Objectives. We sought to assess the comparative value of inflammatory markers on the occurrence of left ventricular systolic dysfunction (LVSD) after an acute coronary syndrome (ACS). Methods. During 2006–2008, 760 patients with an ACS were enrolled. C-reactive protein (CRP) and white blood cell (WBC) count were measured during the first 12 hours of hospital admission. Results. CRP levels and WBC count were significantly higher in those who developed LVSD compared to those who did not. The analysis revealed that a 10 mg/dL increase of CRP levels and a 1000/μL increase in WBC are associated with a 6% and a 7% increase in the likelihood of developing LVSD, respectively. Furthermore, WBC count at entry and CRP have almost the same predictive value for development of LVSD after an ACS (R2 = 0.109 versus R2 = 0.093). Conclusions. Serum CRP levels and WBC count at entry are almost equally powerful independent predictors of LVSD, after an ACS. Heart failure could be described as a modern plague, as it is the leading cause of hospital admissions in the United States . Among oThe assessment of the risk for developing left ventricular systolic dysfunction and eventually systolic heart failure in ACS patients is of considerable clinical and public health importance; while the comparative role of CRP and WBC count in occurence of left ventricular systolic dysfunction in the setting of ACS is still unclear. The aim of this study is to investigate the implication of inflammation, characteristically expressed by the levels of CRP, and white blood cell count, on the occurrence of LVSD in the acute coronary syndrome (ACS) process, thus providing insights in the contribution of inflammation to the deterioration of the systolic function of the heart in the setting of ACS. Moreover, we aim to estimate the comparative predictive value of the two markers assessed.During 2006–2008, we enrolled 798 consecutive patients who developed an ACS event. From the above we finally included in the study 283 males (64 ± 14 years) and 73 females (71 ± 12 years) postacute coronary syndrome patients with impaired ejection fraction, defined as below 40% and 317 males (62 ± 11 years) and 87 females (67 ± 11 years) with normal ejection fraction, defined as above 50%. The total number of patients were therefore 760, while the rest 38 exhibited an ejection fraction of 40–50% and were not included in the following analysis. Patients that were estimated as having an EF of 40–50% were not included, as this is only mild impairment of ventricular function. The echocardiographic evaluation of the left ventricular function that was used in this analysis was the one performed at the discharge day, in order to overcome the stunning of the first days after the acute coronary event.At entry a 12-lead electrocardiogram was performed, and clinical symptoms were evaluated in all patients, by a cardiologist of the study. Based on the electrocardiographic findings patients were classified as having ST-segment elevations, non-ST segment elevations, or other electrocardiographic abnormalities. Moreover, troponin I measurements were performed to detect evidence of myocardial cell death. We included only cases with diagnosis of ACS  or unstable angina (UA)). In particular, acute myocardial infarction was defined according to the latest guidelines .Using a Hewlett Packard 5500 Sonos with a multifrequency transducer  we evaluated the systolic function of the left ventricle during the first 48 hours and at the discharge day. Systolic heart failure was defined as left ventricular ejection fraction at the discharge day below 40%, according to the recent European Society of Cardiology guidelines for the diagnosis and treatment of acute heart failure . For thiThe study was approved by the Medical Research Ethics Committee of our Institution and was carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association, while each patient gave written consent for participating.Dade-Behring Marburg GmbH, Marburg, Germany). Low-density lipoprotein cholesterol was calculated using the Friedewald formula: total cholesterol—HDL cholesterol—1/5 × (triglycerides). An internal quality control was in place for assessing the validity of cholesterol and triglycerides methods. The intra- and interassay coefficients of variation of cholesterol and triglycerides levels did not exceed 4%.In all patients a detailed medical history was recorded, including previous hospitalization for cardiovascular disease , presence and management of hypertension, hypercholesterolemia, renal failure, and diabetes mellitus. Moreover, we recorded patients' medical family history. In addition to troponin I, we also measured the MB fraction of creatine phosphokinase (CPK), urea, and uric acid. The biochemical evaluation was carried out in the same laboratory that followed the criteria of the World Health Organization Reference Laboratories. Total-, high-density lipoprotein, cholesterols, blood glucose, and triglycerides were also measured in all participants, using colorimetric enzymic method in a Technicon automatic analyzer RA-1000 . Based on baseline serum creatinine (Cr), the CrCl was calculated using the Cockcroft-Gault formula 14): CrCl = [[(140 − age) × weight] / (72 × serum creatinine)] for men, while for female gender, the result of the above equation was multiplied by 0.85 [: CrCl = Sociodemographic characteristics included age, sex, marital status, number of children, years of school, type of occupation. Height and weight were measured and to the nearest 0.5 cm and 100 g, respectively. Body mass index (BMI) was then calculated as weight (in kilograms) divided by height (in meters) squared. Physical activity was defined as any type of exercise  at least once per week during the past year. Other participants were defined as physically inactive. Current smokers were defined as those who smoked at least one cigarette per day or have stopped cigarette smoking during the past 12 months. Former smokers were defined as those who had stopped smoking more than one year previously. The rest of them were defined as never smokers or rare smokers.In this work continuous variables are presented as mean values ± standard deviation. The categorical variables are presented as absolute and relative (%) frequencies. Associations between continuous variables and groups of patients were evaluated through the analysis of variance (ANOVA), after controlling for equality of variances (homoscedacity). Associations between categorical variables were tested by the use of the chi-squared test, without the correction of continuity. Correlations between continuous variables were tested by the use of Pearson's correlation coefficient. Due to multiple comparisons we applied the Bonferroni correction to correct for the inflation of Type—I error. Logistic regression analysis was applied in order to evaluate the association between the investigated inflammatory markers and the development of LVSD, after various adjustments were made. Deviance residuals and Hosmer-Lemeshow criterion were used to test models' goodness-of-fit. All statistical calculations were performed on the SPSS version 12.0 software .μL and upper tertile > 11000/μL) and we revealed that those patients in the upper tertile were younger, had more often myocardial infarction than unstable angina, had higher levels of troponin I at entry, had less often previous history of coronary heart disease, and were more often current smokers    . Moreove < .001) .R Square for the two logistic regression models, that is to say, the amount of variance explained by each model, we observe that WBC count seems to be slightly but not significant more powerful, in predicting the development of left ventricular systolic dysfunction, than CRP (R2 = 0.109 versus R2 = 0.093). (We used two logistic regression models using the same confounders each time and entering CRP the first time and WBC count afterwards. Comparing the  0.093). .In this study we revealed that higher values of white blood cell count are associated with higher probability of developing left ventricular systolic dysfunction after an acute coronary syndrome, independently of diagnosis of myocardial infarction or other common conditions that might contribute to this. We also demonstrated that CRP is an independent predictor of development of left ventricular systolic dysfunction after an ACS, as well, after controlling for common confounders . Although WBC count seems to be a slightly more powerful predictor for the development of systolic dysfunction than CRP, this difference was not statistically significant.In the setting of acute coronary syndromes, inflammation is known to have a key role in disease progression and development of complications. We assessed left ventricular dysfunction occurrence using two widely used and easily measured markers: CRP is a proven marker of inflammation, yet the WBC count seem to hold its role in predicting poor prognosis in a manner that exceeds just inflammation.It is well known that the leucocyte count is elevated in the setting of myocardial infarction. Leukocytes are the first cells drawn to an infarct area of necrosis trying to repair the tissue damage. As we revealed in our study that the initial WBC count seems to be higher in younger patients, who more frequently suffer from myocardial infarction rather than unstable angina, have higher heart rate at entry, have higher troponin I levels, have less frequently prior history of coronary heart disease, and are more often current smokers . These cThe leukocytes seem to mediate left ventricular systolic dysfunction in the setting of an acute coronary syndrome in many ways; elevated white blood cell count is associated with more extensive coronary artery disease, as assessed by coronary angiography . LeukocyIt appears that leykocytes may have an important role in tissue repair, but seem to enhance a portion of further tissue damage, thus explaining their contribution to the development of systolic dysfunction, regardless of the infarct itself.It is previously shown that CRP is elevated in cases of myocardial infarction, as CRP rises in response to various inflammatory stimuli, including tissue necrosis and myocardial infarction , 22. DurCRP may be linked to left ventricular systolic dysfunction progression through three different mechanisms: its relation to the extent of coronary artery disease, its relation to thrombus burden, and the proinflammatory effect that may mediate further tissue damage in cases of myocardial infarction. CRP is reported to be associated to CAD extent in myocardial infarction patients  but none It is known that CRP concentration demonstrates diurnal variation that is statistically significant and may bias epidemiological studies , 27. CRPAmong the two inflammatory markers assessed in this work, the WBC count seems to have a slightly better predictive power for the development of left ventricular systolic dysfuncton after an ACS, when compared to CRP. CRP is related to systolic dysfunction after an ACS through three different mechanisms: that of total atherosclerotic burden which means that it is related to more extensive coronary vascular disease, that of thrombus burden which means that having procoagulant effects, may account for a portion of thrombus formation, and that of inflammatory escalation. On the other hand, leukocytes are implicated more actively and in more pathophysiologic steps than CRP; they are related to more extensive coronary vascular disease and they contribute to inflammatory escalation, oxidative stress, proteolytic enzymes release; microvascular plugging, lytic action of macrophages. This can partly explain the findings of another study that associates high neutrophil count  with higher mortality rates following an ACS, independently of CRP levels  and is pIn retrospective case-control studies, two main sources of systematic errors may exist, the selection and the recall bias. In order to eliminate selection bias we tried to set objective criteria, both for patients and controls having the same echocardiographic evaluation of left ventricular function obtained by two independent physicians at the discharge day, in order to eliminate the impact of stunning myocardium of the first days after the event. Also, in case-control studies, it is usually observed that patients who had a recent adverse event are more likely to place greater emphasis (overestimate) on several factors related to the disease than the control group . In order to reduce this type of bias, we made an effort to obtain accurate information from the patients as well as from their relatives or their accompanying persons. Besides, the two groups were patients with different disease severity. Another limitation is that we have also included patients with previous history of coronary heart disease. These patients may have had impaired left ventricular function before the index event. In order to eliminate this bias we have included the information of previous known history of coronary heart disease in the multivariate analysis; the percentage of patients with previous CHD history had no significant difference between the two groups of patients.The CRP assay was not a high sensitivity one, but this fact is not expected to influence our results, as all patients are suffering from an acute coronary syndrome and are, therefore, expected to exhibit elevated values of CRP.Concerning the medical information, we tried to avoid recall bias by obtaining accurate and detailed data from subjects' medical records. However, over/under estimation may still exist, especially in the measurement of smoking habits and the onset of the investigated cardiovascular risk factors. Moreover, the coronary patients who died at entry or the day after were not included in the study. This bias could influence our results, but, since the proportion of deaths during the first two days was estimated between 2–4%, we believe that the inability to include the fatal events did not alter significantly our findings. Furthermore, regarding the potential effect of uncontrolled—unknown confounders, we tried to reduce it by using the same study base, both for patients and controls, but their influence on the outcome may still exist.Elevated WBC and CRP levels are independent predictors of development of left ventricular systolic dysfunction after an ACS, regardless of several confounders including diagnosis of myocardial infarction. The WBC count seems to be slightly more predictive than CRP in this direction. Hopefully clinicians may consider the initial WBC count and CRP as almost equally powerful measures of possible left ventricular systolic dysfunction occurence, that may lead to heart failure. The inflammatory process may also be targeted for therapy, as this may provide some protection against heart failure occurrence.


