thickness ,12.In this study, we investigate whether segmental systolic and diastolic myocardial dysfunction is detectable with CMR and can be used to identify carriership in carriers with normal left ventricular (LV) wall thickness when compared to controls.Carriers were included in whom LV wall thickness was less than 10 mm measured by routine echocardiography within one year before entering the study . All carAs a control group, age and gender matched non-smoking healthy volunteers were selected who had no medical history, no known familial cardiac disease, no obesity and normal blood pressure. Family members of the carriers without the pathogenic mutation, who met the inclusion criteria of healthy volunteers, were also included. Study participants had to be in sinus rhythm, and free from standard exclusion criteria for CMR. In all participants, standard physical examination, CMR and echocardiography were performed.The study was approved by the institutional medical ethics committee and conducted according to the declaration of Helsinki. Written informed consent was obtained from all participants before entering the study.CMR was performed on a 1.5-Tesla whole body scanner , using a six-channel phased-array body coil. All cine studies were acquired in a single breath hold of 8-10 seconds during mild expiration.After survey scans, a retro-triggered, balanced, steady-state free precession gradient-echo sequence was used for cine imaging. A cine dataset fully covering the left atrium (LA) and LV was acquired as described previously . Image pA multiple breath-hold, retrospective triggered balanced steady state free precession myocardial sinus tagging sequence was obtained using the linearly increasing start-up angle approach . Three L-1 gadolinium-dtpa [Late gadolinium enhancement (LGE) images were obtained 10-15 minutes after injection of 0.2 mmol·kgium-dtpa . A singlCine images where analyzed off-line, using MASS analysis software  blinded for genotypes. From the LA cine dataset, LA volumes were calculated from manually drawn endocardial contours in every phase of the cardiac cycle, excluding the pulmonary veins and including the LA appendage, as described previously . LA maxiOn the LV cine data set, epi- and endocardial contours were manually drawn in end-diastole and end-systole. Global LV parameters, including LV end-diastolic (ED) volume, LV end-systolic volume, stroke volume, LV ejection fraction (lvef) and LV mass were determined. Also, LV mass to LV volume ratio in end-diastole was determined . All volFor segmental analysis, the basal, mid and apical LV cine slices best corresponding with the myocardial tissue tagging slices were selected. These three slices were subdivided into 16 segments - excluding the apex- according to the standardized myocardial segmentation for tomographic imaging of the heart . Per LV Offline analysis of the myocardial tissue tagging images was performed with in-house developed software, programmed in a matlab 7.1(R14) environment , as described previously . SegmentFrom these segmental circumferential strain datasets, the following parameters were determined: peak systolic circumferential strain (peak SCS) and peak diastolic circumferential strain rate (peak DCSR).CMR study to minimize the effect of differences in physiological conditions of the participants between echocardiographic and CMR measurements.Echocardiography was performed using a General Electric Vivid-7  ultrasound system. Echopac  was used for offline analysis of recordings. Values of presented parameters are the means of 3 recorded measurements per parameter. The echocardiogram was performed immediately before or after the Colour tissue Doppler imaging was performed on an apical 4-chamber view using a 2.5-MHz transducer and frame rates over 80/second. Systolic, early diastolic and late diastolic peak myocardial velocities of the septal and lateral mitral valve annulus corner were obtained by placing a 6-mm sample volume at the junction of the mitral annulus at septal and lateral myocardial wall. The angle of incidence between the scan lines and motion of the base of the heart was minimized.All data are presented as mean ± standard deviation. The unpaired Student's t-test was used for comparison of normally distributed global LV and LA parameters between carriers and controls or a non-parametric Mann-Whitney U test when appropriate.For segmental analysis, ED wall thickness, wall thickening, peak SCS and peak DCSR were compared between carriers and controls. While interdependency of segments was considered within slices and patients, multilevel analysis allowing random intercepts was performed. With multiple regression analysis, the effect of HCM carriership, age, gender, ED wall thickness and ED wall radius on wall thickening, peak SCS and peak DCSR was evaluated, correcting for interdependency of segments. Pearson's