Two cases of pediatric patients with heart failure are presented. One child presented with vomiting and the other a child with a history of asthma who had respiratory distress. Though their presenting complaints are common, the diagnosis was made based on careful examination and consideration of abnormal findings. Abnormal vital signs  or physical exam findings  can provide important clues to accurate and timely diagnosis. Diagnosing the rare patient with myocarditis or cardiomyopathy in a child in the acute care setting is essential, but frequently such patients present with symptoms more commonly associated with other illness or disease. How can the practitioner identify the clues that the common symptom presentation is anything but common? We present two cases of children with heart failure and discuss the important aspects of diagnosis.A previously healthy 3-year-old Hispanic female is brought to the emergency department (ED) for vomiting. Her parents reported that she had three episodes of non-bloody, non-bilious emesis over 1 day and seemed fatigued. They reported no fevers, diarrhea, abdominal pain, rashes, or upper respiratory symptoms. Her past medical history was unremarkable except for an episode of hemolytic anemia at 15 months following a viral illness. The patient was initially taken to her primary care provider where she was found to be less interactive than usual, pale, and unwilling to walk or play.The patient was sent to the ED for further evaluation. She was somnolent but responsive to tactile stimulation. Her extremities were cool and mottled with delayed capillary refill. The lungs were clear and the heart tones were normal with no murmurs, gallops, or rubs. Her heart rate was 40 beats per minute. Electrocardiogram (ECG) monitoring revealed intermittent third degree heart block with bradycardic episodes, during which she had decreased responsiveness. A venous blood gas revealed metabolic acidosis, with a pH 7.09 and a base deficit of 16. She was given a 10 mg/kg normal saline bolus, started on an isoproterenol drip, and placed on 6 liters of oxygen by mask. Her heart rate increased to 140 and her oxygen saturation was maintained at 100%. A chest radiograph showed no cardiomegaly, effusion, pulmonary infiltrate, or edema. She was subsequently transferred to the pediatric intensive care unit for ongoing evaluation and treatment.Laboratory values indicated myocardial damage: BNP 1150, troponin I 50.54, and CK-MB 65. An echocardiogram revealed normal ventricular contractility with left ventricular wall edema and an abnormal shortening fraction of 29%. Multiple studies were sent, including blood cultures, viral PCR for enterovirus, Mycoplasma, EBV, CMV, parvovirus, and Lyme titers, all of which returned negative. Rheumatologic studies were sent and were significant for low complement levels.A cardiac catheterization and biopsy showed severe lymphocytic infiltration with myocyte necrosis, myocardial edema, and early interstitial collagen deposition. She was treated with IVIG and methylprednisone for presumed myocarditis with improvement of her symptoms, lab values, and rhythm.The patient was discharged home on hospital day 12 on captopril and a prednisone taper with a return to normal cardiac function. Follow-up in cardiology clinic revealed a normal exam, return to baseline behavior, and normal echocardiogram.An 8-year-old African-American male with a history of asthma presented to his primary care provider for increasing exercise intolerance, shortness of breath, and cough for one day. He was started on methylprednisone and albuterol for possible exacerbation of his asthma. He returned to his pediatrician four days later for follow-up with increasing respiratory distress and shortness of breath and was referred to the ED for further evaluation.On arrival to the emergency department, the patient was alert, awake, and cooperative. He walked into the room effortlessly, though did appear to have mild shortness of breath. His examination was notable for quiet heart sounds a possible holosystolic murmur and a quiet gallop. Although his liver edge was hard to feel, given the size of the patient, he was tender in the right upper quadrant. His extremities were warm and well-perfused, although radial pulses felt weak. He was placed on oxygen via nasal cannula. A chest radiograph showed an enlarged cardiac silhouette with pulmonary edema. An echocardiogram demonstrated a severely dilated left ventricle, severely depressed left ventricular function, moderate mitral and tricuspid regurgitation, and elevated right-sided pressures. He was noted to have a shortening fraction of 14%. Initial labs were unremarkable except a BNP 1150. He was admitted to the cardiac intensive care unit for further evaluation and treatment.Streptococcus viridans. He was placed on ceftriaxone for possible bacteremia.The patient was initially maintained on oxygen via nasal cannula but developed increased work of breathing that required CPAP and diuretic therapy. He was placed on milrinone captopril, and furosemide to improve cardiac function and decrease fluid overload. A cardiac catheterization confirmed a dilated cardiomyopathy and biopsy showed nonspecific acute inflammation. Prophylactic heparin anticoagulation was initiated due to his dilated ventricles and poor ventricular function. Viral studies and blood cultures were negative except for one culture that grew Despite slow improvement in cardiac enzyme studies, the patient continued to require increasing amounts of milrinone and diuretic therapy. He developed increasing respiratory distress with increasing CPAP needs and sildenafil was initiated due to concern for pulmonary hypertension. His condition continued to deteriorate and the patient was placed on a waiting list for cardiac transplantation.Early and accurate diagnosis of a child with heart failure can be a difficult task. Though the majority of cases of pediatric heart failure occur in the first year of life in children with congenital heart disease, older children may present with failure due to acquired disease such as myocarditis or cardiomyopathy, as illustrated by our cases.Myocarditis is caused by inflammation of the myocardium with necrosis of the myocytes.Viral infections, predominantly adenovirus and coxsackievirus, are responsible for the majority of cases. However, bacteria, drugs, and toxic exposures have also been implicated -3. ThougAs damage to the myocardium continues, patients may develop varying degrees of ventricular dysfunction and/or dilatation. Dilated cardiomyopathy is characterized by a dilated left ventricle with systolic dysfunction and signs of congestive heart failure. SeveralHeart failure occurs when the heart is unable to provide adequate blood volume to meet the circulatory and metabolic demands of the body. In a healthy child, the heart can compensate for increased demands by increasing the heart rate, increasing the contractility of the ventricles, increasing preload, or decreasing peripheral resistance, all of which lead to increased flow of blood volume to those areas in need of more oxygen. When the demands of the body placed on the heart exceed its ability to compensate, failure occurs.In fulminant cases, patients present in decompensated shock with classic signs of pulmonary edema, tachycardia, and hypoxia making the diagnosis clear and subsequent treatment immediate. But the practitioner must also consider the possibility of cardiac disease in those individuals with more atypical symptoms or insidious onset. Older patients may complain of shortness of breath, fatigue, or wheezing, making the presentation difficult to distinguish from asthma exacerbations . YoungerPatients may present with symptoms of low cardiac output including fatigue, cool extremities, dizziness, altered level of consciousness, or syncope. Initial damage to the myocardium can lead to exercise intolerance from decreased myocardial function. Increasing dilatation of the heart chambers with poor contractility and function can lead to pulmonary congestion. Atrio-ventricular nodal infiltration presents as rhythm disturbances and complete heart block while ventricular dysrhythmias can lead to seizures, chest pain, and sudden death.There are no definitive tests for myocarditis or cardiomyopathy. The clinician must be alert for the possibility of heart failure in any patient, and should start with a thorough physical examination, paying special attention to presenting vital signs.The patient's heart rate may be a clue of underlying cardiac disease. Tachycardia is commonly seen and usually relates to fever, fear, or a pulmonary problem. However, tachycardia may also be seen in a failing heart with arrhythmias or decrease in ventricular contractility, causing poor cardiac output. Bradycardia is more rarely seen in the acutely ill patient and merits further evaluation for cardiac dysfunction.Respiratory rate and blood pressure can both help identify patients at high risk for cardiac disease. Though tachypnea is usually seen in patients with fever and pulmonary processes, the practitioner must consider the possibility of pulmonary edema from a failing heart. Hypotension is an ominous sign. While most patients with mild heart failure remain normotensive early in the course of illness, cardiac decompensation with progression of illness will lead to hypotension and cardiogenic shock.Patients with heart failure may present with a normal cardiovascular examination, but a careful survey can reveal important markers of cardiac disease. A new murmur or gallop may be heard with valvular or myocardial dysfunction. A hyperactive precordium may be felt on palpation as the dysfunctional myocardium struggles to maintain cardiac output. Diminished peripheral pulses or mottled, cool extremities can provide valuable evidence of diminished peripheral perfusion. Poor perfusion may indicate poor ventricular function instead of dehydration, even in light of vomiting or decreased oral intake.Wheezing is the classic sign of asthma exacerbation but can also be an important physical finding in patients with myocarditis or cardiomyopathy. Children with cardiac dysfunction are most likely to present with increased work of breathing, tachypnea, retractions, and nasal flaring as opposed to rales or other adventitial lung sounds. The practitioner should consider a cardiac etiology for respiratory symptoms in a known asthmatic if conventional treatments fail to produce improvement or there are other clues present .Abdominal pain can be a presenting symptom in patients with heart failure. Venous congestion due to a failing heart can not only cause pulmonary edema, but also lead to hepatomegaly. Right upper quadrant pain and hepatomegaly in the presence of other concerns should also bring up concerns for a cardiac cause for abdominal pain. Abdominal pain, nausea and vomiting may result from hepatic congestion, rather than the more common diagnoses of gastroenteritis or appendicitis. Physical examination may reveal an enlarged liver or tender liver edge.Initial testing should include an ECG, chest radiograph, and cardiac enzymes once heart failure is suspected . A 12 leUltimately, diagnosing heart failure in the pediatric population begins with maintaining a high index of suspicion. Vital signs should be reviewed and potential diagnoses broadly considered. Additionally, physical exam should be thorough and directed. Only after the diagnosis is considered can additional testing help corroborate your diagnosis and lead the appropriate treatment. It is often difficult to make the diagnosis of heart failure if failure is not consciously considered as a possibility. Armed with knowledge and clinical suspicion, the astute physician will make this diagnosis hard to miss.Verbal informed consent was obtained from the family of the patient presented in case #2. Written informed consent could not be obtained from the patient in case #1 because the family was lost to follow-up. Despite repeated attempts we were unable to trace the patient or family. We believe this case report holds a worthwhile clinical lesson which could not be communicated effectively in any other way. Every effort has been made to keep the patients' identities anonymous. We would not expect the patients or their families to object to publication.The authors declare that they have no competing interests.DC and EK identified the cases. DC wrote up the cases and discussion. DC, EK, and JB all provided major contributions in writing and editing the manuscript. All authors read and approved the final manuscript. The authors are fully responsible for the manuscript.