correlation coefficient was used to describe bivariate correlations between continuous variables. All regression models were evaluated for interaction of main effects. Evaluation of within slice differences of segmental parameters was performed with a one-way anova, using the Bonferroni post-hoc test for multiple comparisons. The Bland-Altman method for agreement analysis was used to evaluate the intra- and interobserver agreement of the strain data . Also, tIn total, 28 carriers 11 males) from nine different families were included, of whom 22 (79%) had a myosin binding protein C3 founder mutation (MYBPC3) (2327insG) and 6 21%) an α-tropomyosin mutation (Glu62Gln) ,21. Fift% an α-tr1 males fBoth LA minimum and LA maximum volume were larger in carriers compared to controls (p < 0.05) but LA passive emptying and LA active emptying were comparable, see table All data per segment are presented in Additional file Averaged ED wall thickness was comparable between carriers and controls . In both septal segments of the basal slices, ED wall thickness was larger in carriers compared to controls , see figure In both basal septal segments, wall thickening was lower in carriers compared to controls . In the lateral segments, wall thickening was comparable between groups, see figure No significant differences in averaged peak SCS were observed between carriers and controls. Peak SCS was lower only in the basal inferolateral segment in HCM carriers compared to controls , see figure Multilevel regression analysis showed that HCM mutation carriership, , gender  and ED wall thickness  were all independent predictors of peak SCS. There was no interaction of main effects. The effect of ED wall radius on peak SCS was significantly larger in controls (p < 0.05) compared to carriers; regression coefficients β were -0.19 ± 0.03 (p < 0.001) and -0.11 ± 0.04 (p < 0.01) respectively, indicating that an increase in ED wall radius was related to larger peak SCS. This effect was stronger in controls compared to carriers (p < 0.05).-1 versus 115 ± 17%·s-1, p < 0.001). In addition, the difference in peak DCSR between carriers and controls was largest in the basal lateral segments , see figure Averaged peak DCSR was lower in all slices in carriers, especially in the basal slice , gender  and ED wall thickness  were all independent determinants of peak DCSR. Again, ED wall radius was an independent determinant of peak DCSR in controls (p < 0.001), but not in carriers.The effect of ED wall thickness on segmental functional parameters is illustrated in figure Septal and lateral systolic, early diastolic and late diastolic velocities assessed with tissue Doppler imaging were comparable between both groups in our study population, see table -1 for peak DCSR within the lateral wall yielded a sensitivity, specificity, positive and negative predictive value was 58%, 80%, 73% and 65% respectively. As presented in figure -1 versus 18 (72%) of controls, p < 0.001, yielding a negative predictive value of 90%. Seven carriers (28%) had a SL ratio >1.2 and peak DCSR >105%.s-1 versus 3 controls . In addition, 11 carriers (45 percent) had a SL ratio >1.2 ánd a peak DCSR <105%.s-1 versus none of the controls, p < 0.001, yielding a positive predictive value of 100%. Thus, combining both functional and morphological parameters increases the accuracy to identify carriers, but does not completely exclude HCM mutation carriership.Receiver operator characteristics analysis identified both SL ratio and peak DCSR of the lateral wall of the basal segment as valuable parameters to discriminate carriers from controls. Area under curve of SL ratio and basal inferolateral peak DCSR were comparable . Using an optimal cut-off value of 1.2 for SL ratio yielded a sensitivity, specificity, positive and negative predictive value of 75%, 88%, 81% and 77% respectively. An optimal cut-off value of 105%.sThis is the first study that used CMR to assess global LA and LV volumes and regional intramural myocardial function in carriers with normal wall thickness. The asymmetry in wall thickness between the septum and lateral wall, which is characteristic for HCM, was already present in these carriers with normal wall thickness. Typical focal LGE was present in 2 carriers. Also, LA volumes were larger in carriers. In addition, HCM mutation carriership was identified as an independent determinant of reduced peak SCS and peak DCSR, which was predominantly present in the basal lateral segments. Peak DCSR further deteriorated with increase in wall thickness. Using both the SL ratio and peak DCSR for identification of carriers had a high accuracy to identify carriers, but did not completely exclude HCM mutation carriership.The finding of myocardial dysfunction in carriers with normal wall thickness supports the hypothesis that the hypertrophy in HCM represents a compensatory mechanism in response