Echocardiography is the method of choice to establish a diagnosis and determine a treatment plan for patients with noncompaction of ventricular myocardium (NVM). The 2-dimentional echocardiography, 3-dimentional echocardiography, color Doppler echocardiography and contrast-enhanced echocardiography are of critical importance for diagnosis and family screening of NVM. In normal human hearts of children and adults the left ventricle (LV) has up to 3 prominent trabeculations and is, thus, less trabeculated than the right ventricle ,2. RarelNVM is recently included in the 2006 classsification of cardiomyopathies as a Genetic Cardiomyopathy . NVM occThere are 2 sets of echocardiographic criteria for IVNC diagnosis: the Jenni criteria, which stress the presence of a 2-layered structure, and the Chin criteria, which focus on the depth of the recess compared with the height of the trabecula ,9. In bo2DE is by far the most commonly used diagnostic modality. However, recent studies have found that the diagnosis of this disorder is often delayed because of difficulty in elucidating the diagnostic findings . FrequenOccasionally, the affected myocardial segments are hypokinetic, contrary to certain forms of apical cardiomyopathy that can otherwise mimic NVM. However, differential echocardiographic diagnosis includes prominent normal myocardial trabeculations, false tendons and aberrant bands, cardiac tumors, and left ventricular apical thrombus. In these cases, the evidence of the direct blood flow from the ventricular cavity into deep intertrabecular recesses via color Doppler echocardiography analysis is helpful for the differentiation of NVM from other echocardiographic abnormalities in which this finding is not observed .3DE allowed for accurate diagnosis, detailed characterization, and description of the extent of the affected myocardium in NVM in all four patients of this case series by Baker et al. . Entire Conventional echocardiography is the diagnostic modality of choice for INVM. In classic cases, the diagnosis of NVM is not difficult. However, when noncompaction is subtle or incomplete, disorders such as prominent normal myocardial trabeculations, hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricularapical thrombus should be included in the differential diagnosis. Conventional echocardiography has some diagnostic limitations in obese patients or patients with lung disease who have poor acoustic windows.Currently, echocardiography with various contrast agents is being used to enhance endocardial border delineation ,15. Koo The familial character of LVNC has been recognized and probably up to 44% of patients do have affected family members. Although there are no systematic investigations on the familial occurrence of LV NVM, there are single reports that demonstrate LV NVM to occur in multiple family members. Family screening may unmask affected family members for primary prevention including anti-coagulation and implantable cardiovertor defibrillators (ICD) therapy, especially to early diagnosis of asymptomatic patients of NVM. 2DE, 3DE, Contrast echocardiography could all be the pretty good diagnostic modality of choice for NVM, which need to be further studied.The apical and midventricular segments of both the inferior and lateral wall are affected in more than 80% of patients . InvolveAlthough echocardiography has been the diagnostic test of choice for noncompaction, other modalities have been used for the diagnosis, including contrast ventriculography , computeOccasionally, the affected myocardial segments are hypokinetic, contrary to certain forms of apical cardiomyopathy that can otherwise mimic IVNC. However, differential echocardiographic diagnosis includes prominent normal myocardial trabeculations, false tendons and aberrant bands, cardiac tumors, and left ventricular apical thrombus. In these cases, the evidence of the direct blood flow from the ventricular cavity into deep intertrabecular recesses via color Doppler analysis is helpful for the differentiation of IVNC from other echocardiographic abnormalities in which this finding is not observed ,23.In conclusion, echocardiography is the method of choice to establish a diagnosis and determine a treatment plan for patients with NVM. Despite the widespread use of echocardiography, NVM is commonly misdiagnosed because of the lack of knowledge of this disorder, with a significant negative impact on the prognosis of these patients. Therefore, it is still important to make echocardiographers more familiar with this condition and its pathology.The authors declare that they have no competing interests.


Regular physical activity and exercise are well-known cardiovascular protective factors. Many elderly patients with heart failure find it difficult to exercise on land, and hydrotherapy (training in warm water) could be a more appropriate form of exercise for such patients. However, concerns have been raised about its safety.The aim of this study was to investigate, with echocardiography and Doppler, the acute effect of warm water immersion (WWI) and effect of 8 weeks of hydrotherapy on biventricular function, volumes and systemic vascular resistance. A secondary aim was to observe the effect of hydrotherapy on brain natriuretic peptide (BNP).peakVO2 14.6 ± 4.5 mL/kg/min] were examined with echocardiography on land and in warm water (34°C).Eighteen patients [age 69 ± 8 years, left ventricular ejection fraction 31 ± 9%, Twelve of these patients completed 8 weeks of control period followed by 8 weeks of hydrotherapy twice weekly.During acute WWI, cardiac output increased from 3.1 ± 0.8 to 4.2 ± 0.9 L/min, LV tissue velocity time integral from 1.2 ± 0.4 to 1.7 ± 0.5 cm and right ventricular tissue velocity time integral from 1.6 ± 0.6 to 2.5 ± 0.8 cm . Heart rate decreased from 73 ± 12 to 66 ± 11 bpm (p < 0.0001), mean arterial pressure from 92 ± 14 to 86 ± 16 mmHg (p < 0.01), and systemic vascular resistance from 31 ± 7 to 22 ± 5 resistant units (p < 0.0001).There was no change in the cardiovascular response or BNP after 8 weeks of hydrotherapy.Hydrotherapy was well tolerated by all patients. The main observed cardiac effect during acute WWI was a reduction in heart rate, which, together with a decrease in afterload, resulted in increases in systolic and diastolic biventricular function. Although 8 weeks of hydrotherapy did not improve cardiac function, our data support the concept that exercise in warm water is an acceptable regime for patients with heart failure. Regular physical activity and exercise are well-known cardiovascular protective factors . In patiHowever, because warm water immersion (WWI) causes increased venous return and preload , it has The primary aim of this study was to investigate, with echocardiography and tissue Doppler, the acute effect of WWI and effect of 8 weeks of hydrotherapy on biventricular function, volumes and systemic vascular resistance. A secondary aim was to observe the effect of hydrotherapy on brain natriuretic peptide (BNP).We hypothesised that acute WWI should improve biventricular function and that 8 weeks of hydrotherapy should induce a beneficial cardiovascular response.peak VO2 14.6 ± 4.5 mL/kg/min and BNP 172 ± 155 ng/L. Exclusion criteria were uncontrolled hypertension, primary valve disease, and pacemaker rhythm. The patients were in a stable condition without changes in medical treatment in the past 2 months. Baseline characteristics are presented in table Patients were recruited at Sahlgrenska University Hospital, a tertiary referral institution. We enrolled eighteen patients (5 women) with stable chronic heart failure NYHA II-III. The mean age was 69 ± 8 years, left ventricular ejection fraction (LVEF) 31 ± 9%, diastolic+1/3(pressuresystolic-pressurediastolic). Systemic vascular resistance was calculated as: mean arterial pressure/cardiac output.The patients were monitored by electrocardiography throughout the observed sessions and examined whilst standing in a slightly tilted position both on land and in a swimming pool for 20–30 min with the water level up to the sternal notch. Transthoracic echocardiography examinations were performed using Siemens Sequoia 512 with a 3v2c transducer , and data were stored digitally on magnetic optical disks. To protect the probe from water, the transducer was placed in a latex stocking. In accordance with the recommendations of the American Society of Echocardiography, LVEF was calculated using the method of discs, modified Simpson rule . EstimatEchocardiographic examinations were assessed at the same time of the day on all three occasions and performed and evaluated, in a blind approach, by same investigator (BGS). The intra-patient variability is presented in table Ventricular long axis (LAX) function was assessed with M-mode  with the2[Pulsed wave Doppler was carried out for calculation of stroke volume and cardiac output  by regis2.With exception of LVEF, measurements were averaged from at least three heart beats.For analysis of BNP, blood samples were collected from patients after 30 min in a recumbent resting position. The samples were placed in chilled tubes, centrifuged and frozen at -70°C until plasma concentration was measured using a immunoradiometric method  .Data was analysed using SPSS 11 for Windows . The differences between the three sessions were analysed with one way ANOVA . Paired data (land vs WWI) were analysed with the Wilcoxon signed rank test. Relations of paired data were analysed with paired sample T-test. Coefficient of variation (CV) was calculated according to the formula: CV% = s*100/mean, where s (intra-patients error) = SD/√2 and mean = pooled mean value. Data are expressed as mean ± SD. A p-value < 0.05 was considered as statistically significant.All patients responded favourably during WWI, and no cardiovascular or other events occurred during the training or investigations session.During acute WWI, the heart rate decreased from 73 ± 12 to 66 ± 11 bpm (p < 0.0001) and diastolic blood pressure from 75 ± 11 to 68 ± 12 mmHg (p < 0.01). The mean arterial pressure decreased from 92 ± 14 to 86 ± 16 mmHg (p < 0.01), and systemic vascular resistance from 31 ± 7 to 22 ± 5 resistant units (p < 0.0001).There was a significant hemodynamic response during WWI as reflected in several variables: cardiac output improved from 3.1 ± 0.8 to 4.2 ± 0.9 L/min, and stroke volume from 43.9 ± 13.6 to 64.4 ± 16.5 mL (both p < 0.0001); LVEF improved from 31 ± 9 to 35 ± 8% (p < 0.05); in addition, we found improved LAX function as LV TVTI increased from 1.2 ± 0.4 to 1.7 ± 0.5 cm and RV TVTI from 1.6 ± 0.6 to 2.5 ± 0.8 cm  and E/A ratio from 0.72 ± 0.37 to 1.21 ± 0.75 (p < 0.05).Left ventricular end diastolic volume increased from 123 ± 36 to153 ± 56 mL, LV end systolic volume from 85 ± 32 to 100 ± 40 mL and estimated pulmonary capillary wedge pressure from 10.0 ± 5.8 to12.4 ± 5.2 mmHg .In three patients with left bundle branch block, we observed pronounced post-systolic contraction when the patients were investigated on land. During WWI, this abnormal contraction was abolished Figure . FurtherThe effect of WWI was similar during all three sessions with no significant differences after 8 weeks of hydrotherapy Table . There wThis is the first report to show an acute improvement in biventricular function during WWI in patients with stable CHF. In addition, the effect of hydrotherapy on diastolic and systolic cardiac function and volumes has not been studied previously.The profound decrease in heart rate during immersion was maintained and the hemodynamic response persisted in all three sessions, which is likely to be of importance for tolerance of water immersion.The increase in LV volume was caused by hydrostatic pressure and, according to the Bainbridge reflex, would be expected to result in an increase in heart rate . HoweverWe showed that WWI improved several echocardiographic indices of systolic and diastolic function. A lower heart rate alleviates ventricular filling and prolonged diastasis eases myocardial perfusion and is associated with improved systolic function . In our For many years, the M-mode technique was the established method to study LAX function. However, with the development of newer and relatively preload-independent techniques such as TDI and strain rate, the interest in measuring LAX function has increased dramatically. We have recently shown that LAX function is of major importance for long-term survival . In thisAn abnormal post-systolic contraction in patients who suffered from left bundle branch block was shown to be normalized by WWI. Post-systolic contraction is a delayed ejection motion of the myocardium , a phenoOur experimental protocol was comfortable for the patients compared with other studies where patients have been exposed to heart catheterization  or inves2 after 8 weeks of hydrotherapy. One explanation for this could be insufficient exercise intensity . It has been shown that hydrotherapy three times weekly improves functional capacity compared with a deterioration in patients randomized to a control group [Exercise is an important complement to medical treatment, to prevent and reduce symptoms of heart disease, however, regular exercise is required to maintain a positive result . ControlPlasma concentrations of natriuretic peptides have been shown to be powerful predictors of mortality and disease severity in patients with CHF . Long-teThis study has some limitations. We chose a follow-up period before the exercise intervention. As in other training studies, it is impossible to use proper blinded controls. The study population is small. We did not record actual intracardiac pressures, vascular resistance or neurohormone levels. Nevertheless, systolic and diastolic responses of acute WWI were identical in all three sessions, showing that the positive hemodynamic effects were reproducible.Under the conditions used in this study, hydrotherapy was well tolerated. The main observed cardiac effect during acute WWI was a reduction in heart rate, which, together with a decrease in afterload, resulted in increases in systolic and diastolic biventricular function, despite an increased preload. Although 8 weeks of hydrotherapy did not improve cardiac function, the exercise form is a safe method to be used during physical training and rehabilitation of stable heart failure patients.AVP: atrioventricular plane; BNP: brain natriuretic peptide; EF: ejection fraction; LAX: long axis; LV: left ventricular; LVOT: left ventricular outflow tract; RV: right ventricular; TDI: tissue Doppler imaging; VTI: velocity time integral; TVTI: tissue velocity time integral; WWI: warm water immersion.The authors declare that they have no competing interests.Each author has contributed significantly to this submitted work. BGS contributed to the design of the study, participated in the cardiopulmonary exercise test, performed the ultrasound investigations, measurements, calculation and statistical analysis, interpretation of data, wrote the manuscript and was responsible for the final version. ÅC contributed to the design of the study, trained the patients in warm water, and contribute to important intellectual content. MST participated in the ultrasound performance, and contributed to important intellectual content. EA participated in the cardiopulmonary exercise test and collected the blood sample. DK was responsible for the safety during the cardiopulmonary exercise test. BA contributed to the design of the study, interpretation of data, revised the article for important intellectual content. All authors read and approved the final manuscript.


In the elderly the diagnosis of chronic heart failure is often challenging and the availability of echocardiography can be limited. Plasma levels of NT-proBNP are valuable tools to diagnose patients with heart failure. However, the performance of this biomarker to detect cardiac abnormalities in the very elderly remains unclear. The aims of this study were to investigate the relation between NT-proBNP and cardiac abnormalities and to evaluate the use of NT-proBNP to exclude structural and functional cardiac abnormalities in a community-based sample of "well-functioning" nonagenarians.A diagnostic cross-sectional study embedded within the Leiden 85-plus Study in the municipality of Leiden, the Netherlands. Plasma NT-proBNP levels were measured and 2-dimensional echocardiography was performed in a subgroup of 80 well-functioning nonagenarians. Linear regression analysis was used to explore the relation between NT-proBNP and cardiac abnormalities and ROC curve analysis was used to assess the performance of NT-proBNP to exclude cardiac abnormalities. The upper limit of the lowest tertile of NT-proBNP was used as a cut-off value.NT-proBNP levels were associated with abnormal left ventricular (LV) dimensions, LV systolic and diastolic function, left atrial enlargement and valvular heart disease. LV mass, E/A ratio and degree of aortic regurgitation were identified as independent predictors of NT-proBNP. NT-proBNP levels were higher with greater number of echocardiographic abnormalities (P < 0.001). A cut-off level of 269.5 pg/mL identified patients with abnormal LV dimensions or depressed LV systolic function  77%, area under the curve 0.75 (95% CI 0.64-0.85)). In addition, high NPV were found for LV systolic dysfunction, left atrial enlargement, severe valvular heart disease and pulmonary hypertension. The test performance of NT-proBNP to exclude any echocardiographic abnormality showed a sensitivity of 82% and a NPV of 65%.In this convenience sample of well-functioning nonagenarians NT-proBNP was related to a wide variety of functional and structural echocardiographic abnormalities. Moreover, NT-proBNP could be used to exclude echocardiographic abnormalities in well-functioning nonagenarians and might be used to indicate who needs to be referred for further cardiovascular examination. Chronic heart failure is becoming more frequent in our aging societies. The prevalence of heart failure increases with age from 0.7% in people aged 55-64 years to 13.0% in those aged 75-84 years ,3. This Plasma levels of BNP (brain natriuretic peptide) and NT-proBNP  are valuable tools to diagnose patients with heart failure. These measures have shown to provide prognostic information of mortality and major cardiovascular events, not only in patients with chronic heart failure or coronary artery disease but also in the general population, and this can improve patient management -8. In adHowever, multiple factors are known to influence the circulating levels of natriuretic peptides. The prevalence of possible influencing factors, like renal dysfunction and anemia, increases in the very elderly ,12. An uth birthday. There were no exclusion criteria regarding health status or demographic characteristics. At baseline and yearly up to the age of 90, the participants were visited at their place of residence. For the current study, a convenience sample of 82 participants was invited for echocardiography. The study nurse invited those participants who were physically able to visit the research centre and whose cognitive function allowed them to undergo various technical investigations. All but one underwent echocardiography. All participants in the study gave informed consent and the Medical Ethics Commission of the Leiden University Medical Centre approved the study.The Leiden 85-plus Study is an observational, prospective population-based study of inhabitants of the city of Leiden, The Netherlands. The study design and characteristics of the cohort have been described in detail . In brieEvaluation of the functional status of participants included measures of cognitive function, subjective well-being, disability and depressive symptoms. Cognitive function was assessed by the Mini-Mental State Examination (MMSE), with scores ranging from 0 to 30 points  . SubjectBlood samples were taken within the month after every participant's 90th birthday, and were kept frozen at -80°C. In 2006 citrated plasma levels of NT-proBNP were measured in one batch using the NT-proBNP assay of Roche Diagnostics  on a Roche Modular E-170 automated immunoanalyser. The within-run coefficient of variation was less than 2% and total variation was less than 6% at all levels measured (400-13500 pg/mL).All patients were imaged between January and September 2004, in stable hemodynamic conditions. In the majority of the patients, transthoracic echocardiography was performed the same day of the blood test. In patients who underwent echocardiography at a different day, no cardiac events were recorded between the two tests. The echocardiographic evaluation was performed by one experienced observer blinded to the NT-proBNP levels.2 in men and >122 g/m2 for women [All patients were imaged in the left lateral decubitus position using a commercially available system  equipped with a 3.5-MHz transducer. Echocardiographic images were acquired at a depth of 16 cm in the parasternal and apical views. Left ventricular (LV) dimensions were measured from M-mode images at the parasternal long-axis view. The LV ejection fraction was derived using the Teichholz formula . Left veor women .Left ventricular diastolic function was assessed from pulsed-wave Doppler recordings of the transmitral inflow, measuring the early (E) and atrial (A) wave peak velocities and the E/A ratio . In addiThe function of the mitral, aortic and tricuspid valves were evaluated with color Doppler echocardiography after optimising the gain and Nyquist limit. Standard continuous and pulsed-wave Doppler recordings were acquired. Stenotic and regurgitant valve diseases were evaluated according to semiquantitative and quantitative methods recommended by the American Society of Echocardiography . When trAs previously described, plasma levels of NT-proBNP are influenced by gender, body mass index (BMI), renal dysfunction, anemia and medications for heart failure ,12,24,25Echocardiographic parameters were compared between tertiles of NT-proBNP using the Jonckheere-Terpstra test or the Chi-squared test with linear-by-linear association.Levels of NT-proBNP were log-transformed and the association with echocardiographic parameters was explored further using linear regression analysis corrected for confounding variables. Analysis of variance (ANOVA) testing was used to compare the mean LogNT-proBNP values between different categories of increasing number of cardiac abnormalities.The performance of NT-proBNP to exclude structural and functional abnormalities was assessed using receiver operating characteristic (ROC) curve analysis. The upper limit of the lowest tertile was used as a cut-off value for NT-proBNP and the sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were calculated. The highest cut-off value with an NPV of 100% was reported. Data analyses were performed using SPSS 16.0 .The initial cohort consisted of 599 participants at age 85 years. A total of 276 individuals survived up to the age of 90 years. Levels of NT-proBNP were determined in 274 participants. Both echocardiographic data and NT-proBNP levels were available in 80 well-functioning subjects. The prevalence of cardiovascular and non-cardiovascular comorbidities was similar for patients with and without echocardiography Table . There wn = 69, 86%) and had a preserved LV ejection fraction . According to current criteria, LV hypertrophy was present in 35% (n = 9) of men and 45% (n = 23) of women  ) and gender was no independent predictor of NT-proBNP in the linear regression analysis (P = 0.88), no gender-specific cut-off values were used (Table Because NT-proBNP levels did not differ between men and women (501.1 pg/mL (IQR 211.3-1468.3 pg/mL) and 349.5 pg/mL (IQR 214.9-682.5 pg/mL) respectively  was calculated. If only the participants with an NT-proBNP level >269.5 pg/mL (n = 54) would be