to abnormal intrinsic myocardial mechanical properties, as has been stated previously ,8,9. In A study performed by Nagueh and co-workers, who also measured myocardial function with tissue Doppler imaging in a small cohort of HCM mutation carriers, found that both systolic and diastolic myocardial velocities were reduced . However2+ sensitivity of the myofilaments is increased, thereby enhancing initial contractility but reducing myocardial relaxation [Therefore, diastolic dysfunction seems to be the earliest clinically detectable functional alteration as a result of the mutation. This is in line with experimental data on functioning of mutated sarcomeric proteins in a HCM model, which demonstrate that as a result of the HCM mutation, Calaxation -26. AfteIn previous observations, we found in that peak SCS was largest in the inferolateral segments of the LV in healthy volunteers . In thisThe reduction of regional peak DCSR was further enhanced with increase in ED wall thickness. It is unlikely that replacement fibrosis plays an important role in the deterioration of diastolic function in carriers with increase of ED wall thickness. However, diffuse interstitial fibrosis and/or myocyte disarray cannot be visualized with LGE imaging, so the attribution of these histological hallmarks of HCM on the development of diastolic dysfunction still needs to be further investigated. New promising CMR techniques have been developed that allow quantification of diffuse interstitial fibrosis. This would enable us to quantify the total fibrotic burden of the LV in HCM patients . In this-1 had a positive predictive value of 100% for carriership. Having a SL ratio <1.2 and a peak DCSR >105%.s-1 had a negative predictive value of 90 percent. Therefore, functional abnormalities alone are not specific enough to be used to exclude HCM mutation carriership when screening asymptomatic family members of HCM patients in whom no mutation has yet been identified.Since HCM is relatively uncommon with an estimated prevalence in general population of 1:500, screening for carriers is only efficient in first degree, asymptomatic family members of HCM patients, who have a 50 percent pre-test likelihood of disease. In this preselected population, the presence of both a SL ratio >1.2 and a peak DCSR in the lateral segments <105%.sSince structural abnormalities, as well as focal areas of LGE have also been described in carriers with normal wall thickness, we advocate to also include evaluation of morphology and presence of LGE when screening for carriers to increase the accuracy of screening ,29,30. INot all circumferential strain data were analysable, which may potentially have introduced a selection bias of the results. Also, baseline diastolic blood pressure was significantly lower in carriers, which may be related to the selection of carriers without LV hypertrophy. Study numbers are limited, which may have caused non-significant results due to insufficient power. Also, we only evaluated 2 mutations. Yet, these mutations in these genes account for approximately 25% of the total HCM population in the Netherlands, and about 20% of HCM patients worldwide . The sliHCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers.Carriers: hypertrophic cardiomyopathy mutation carriers; CMR: cardiovascular magnetic resonance; ED: end diastolic; HCM: hypertrophic cardiomyopathy; LA: left atrial; LGE: late gadolinium enhancement; LV: left ventricular; LVEF: left ventricular ejection fraction; MYBPC3: myosin binding protein C3; peak DCSR: peak diastolic circumferential strain rate; peak SCS: peak circumferential strain rate; SL ratio: maximal septal-to-lateral wall thickness ratio.The authors declare that they have no competing interests.TG - development of concept, gathering data, writing the manuscript. IKR - development of myocardial tagging quantification software, analysis of data, writing part of the methods section. MJWG - development of concept, writing part of the discussion section, critical revision of intellectual content. MDS - statistical analysis of data. PAD - development of concept, critical revision of intellectual content. RJvdG - development of software to measure en-diastolic wall radius, critical revision of intellectual content. YMP - development of concept, patient selection, critical revision of intellectual content. JvdV - development of concept, writing parts of the discussion section. AAMW - development of concept, patient selection, critical revision of intellectual content. ACvR - development of concept, chair of department, critical revision of intellectual content, final approval of manuscript submitted All authors read and approved the final manuscript.Appendix A. segmental data of carriers and controlsClick here for file