referred for echocardiography, 9 cases would be missed (18%) and 13 negative echoes  would be done (43%).In this convenience sample of well-functioning nonagenarians we showed NT-proBNP is not just an indicator of increased cardiac pressure but is related to a wide variety of functional and structural echocardiographic abnormalities. This confirms the hypothesis that natriuretic peptides could possibly be used to identify 'pancardiac' damage, even when it is silent . In a prA recent systematic review concluded important questions about the implementation of measuring NT-proBNP in daily practice remain unsolved for the diagnosis of cardiac dysfunction in elderly patients aged 75 and over from the general population . The preSome limitations should be acknowledged. First, we were not able to correlate levels of NT-proBNP to echocardiographic measurements for the entire cohort. Seen the small sample of well-functioning nonagenarians we should be careful to generalize the findings of the present study to the entire population of well-functioning nonagenarians. Second, there was no available data on the symptomatology of the participants. However, participants in the convenience sample only differed in functional status, but had the same burden of cardio-vascular comorbidities compared to the limited-functioning elderly. Third, the fact the NT-proBNP levels were determined in 2006 after being frozen might have influenced the absolute value, but it is unlikely that it has affected the ranking. In addition, the applicability of current echocardiographic cut-off values to nonagenarian subpopulations may be debatable since the thresholds for normal values are usually derived from younger subpopulations. Finally, LVEF measured with biplane Simpson's methods was not systematically available in all patients.In conclusion, this study showed NT-proBNP is related to a wide variety of functional and structural echocardiographic abnormalities in well-functioning nonagenarians. Furthermore, low values of NT-proBNP were able to exclude echocardiographic abnormalities and could be used to identify nonagenarians that need to be referred for further cardiovascular examination.BNP: Brain natriuretic peptide; NT-proBNP: N-terminal pro-brain natriuretic peptide; ROC: Receiver operating characteristic; LV: Left ventricular; CI: Confidence intervals; MMSE: Mini-Mental State Examination; GARS: Groningen Activity Restriction Scale; ADLs: Activities of daily living; GDS-15: 15-item Geriatric Depression Scale; BMI: Body mass index; ANOVA: Analysis of variance; NPV: Negative predictive value; PPV: Positive predictive value; ΔP: Pressure gradient; SD: Standard deviation; IQR: Inter quartile range; EDD: End-diastolic diameter; ESD: End-systolic diameter; PAP, Pulmonary artery pressure.JB has received grants from Biotronik , Medtronic , Boston Scientific Corporation , Bristol-Myers Squibb Medical Imaging , St. Jude Medical , GE Healthcare  and Edwards Lifesciences .JG had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. JG and RGJW are responsible for the study concept and design. BV and VD performed the statistical analysis and drafted the manuscript. All authors participated in the analysis and interpretation of the data and critically revised the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/10/85/prepub


Screening of primary care patients at risk for left ventricular systolic dysfunction by a simple blood-test might reduce referral rates for echocardiography. Whether or not natriuretic peptide testing is a useful and cost-effective diagnostic instrument in primary care settings, however, is still a matter of debate.N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical information, and echocardiographic data of left ventricular systolic function were collected in 542 family practice patients with at least one cardiovascular risk factor. We determined the diagnostic power of the NT-proBNP assessment in ruling out left ventricular systolic dysfunction and compared it to a risk score derived from a logistic regression model of easily acquired clinical information.23 of 542 patients showed left ventricular systolic dysfunction. Both NT-proBNP and the clinical risk score consisting of dyspnea at exertion and ankle swelling, coronary artery disease and diuretic treatment showed excellent diagnostic power for ruling out left ventricular systolic dysfunction. AUC of NT-proBNP was 0.83  with a sensitivity of 0.91  and a specificity of 0.46 . AUC of the clinical risk score was 0.85  with a sensitivity of 0.91  and a specificity of 0.64 . 148 misclassifications using NT-proBNP and 55 using the clinical risk score revealed a significant difference  that was based on the higher specificity of the clinical risk score.The evaluation of clinical information is at least as effective as NT-proBNP testing in ruling out left ventricular systolic dysfunction in family practice patients at risk. If these results are confirmed in larger cohorts and in different samples, family physicians should be encouraged to rely on the diagnostic power of the clinical information from their patients. Early detection of left ventricular systolic dysfunction is important, since early treatment with ACE inhibitors has been shown to delay the progression toward overt congestive heart failure (CHF) and to prolong life . Since dTo date, general practitioners have to identify patients in need of a referral to echocardiography by clinical information, which is routinely obtained from medical history and physical examination. Eventually, a pre-selection of patients at risk could reduce referral rates for echocardiography . TherefoRecent studies showed that the assessment of patients at high risk for left ventricular systolic dysfunction by means of N-terminal pro-brain natriuretic peptide (NT-proBNP) assays was valuable in the diagnosis of left ventricular systolic dysfunction ,7 and heWe therefore investigated the diagnostic ability of NT-proBNP testing compared to a risk score derived from a logistic regression model of easily acquired clinical information to detect left ventricular systolic dysfunction in primary care patients at risk.Between January 2003 and June 2004, 2,273 primary care patients from 58 practices in the city of Göttingen (North Germany) and the surrounding communities were invited by their general practitioners to participate in the study. Inclusion criteria were the presence of at least one cardiovascular risk factor documented by the family physician, including arterial hypertension, diabetes, family history of early heart disease, and coronary artery disease. Patients were classified as hypertensive if hypertension was documented by their treating physician or if they were on antihypertensive therapy. Patients were classified as diabetic if this diagnosis was made by their treating physician or if they were on antihyperglycemic therapy.Exclusion criteria were the diagnosis of heart failure documented by the family physician or the presence of a terminal or disabling chronic disease. Patients received a leaflet with general information about the purpose of the study and how to participate. A total of 542 patients agreed to participate and were examined at the Georg-August-University, department of cardiology. Patients were interviewed, clinically examined, and assessed by echocardiography. Fifteen ml of blood were taken from a forearm vein for the measurement of NT-proBNP level.® assay  to measure NT-proBNP in defrosted samples. The lowest detectable measurement for this assay was 5 pg/mL. The interassay coefficient of variation was 2.7% for 175 pg/mL, 2.7% for 355 pg/mL, 1.9% for 1068 pg/mL and 1.8% for 4962 pg/ml. The laboratory technician who measured NT-proBNP levels was at a different site and blinded to the characteristics of the patients and the results of echocardiograms. NT-proBNP reagents were kindly provided by Roche Diagnostics .Before the study appointment, patients completed an overnight fast except for taking their regularly prescribed medications. A 21-gauge butterfly needle was inserted intravenously in the forearm, and after a 30-minute supine rest, blood samples were drawn into lithium-heparinate tubes; these were centrifugated and the supernatant was divided into aliquots and stored at minus 70°C. We used the ElecsysEchocardiograms were performed with a Phillips Ultrasound System (Phillips Sonos Agilent) using a 3.5-MHz transducer with the patient in the left lateral position. A complete resting 2D echocardiogram and Doppler ultrasound examination was performed. We obtained standard 2D parasternal long and short-axis to determine left ventricular dimensions. We calculated left ventricular ejection fraction (EF) by the quantitative 2-D (biplane Simpson) method. An EF<50% was defined as systolic ventricular dysfunction. Echocardiograms were additionally rated concerning abnormalities defined as diastolic dysfunction . Three oAssessing group differences, we used t-tests for continuous variables and Chi-Square-tests for comparisons of frequencies. A multiple logistic regression analysis was done to identify clinical variables that have a statistically significant diagnostic value in predicting left ventricular systolic dysfunction. We used a backward conditional model, including sociodemographic and clinical variables. Selected variables were used to estimate an individual patient risk score, thus, the sum of the β coefficients for each of the specific risk factors multiplied by their actual values .We assessed the diagnostic performance of the NT-proBNP assay and the risk score by using receiver operating characteristic curves (ROC). The overall discriminative power of NT-proBNP and the clinical risk score is shown by the area under the curve (AUC). Comparisons between AUCs were assessed according to the method of Hanley & McNeil . In addiAll analyses were two-tailed and the alpha was defined at 0.05. Statistical analyses were carried out using SPSS and Microsoft EXCEL. The study was approved by the local ethics committee, and all patients gave written informed consent before examination.Table A logistic stepwise regression with left ventricular dysfunction as the dependent variable and 17 independent variables as covariates was conducted. The backward conditional model selected the following three covariates: dyspnea at exertion combined with ankle swelling, history of coronary artery disease, and treatment with diuretics. Other variables were entered into the model but were excluded by the stepwise regression: age (dichotomized by the median), sex, BMI>30, diabetes mellitus, hypertension, hyperlipidemia, myocardial infarction, family history of early heart disease, treatment with ACE inhibitors, β blockers, calcium channel blockers, AT1 blockers, or lipid lowering agents Table .Figure 1 × dyspnea at exertion × ankle swelling) + (β2 × coronary artery disease) + (β3 × diuretics). AUC of the clinical risk score indicates its diagnostic value for left ventricular systolic dysfunction and can be rated as excellent.Figure The cut-off point was determined as having a moderate specificity and a high sensitivity compared to the NT-proBNP test. The negative likelihood ratio of a clinical risk score below 1.11 is 0.14 and indicates that the probability of a negative test result is seven times lower in patients with impaired left ventricular systolic dysfunction than in patients with preserved left ventricular function. Table The minimal difference of 0.019 between AUCs of NT-proBNP and the clinical risk score was not significant  to 210 (cases where left ventricular systolic dysfunction could not be ruled out), with 21 true positives and 189 false positives. That means, 93 more cases could have been ruled out with the clinical risk score than with NT-proBNP assessment, which would have reduced the number of referrals from 542 to 303, with 21 true positives and 282 false positives.According to our comparison, an evaluation of clinical information could be at least as effective as NT-proBNP testing in ruling out left ventricular systolic dysfunction in primary care patients at risk. Therefore, general practitioners should be encouraged to rely on the diagnostic power of the clinical information their patients provide.Roche Diagnostics  was an official member of the study group and supported the present investigation with NT-proBNP test kits. There are no other competing interests.JK and MS performed statistical analyses, wrote and edited the manuscript; DW recruited the patients and coordinated the study; CL, SK, and RW performed the clinical and echocardiographic assessment; CP supervised the measurement of the NT-proBNP levels; MMK, CHL, BP, and LB led conception and design; all authors have contributed to the conception and design and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Signal averaged electrocardiography is a noninvasive method to evaluate the presence of the potentials that are generated by tissues, activated later than their usual timing in the cardiac cycle. The purpose of this study was to demonstrate the correlation of data obtained via signal averaged electrocardiography and left ventricular dyssynchrony.We included the patients with advanced systolic left ventricular dysfunction (ejection fraction ≤ 35%) and intraventricular conduction delay. All patients underwent surface 12-lead electrocardiography, signal averaged ECG, and tissue Doppler echocardiography.The study included 72 patients with mean age of 56.45±13.59 years. Mean QRS duration was 0.14 ± 0.02 sec; 63.9% of patients had left bundle branch block. Linear regression demonstrated significant correlations between filtered QRS duration and interventricular mechanical delay , root mean square 40 and peak velocity difference , root mean square 40 and Ts-SD-12 , low amplitude signals duration and peak velocity difference  and finally low amplitude signals duration and Ts-SD-12  as well. Area under the curve in ROC of filtered QRS duration was significant for the detection of interventricular mechanical delay. Areas under the curves in ROC of low amplitude signal duration and root mean square 40 were significant for the detection of peak velocity difference.Signal averaged electrocardiography can have a role in predicting the amount of ventricular dyssynchrony. The duration of low amplitude signals and root mean square 40 have significant linear relations to some indices of intraventricular dyssynchrony. Cardiac resynchronization therapy (CRT) is an effective treatment for patients with severe heart failure and concomitant wide QRS complex on ECG. It can improve cardiac function, clinical status, quality of life and even survival in the above mentioned group . CurrentHigh resolution ECG is designed for body surface recording of the cardiac signals that are not visible on standard ECG. Signal averaging is an approach to produce high resolution ECG. In this type of electrocardiography, late potentials are generated by tissues, activated later than their usual timing in the cardiac cycle . MeanwhiThe patients included in the study were selected consecutively among those referred to our centers with impression of heart failure and subsequent treatment. Following inclusion criteria were considered: (1) advanced systolic left ventricular dysfunction (left ventricular ejection fraction ≤ 35%); (2) underlying cause being idiopathic dilated cardiomyopathy (DCM) or  ischemic heart disease (IHD), (3) NYHA class III or IV, (4) QRS complex duration ≥ 120 ms. All patients signed written informed consent. We excluded patients with: (1) non-sinus rhythm; (2) previous pacemaker implantation; (3) a recent myocardial infarction (< 3 months); (4) severe aortic disease (5) right bundle branch block. All patients underwent a standard 12-lead ECG, a SAECG and an echocardiographic examination, including specific evaluation of interventricular and intraventricular dyssynchrony. The study was approved by the institutional review board.Imaging was done in the left lateral decubitus position, recording  parasternal and apical views  using a commercially available system . A 3.5-MHz transducer was used. Left ventricular volumes  and left ventricular ejection fraction were calculated from the conventional apical two- and four-chamber images, by the biplane Simpson's technique. Mitral regurgitation was graded according to the jet area method.The aortic and pulmonary pre-ejection times were measured, starting from the beginning of QRS complex to the beginning of the flow velocity curve. The difference between the two values determined interventricular mechanical delay (IVMD), as the index of interventricular dyssynchrony. M-mode was used to obtain septal to posterior wall motion delay (SPWMD). Color-coded tissue Doppler imaging was acquired in 2-D mode from the apical 4-chamber and 2-chamber views to assess myocardial regional function. Off-line analysis of the time to peak velocity was performed at the level of the basal and middle segments of the interventricular septum and the lateral, inferior, anterior, posterior and anteroseptal walls, with reference to the QRS complex. The peak velocity difference (PVD) was measured as the time difference between the earliest and latest contracting segment. To determine septal to lateral wall delay (SLWD), the sample volume was placed in the basal portion of the septum and the lateral wall. Peak systolic velocities and time-to-peak systolic velocities were obtained and septal-to-lateral delay in peak velocity was calculated. In addition to PVD, SLWD and SPWMD, the standard deviation of time to peak systolic velocity of the 12 LV segments (Ts-SD-12) and six basal segments (Ts-SD-6) were calculated in each patient as indices of intraventricular dyssynchrony.QRS duration was measured on surface ECG. ECG was recorded at a speed of 25 mm/second and a scale of 10 mm/mV. QRS duration was measured as the widest QRS complex in precordial leads. QRS durations equal or more than 0.12 sec, no q-wave but slurred, broad R waves in leads I, aVL and V6 and rS or QS deflections in lead V1 were considered as the ECG features of left bundle branch block (LBBB). On the other hand, QRS durations equal or more than 120 ms, broad and notched R waves in leads V1 and V2 and deep S deflections in left precordial leads and I were noted as the ECG features of right bundle branch block (RBBB). A prolonged QRS not associated with the typical features of bundle branch block, was labeled as nonspecific intraventricular conduction delay (IVCD).The filtered QRS duration, root-mean-square voltage of the terminal 40 milliseconds in the filtered QRS complex (RMS40), and duration of low-amplitude signals <40 μV in the terminal filtered QRS complex (LAS40) were calculated, using signal averaged ECG  with noise level <0.3 μV and high-pass filtering of 40 Hz. Two hundred cardiac cycles were acquired and averaged each time. The key hardware elements of the system were an amplifier, a convertor for digitization of signals, a signal processor and a printer. In this system, a computer algorithm was utilized to identify QRS onset and offset. Filtering was applied to reduce the residual noise and improve identification of low potentials.Continuous data were expressed as mean ± standard deviation values. Linear regression analysis was the chosen method for evaluating the association between signal averaged data and echocardiographic characteristics of patients with dyssynchrony indices. A P value less than 0.05 was considered to be statistically significant.Receivers operating characteristic curves (ROC curves) were used to determine the area under the curve (AUC) and the optimum cut off level of each SAECG indices and the 95% confidence intervals (CI) were obtained. The optimum value is the value that minimizes the distance from the upper left corner of the plot frame.The study population consisted of 72 patients; 55 (76.4%) men and 17 (23.6%) women. The mean age was 56.45±13.59 years. The underlying etiology of heart failure was ischemic in 63.9% of patients. Seventy one (98.6%) patients were in NYHA class III. The baseline characteristics of the study population are summarized in All patients had sinus rhythm on ECG. Mean QRS duration was 0.14 ± 0.02 sec (range: 0.12–0.2 sec); 46 (63.9%) patients had LBBB morphology and 26 (36.1%) patients had nonspecific IVCD morphology. The mean filtered QRS duration was 153.81 ± 20.61 ms (range= 116-234 ms). The mean RMS40 was 14.36± 13.43 μV (range=3-73 μV) and the mean LAS40 was 46.85± 22.36 ms (range=4-98 ms).Considering echocardiography findings, the mean left ventricular ejection fraction (LVEF) was 18.14 ± 5.67% (range 10-33%). 15.3% of patients had severe mitral regurgitation (MR). Detailed echocardiographic characteristics of the patients are presented in Linear regression demonstrated a significant correlation between filtered QRS duration and IVMD  , whereasThere were significant relations between RMS40 and PVD   and RMS4 A significant correlation was found between low amplitude signals duration and PVD   and betwAccording to previous studies, IVMD of 40 ms was considered as significant interventricular dyssynchrony and PVD of 110 ms and Ts-SD-12 of 33 ms were considered as cut off values of significant intraventricular dyssynchrony [Area under the curve in ROC of filtered QRS duration for detection of interventricular dyssynchrony was 0.791  . The curArea under the curve in ROC of RMS40 for the detection of PVD was 0.724  . SpecifiArea under the curve in ROC of LAS for the detection of PVD was 0.720  . SpecifiSAECG indices did not show any significant AUC for detection of other echo parameters.Currently, CRT is considered an important therapy for patients with advanced heart failure and concomitant wide QRS complex. Prolongation of QRS (>120 ms) occurs in 14% to 47% of patients with heart failure. LBBB occurs more commonly than RBBB (25% to 36% vs. 4% to 6%) [However, QRS duration measurement is not an optimum way to select suitable candidates for CRT. Analysis of the CRT patients have shown that despite prolonged QRS duration, at least 30% of the patients did not respond to CRT and there were no significant difference in baseline QRS duration, between clinical and echocardiographic CRT responders versus non-responders . KashaniThe signal averaged electrocardiography is a non-invasive test for risk stratification of sudden cardiac death, especially in survivors of MI. This technique results in an improvement of the signal to noise ratio, thus allowing analysis of signals that are too small to be detected by routine measurement . Our datLike QRS duration in surface ECG, the amount of filtered QRS duration had only a significant relation to interventricular dyssynchrony. The presence of fQRS of 144 ms indicates the presence of significant interventricular dyssynchrony with 76% specificity. According to previous studies, intraventricular dyssynchrony is more important for prediction of CRT response than interventricular dyssynchrony . So filtOur results are in contrast with the results of two recent studies ,11 whichSeveral limitations of the study also need to be acknowledged. First, this is a small study and evaluation of a large group of patients is needed to confirm our results. Second, we used echocardiography to assess ventricular dyssynchrony as the standard. According to previous studies, most echocardiographic techniques have limited interobserver reproducibility and significant training is required . Third, According to our data, signal averaged electrocardiography can have a role in predicting the amount of inter- and intraventricular dyssynchrony. The duration of low amplitude signals and root mean square 40 have significant linear relations to some indices of intraventricular dyssynchrony (PVD and Ts-SD-12). The clinical significance of our findings warrants further investigation.