T2-Weighted (T2W) magnetic resonance imaging (MRI) pulse sequences have been used to detect edema in patients with acute myocardial infarction and differentiate acute from chronic infarction. T2W sequences have suffered from several problems including (i) signal intensity variability caused by phased array coils, (ii) high signal from slow moving ventricular chamber blood that can mimic and mask elevated T2 in sub-endocardial myocardium, (iii) motion artifacts, and (iv) the subjective nature of T2W image interpretation. In this work we demonstrate the advantages of a quantitative T2 mapping technique to accurately and reliably detect regions of edematous myocardial tissue without the limitations of qualitative T2W imaging.in vivo imaging. The optimized protocol was used to study the spatial, view-dependent, and inter-subject variability and motion sensitivity in healthy subjects. Using the insights gained from this, the utility of T2 mapping was demonstrated in a porcine model of acute myocardial infarction (AMI) and in three patients with AMI.Methods of T2 mapping were evaluated on phantoms; the best of these protocols was then optimized for T2-prepared SSFP demonstrated greater accuracy in estimating the T2 of phantoms than multi-echo turbo spin echo. The T2 of human myocardium was found to be 52.18 ± 3.4 ms (range: 48.96 ms to 55.67 ms), with variability between subjects unrelated to heart rate. Unlike T2W images, T2 maps did not show any signal variation due to the variable sensitivity of phased array coils and were insensitive to cardiac motion. In the three pigs and three patients with AMI, the T2 of the infarcted region was significantly higher than that of remote myocardium.Quantitative T2 mapping addresses the well-known problems associated with T2W imaging of the heart and offers the potential for increased accuracy in the detection of myocardial edema. Many pathologic conditions alter the myocardial tissue water content, which in turn alters the T2 relaxation time. Higgins et al.  showed iin vivo studies have measured the T2 of healthy human myocardium  demonstrate a practical T2-mapping method based on T2p-SSFP that minimizes the problems of current T2W imaging methods; ii) report a comprehensive analysis of T2 computed over the entire myocardium vis-à-vis variation across slice positions and orientations, subjects, and myocardial segments; iii) demonstrate this technique in a porcine model of AMI, and in patients with AMI. We hypothesize that quantitative T2-mapping addresses the limitations of qualitative T2W imaging and provides a practical and accurate method of assessing myocardial edema associated with acute ischemia, infarction, and other pathological conditions affecting myocardial water content.The T2-mapping pulse sequence was developed on a 1.5 T MR system ; the T2-map calculation algorithm was implemented in MATLAB . In all hypotheses testing, a p-value < 0.05 was considered statistically significant. All analyses were performed using MINITAB statistical software package .T2P = 0 ms, 24 ms, 55 ms). Table A T2-prepared steady-state free precession sequence  was usedThe T2-prepared single-shot SSFP sequence was similar to that described by Huang et al. . The T2 T2 maps were generated by fitting the following two-parameter equation to corresponding pixels from each of the three images:S is signal intensity, M0 is a lumped parameter that includes the equilibrium magnetization and local receiver coil gain, and TET2P is the T2 preparation time. The above equation was fit using a linear 2-parameter model after logarithmic transformation. To minimize breath-hold duration (and thus patient discomfort), we limited the number of TET2P times to three, the minimum required for a linear least-squares fit. A wait time of 2 RR intervals was inserted between images to allow for sufficient relaxation; thus, a total of 7 RR intervals were required to acquire the three T2p images. The sequence timing was adjusted for each T2p time to ensure that the SSFP readout was always timed to the same phase of the cardiac cycle. The entire scheme (image acquisition + T2 map generation) is depicted in Figure where T2P times  were chosen based on the expected range of T2 values in the myocardium. Recent work . TET2P = 24 ms was the minimum time permitted by the preparation scheme and was chosen as an intermediate point on the curve to support a least-squares fit.The TEe et al.  showed t2 and agar [T2P images were compared to evaluate the influence of T1 recovery on the accuracy of the T2 maps. The phantom T2's were also measured using a conventional multi-echo turbo spin echo (MESE) approach to compare it's accuracy with T2p-SSFP. Two MESE protocols were used: 2 echoes  and 3 echoes   and three patients  gave written informed consent to participate in this HIPAA-compliant study approved by the institution's Human Subjects Committee; the animal study was approved by the Institutional Laboratory Animal Care and Use Committee.With