The ever expanding epidemic of end-stage heart failure represents one of the greatest challenges of modern cardiovascular medicine. With medical treatments hampered by significant limitations, physicians caring for patients with advanced heart disease have turned to cardiac transplantation and durable mechanical circulatory assist devices as definitive therapies. These advanced therapeutic modalities are not widely available outside the United States and Europe, but nevertheless offer enormous potential for patients in the Arab Gulf suffering from end-stage heart failure. This review will discuss the management of end-stage heart failure in the Gulf States, with an emphasis on therapies best utilized within a framework of regional cooperation and coordination. The management of patients with end-stage heart failure has emerged as one of the major challenges in cardiovascular medicine. There has been considerable progress in the understanding of heart failure pathophysiology leading to medical therapies that impact the prognosis and symptoms of chronic heart failure.52 and diabetes mellitus in 23.7%.1517The incidence of cardiovascular disease and heart failure is projected to increase substantially in the Arab Gulf States as the region completes an epidemiological transition fueled by socioeconomic change.It is estimated that 5-10% of heart failure patients have end-stage, refractory disease.1927th century, digitalis glycosides such as digoxin reduce hospitalizations for heart failure and provide modest symptomatic relief, but they do not prolonged survival.4041The major advances in heart failure therapies have been primarily seen with systolic heart failure with a reduced ejection fraction. There is no debate that beta-adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin-receptor blockers (ARBs) offer an improved survival, and the frequency of their administration is emerging as a quality of care benchmark.In patients with diastolic heart failure, the most effective therapies will include diuresis, control of blood pressure, and maintenance of sinus rhythm.34344Most medical therapies have been directed toward NYHA Functional Class II-III or AHA/ACC Stage C heart failure and have a limited role once the evolution of heart failure have moved to Class IV NYHA or Stage D Tables  and 2. IMany heart failure patients with a low ejection fraction often also have interventricular conduction delay, as manifest by a widened QRS complex (>120 msec) on electrocardiogram from either a bundle branch block or nonspecific conduction delay. This delay creates dyssynchronous contraction of the left ventricle and can contribute to remodeling, mitral regurgitation and symptoms of congestion.26The primary goals in the management of end-stage heart failure are to reduce hospitalizations and to improve quality of life. Disease management programs have been shown to be effective in this regard, providing a structured continuity between the hospital discharge and the home setting.46Many patients with refractory congestive symptoms and low cardiac output despite conventional therapy will benefit from infusion of a positive inotrope.53Orthotopic cardiac transplantation remains the definitive therapy for terminal heart failure.59The primary barrier to cardiac transplantation in the Gulf States is the ad hoc organization of donor supply. While a limited number of centers have been able to perform the intermittent transplant, no program in the Gulf has achieved sufficient experience that would meet program certification goals of national regulatory bodies. Saudi Arabia is the only country within the Gulf region with a solid organ transplant organization, the Saudi Center for Organ Transplantation (SCOT), and King Faisal Specialist Hospital in Riyadh is the only heart transplant center. In 2008, the last year for which data is available, there were 19 cardiac transplantations in SCOT, preceded by 12 transplants in the year prior.Sadly, mortality is rapidly rising in the Gulf states from motor vehicle collisions as well as cerebral vascular accidents from poorly controlled hypertension—the most common conditions causes brain death while preserving the potential for organ donation. While automobile accidents and strokes present a significant challenge to public health authorities, they also represent an opportunity to coordinate donor management, procurement and distribution. The Gulf Cooperative Countries (GCC) have already established political, travel and trade alliances. Established in 1981, the six GCC countries include Saudi Arabia, United Arab Emirates, Kuwait, Oman, Qatar and Bahrain with a population base approaching 41 million and a unifying culture. Organization of solid organ transplantation dovetails with the GCC charter which specifically outlines a goal of integration and inter-connection between members states in all fields to encourage cooperation and joint ventures.Many existing organ procurement organizations cross political boundaries to serve the collective transplant need. In the United States, the New England Organ Bank represents 6 states and Bermuda, with a population base of 11.2 million. The Eurotransplant Interntational Foundation serves the transplant needs of Austria, Belgium, Germany, Luxembourg, the Netherlands, Slovenia and Croatia, with a population of 124.5 million and coordinated 6,600 solid organ donations. In order to address the current and future needs of all solid organ transplantation for the GCC, a coordinated transnational organ procurement organization representing the interests of the populations of all the Gulf States must be considered.And if any one saved a life, it would be as if he saved the life of the whole people. 64It is beyond the scope of this article to discuss the many religious and cultural issues surrounding solid organ transplantation. Organ donation, harvest and transplantation are a relatively new cultural concept in the Islamic and Arabic world and subject to a variety of interpretations. Renal transplantation, given its longer history, has wider acceptance than other solid organ programs.Given the immediate limitations to cardiac transplantation in the Gulf States and ultimate limitations of donor supply, ventricular assist devices (VAD) may be the most reasonable option for long-term hemodynamic support.665The clear survival advantage and quality of life for patients receiving VADs compared to medical therapy now justifies their use for circulatory support well beyond the transplant setting. In REMATCH, the implantation of a left-sided VAD was associated with a relative reduction in the risk of death of 48 percent during the entire follow-up period of 4 years and an absolute reduction in the mortality rate of 27 percent at one year.6972Prior to VAD implantation, all patients should be evaluated at cardiac centers with specific expertise in advanced heart failure.The ample costs associated with VAD implantation are contingent on the type of device used, length of hospital stay, country-specific health economics, and the nature of the underlying disease.Any cost-effectiveness analysis must also take into account the rapid evolution of technology used. Since the axial flow devices are smaller, simpler to use, and more durable, it can be anticipated that they will also be more cost effective. In addition, the cost of a new medical technology usually declines as it becomes more widespread and management issues standardized. Continued improvements to the next generation of devices can be anticipated to extend durability and reduce complication rates.80The management of heart failure is both a challenge and an opportunity for the health care systems of the Gulf region. Advanced therapies for terminal heart failure remain elusive. While cardiac transplantation remains a potential option, there are logistical limitations in the Arabic world at the present time that limit widespread applicability. The new technologies of mechanical circulatory assistance may be a better option for end-stage patients, and requires thoughtful analysis and candid discussion about the priorities of health care resource allocation. Heart failure patients in the Gulf are deserving of these advanced therapies that will improve the quality and length of their lives.