the insights gained from phantom studies, six healthy volunteers were studied first to evaluate the differences between linear and centric ordering of the T2p-SSFP acquisition. Thereafter, the chosen k-space ordering scheme was used to investigate the Linear and centric k-space ordering were compared in six healthy subjects. A mid-ventricular short-axis (SAX) slice was scanned in each subject using both k-space orderings. The resulting mean T2 values and mean spatial T2 variation were compared. Coefficient of variation was used as a measure of spatial variation.In fourteen additional normal subjects the following slices were imaged: 3 SAX at basal, mid and apical levels of left ventricle, horizontal long axis (HLA) and vertical long axis (VLA). The imaging parameters are described in Table Using these data , inter-subject and spatial variability were assessed as described in following paragraphs.ANOVA was performed to test inter-subject T2 variability. To test for spatial variability of T2 in the short-axis images from the 14 subjects , the data was first adjusted against inter-subject variability by subtracting the mean T2 of the subject from the segment T2 values; variance of T2 across subjects was assumed to be equal. ANOVA was performed to test the hypothesis of equal mean among the 16 segments. Coefficient of variation was used as a measure of variability. Additionally, a simple linear regression was performed to check for correlation between T2 and RR interval to investigate the influence of heart rate on T2 measurement. To test for differences in T2 calculated from short-axis or long-axis views, the four mid-ventricular segments that are represented in short-axis, HLA , and VLA (anterior and inferior) views were used. Paired t-test was performed to assess differences. Additionally, to provide a measure of variability at pixel level, spatial variation of T2 was computed across all pixels in the mid-ventricular slice for each subject.To study the effect of spatially-variant coil sensitivity on T2 maps, we separately acquired T2p-SSFP images for a single mid-ventricular SAX slice in each subject and generated T2 maps for comparison with T2W images acquired using the triple inversion recovery STIR sequence . Only anTo compare the motion sensitivity of T2W and T2 mapping techniques, a short axis slice was imaged close to the base in six of the subjects (three of the previous fourteen subjects + three new subjects). Two scans were run for each technique to acquire images at two cardiac phases: (i) 400 ms after the R-wave and (ii) mid-diastole; matched ROIs were drawn in the lateral wall of the four images thus acquired. Paired t-test was used to test the hypothesis of no difference in signal intensity (T2W) or T2 (T2 Map) between the images acquired at two different points in the cardiac cycle.Acute myocardial infarction was induced in three pigs to determine whether significant changes in measured T2 could be detected. The animals were anesthetized with ketamine (7.5 mg/lb) and acepromazine (0.25 mg/lb). A catheter was then guided under x-ray fluoroscopy via the femoral artery. Thereafter, a balloon occluder was guided through the catheter to the left anterior descending (LAD) coronary artery just distal to the first diagonal branch. Once in place, the occluder was inflated to produce total LAD occlusion to induce ischemia. The occlusion was maintained for 90 minutes to induce infarction following which the balloon was deflated. MRI was performed 3 days after reperfusion. During the scan, anesthesia was maintained using isoflurane in oxygen (1-3%) and mechanical ventilation (20 mmHg). ECG, blood pressure and pulse oximetry were monitored throughout the experimental period.T2 maps were acquired in each animal in one mid-ventricular short-axis slice that included the affected LAD territory. This was followed by an injection of gadolinium-diethylenetriamine pentaacetic acid  and Late Gadolinium Enhancement (LGE) imaging  to evaluThree adult patients with acute myocardial infarction (AMI) were studied to gain insights into the potential clinical applications of this technique. Since the purpose of this study was only intended to evaluate the feasibility of myocardial T2 mapping, the inclusion criteria were restricted to patients with documented cases of AMI based on electrocardiography, x-ray coronary angiography, and cardiac biomarkers. Table Tables T2P image acquisitions.Table Images acquired using centric reordering demonstrated artifacts in the blood pool and myocardium Figure . These a2 = 0.018). The average coefficient of variation of T2 across subjects was 5.3%. Figure The mean T2 value averaged across all 16 segments and among all 14 healthy subjects was found to be 52.18 ± 3.4 ms (range: 48.96 ms to 55.67 ms). ANOVA test for inter-subject variability of T2 values revealed statistically significant differences . This variability showed no linear correlation with heart rate . In two pigs the necrotic tissue as shown by LGE matched the regions of T2 enhancement. The third animal died just before the injection of contrast agent and hence the LGE images were not available. Figure T2P = 55 ms (column 2), T2 maps (column 3) and LGE (column 4) from patient #1. The quantitative results for all three patients are listed in Table Figure The sensitivity of T2W imaging to myocardial edema was first reported by Higgins  over 25 The sensitivity of myocardial signal to motion has been an inherent limitation of techniques such as T2W TSE and STIR imaging where cardiac motion can result in reduced myocardial signal Figure ; this prVariability in myocardial signal in T2W imaging can also result from surface coil intensity inhomogeneity, another important factor limiting the applicability of myocardial edema imaging. Results obtained under conditions of severe surface coil signal inhomogeneity showed that T2 mapping reduced the mean coefficient of variation among myocardial segments from 27.7% with T2W STIR, to 4.25% in the T2 maps Figures  and 4B; Another significant problem recognized even in the first papers on in-vivo T2W imaging of the human heart ,29 is suT2P images . There is evidence that myocardial T2 may vary depending on the recent health status of the individual. A recent study in high-endurance athletes suffering from common cold virus [Yet another advantage of T2 mapping over T2W imaging is that it is a quantitative method. Most clinical studies using T2W imaging to date have relied on subjective visual assessment to detect regions of relative T2 signal hyperintensity ,7. Such ld virus  showed eld virus ,32 have Quantification of T2 offers a distinct advantage over T2W imaging in the detection of global changes in myocardium as may be expected to occur in myocarditis  or cardiWhile our human myocardial T2 results concurred with previously published work Table , phantomin vivo images, possibly due to the oscillatory approach to steady-state having a stronger effect on the central k-space lines. Images and T2 maps acquired using linear ordering did not show this artifact and demonstrated significantly less spatial variation in calculated T2. The overestimation in T2 with linear ordering was likely caused by the acquisition of central k-space lines after the T2p magnetization has been perturbed by a number of RF excitation pulses and the signal has begun to approach SSFP steady-state.First, the k-space ordering chosen for SSFP readout was linear instead of centric despite the higher T2 accuracy in phantoms provided by the latter. However, as shown in Figure o and T2) we chose to use three images for the T2 calculation as the minimum required for a least-squares linear-regression fitting of the logarithmically transformed data to minimize breath-hold times. A recent work by Sparrow et al. [T2P times ensures the breath-hold time (7RR) is within the capabilities of most of the patients.A second probable cause of T2 overestimation may be the number of echo times and fitting method used. Given that our mono-exponential model has two parameters (Mw et al.  demonstrw et al. . While tThere is still the potential for mis-registration between images causing error in the T2 maps. If breath-holding is not feasible, the sequence could be combined with respiratory triggering and/or image registration methods could be applied prior to T2-map calculation. Although a recently described T2W imaging technique  used a mThe analyses of T2 variability between myocardial segments showed no statistically significant differences among the twelve basal and mid-ventricular segments; however, our results suggest a consistent overestimation of T2 in the four apical segments Figure . One potDetection of myocardial edema is not possible by other cardiac imaging modalities, and the lack of a robust CMR approach has limited broad application of this potentially important measure of myocardial status. This work has demonstrated an accurate, fast, quantitative approach to detect the elevated T2 associated with myocardial edema that successfully addresses the well-known limitations of T2W imaging. Further studies are warranted to evaluate the clinical applicability of this technique in the range of conditions that are known to globally or regionally affect myocardial water content.YCC is an employee of Siemens Healthcare. OPS and SVR receive research grant support from Siemens Healthcare.SG, SVR and OPS planned and designed the study. SG, OPS, and YCC designed and implemented the T2-mapping technique. GM constructed the phantoms and measured their relaxation parameters. AM recruited patients and acquired patient data. Data was analyzed by SG. All authors participated in manuscript drafting and editing and approved the final version of the submitted manuscript.