Myocardial perfusion imaging (MPI), using single photon emission computed tomography (SPECT) is a validated method for detecting coronary artery disease. Transthoracic Doppler echocardiography (TTDE) of flow at rest and during adenosine provocation has previously been evaluated in selected patient groups. We therefore wanted to compare the diagnostic ability of TTDE in the left anterior descending coronary artery (LAD) to that of MPI in an unselected population of patients with chest pain referred for MPI. Our hypothesis was that TTDE with high accuracy would identify healthy individuals and exclude them from the need for further studies, enabling invasive investigations to be reserved for patients with a high probability of disease.Sixty-nine patients, 44 men and 25 women, age 61 ± 10 years (range 35–82), with a clinical suspicion of stress induced myocardial ischemia, were investigated. TTDE was performed at rest and during adenosine stress for myocardial scintigraphy.We found that coronary flow velocity reserve (CFVR) determined from diastolic measurements separated normal from abnormal MPI findings with statistical significance. TTDE identified coronary artery disease, defined from MPI, as reversible ischemia and/or permanent defect, with a sensitivity of 60% and a specificity of 79%. The positive predictive value was 43% and the negative predictive value was 88%. There was an overlap between groups which could be due to abnormal endothelial function in patients with normal myocardial perfusion having either hypertension or diabetes.TTDE is an attractive non-invasive method to evaluate chest pain without the use of isotopes, but the diagnostic power is strongly dependent on the population investigated. Even in our heterogeneous clinical cardiac population, we found that CFVR>2 in the LAD excluded significant coronary artery disease detected by MPI. Coronary artery disease (CAD) is the most common cause of death in the western world, despite advances in medical, interventional and surgical treatments. The diagnosis of coronary disease is often based on patient symptoms and an exercise test. However, the sensitivity for the detection of ischemia using exercise in combination with electrocardiography is low, in the range of 60% . MyocardGould et al have shown that resting coronary blood flow does not decrease until coronary artery diameter is reduced by 85%. The coronary flow reserve, however, begins to decrease already with a 30–45% reduction of the arterial diameter ,10. In hnd degree AV-block or higher, obstructive pulmonary disease or treatment with dipyridamole as well as theophylline preparations. The subjects were instructed to abstain from xanthine-containing food and drinks  for at least 24 hours before the study.Sixty-nine patients  were enrolled between November 2004 and October 2005. They were all referred for myocardial perfusion imaging because of suspected or known CAD. Eighteen had a history of a previous myocardial infarction and 14 were revascularised (9 with PCI and 5 with CABG). One patient had an aortic valve prosthesis. Sixty-six patients were in sinus rhythm, 2 in atrial fibrillation and one had a pacemaker. Twenty-three patients had a normal electrocardiogram (ECG). Twenty-two patients had anti-hypertensive treatment and 11 were diabetics. Forty-six patients were on betablockers, 10 on calcium inhibitors and 16 on ACE inhibitors. No changes in medication were made prior to the study. Exclusion criteria were acute myocardial infarction, unstable angina, 2The study was approved by the Regional Ethics Committe at Linköping University. All subjects gave informed consent.Adenosine is a potent vasodilatator producing maximal coronary vasodilatation within 40–50 seconds. The plasma half-life is less than 10 seconds and side-effects (mainly hyperpnea and flush) and hyperaemia thus subside quickly after termination of infusion. Adenosine was administered intravenously (0.140 mg/kg/min) for 5 minutes. A 12-lead ECG was continuously recorded before, during and up to 5 minutes after the adenosine infusion. Blood pressure was determined at rest and at 1–2 minutes intervals during the infusion. Preset criteria for reducing or stopping the infusion were acute bronchospasm, advanced AV block, decrease in systolic blood pressure > 20 mmHg or patient refusal.Echocardiographic examinations were performed with a Sequoia C256 or 512  using a broadband transducer (3V2c and 4V1c respectively). For colour Doppler (CD) flow mapping, the velocity range was set at 12 to 20 cm/s. The colour gain was adjusted to provide optimal images with minimal "bleeding" of colour onto tissue, fig The patients were examined in the left lateral position. The aim was to record flow in the most distal part of the left anterior descending artery (LAD). To image the distal LAD, the transducer was positioned either at the cardiac apex or one intercostal space above and focused on the proximal field. The transducer was rotated and tilted until the distal coronary segment could be visualized by CD at the epicardial part of the anterior wall. Alternatively, a short axis view of the left ventricular apex and anterior groove was interrogated with CD. When diastolic CD blood flow was detected, the transducer was slowly rotated clockwise to obtain the best long axis view of the LAD.If no CD blood-flow from the LAD was visualized in the baseline condition before the infusion, a new resting recording was made at least 5 minutes after the infusion was stopped. No contrast agent was used.Stop frames of the spectral Doppler signal were repeatedly stored during the investigation. Each study was analysed off-line. Measurements were performed by tracing the contour of the Doppler signal on the ultrasound monitor. Signals with a well defined outline were analysed and diastolic peak velocities, mean diastolic velocities and diastolic velocity time integrals were measured at baseline and peak hyperaemic conditions. Due to systolic movements of the heart, the systo-diastolic averaged peak velocity and velocity time integral were not always determined. The measurements were, if possible averaged over three consecutive heart beats. Coronary flow reserve was calculated as the ratio of peak hyperaemic and basal mean diastolic velocities without knowledge of the results of the SPECT myocardial perfusion imaging.Gated myocardial SPECT was performed using a two-day stress/rest protocol. Adenosine was infused continuously for 5 minutes. At 3 minutes into the infusion, Tc-99m tetrofosmin (5.7 MBq/kg bodyweight) was injected. Supine gated SPECT images were acquired 45–60 minutes later. Rest images were obtained 3–5 days later using 8.6 MBq 99mTc- tetrofosmin/kg bodyweight with acquisition starting 45–60 minutes after the injection. The patients were offered cold water to drink before acquisition in order to diminish bowel artifacts.The acquisitions were made on a dual-detector gamma camera  with a low energy high resolution collimator using 64 projections over 180° (right anterior oblique 45° to left posterior oblique 45°), 30 s per projection. A 19% window was asymmetrically placed (129–155 keV) on the 140 keV peak, asymmetry 2%. The gated and un-gated data were separately reconstructed on a Hermes Medical Solutions  workstation. Prefiltering with a Butterworth filter  was applied followed by filtered back projection. No scatter or attenuation correction was applied. The reconstructed transaxial data were realigned along the heart axis. The short axis slices were then processed with the automatic software packages QPS and QGS .The images were interpreted separately by 2 experienced physicians without knowledge of the outcome of the TTDE. Each observer classified the studies as normal, probably normal, equivocal, probably abnormal and abnormal. In case of an equivocal result, the gated study was evaluated in cine mode, making it possible to reclassify the study as either probably normal or probably abnormal. Finally, the normal and probably normal studies were grouped together as were the probably abnormal and the abnormal studies. The perfusion defects were also assigned to LAD, LCX and/or RCA territories. In three cases there was disagreement between the two observers and consensus was negotiated.The "Summed Stress Score" as a measure of perfusion abnormalities was also quantitatively analysed with the software package commonly used in our clinic .Descriptive statistics were used in combination with Students' t-test, paired or un-paired, when appropriate as well as Pearson Chi-square . A p-value of < 0.05 was considered significant.The clinical characteristics of the patient population are summarized in table The outcome in groups where CFVR was successfully calculated is summarized in table Fig The eight patients with normal SPECT but reduced CFVR all had risk factors for endothelial dysfunction.No serious adverse reactions occurred during adenosine infusion. In 5 patients, the hyperpnea and discomfort caused patient movements precluding the Doppler recording but the adenosine-infusion was not disrupted. TTDE without contrast visualized a distal segment of the LAD in 52 of the 69 patients but CFVR could be calculated only in 48 patients (success rate 70%).No significant differences were found regarding age, gender, BMI, systolic blood pressure, known CAD , normal/abnormal myocardial SPECT between the group where CFVR was successfully calculated and the group where CFVR was not obtained. Also, the groups did not differ with reference to ischemic burden according to the "Summed Stress Score" calculated with QPS, .A CFVR >2 identified patients without SPECT signs of fixed or reversible coronary artery disease with a moderately high specificity (79%).Our study population contained patients with previous revascularization, hypertension, cardiomyopathy and diabetes mellitus. These conditions are associated with reduced endothelial function that might obscure the detection of coronary artery disease , thus exSince MPI is the most frequently used non-invasive method for ruling out significant coronary artery disease and its high diagnostic accuracy is well documented ,24, we cWhich conditions may complicate the use of TTDE? Adenosine, a strong dilator of the coronary microcirculation, is considered to have little effect on the epicardial arteries . If the Withdrawal of vasoactive medication was not required in our clinical routine. However, betablockers have been shown to increase CFVR while vasodilators have caused an underestimation of CFVR by reducing the maximal vasodilator response to adenosine. It has In previous studies, adenosine or dipyridamole were used as vasodilators . We chosWe have refrained from using external ultrasound contrast due to signal scattering in colour as well as in spectral Doppler recordings. Recent publications have shown that the use of ultrasound contrast markedly improves the measurement of coronary flow velocity -33. HoweThis study was performed by one experienced ultrasound operator, who in preparation for this study, devoted considerable time to master the skills of coronary scanning. Still, the success rate was low, 70%, partly due to difficult scanning conditions in overweight patients and partly due to the discomfort induced by adenosine itself. Thus, the selection of patients seems as important as training in improving the success rate. In this study, we limited TTDE scanning to the LAD and the result was compared with MPI in the LAD territory. However, other authors have shown the applicability of scanning all three coronary vessels .In conclusion, based on our results, we suggest that CFVR>2 in the LAD will exclude significant coronary artery disease in a clinical setting. A low CFVR is more difficult to interpret since multiple cardiovascular and metabolic risk factors as well as epicardial vessel disease or microvascular dysfunction might be responsible. This complicates the use of TTDE as a method for detecting coronary disease in individual patients with a heterogeneous clinical background. However, because of its non-invasive nature and absence of radiation, the method seems to be well suited for repeated investigations of CFVR in a variety of pathophysiological conditions, such as detecting changes in endothelial function after intensified treatment in patients with cardiovascular risk factors. These results may stimulate future clinical studies on the use of TTDE in clinical practice.The author(s) declare that they have no competing interests.EM planned the study, investigated all patients, performed all measurements and the main part of writing the manuscript. JE participated in the planning of the study, statistical analysis and in the writing process. JO participated in the planning of the study, was responsible for the evaluation of the scintigraphic part and took part in statistical analysis and writing the manuscript. EN was involved mainly in evaluation of the results and in the writing and editing process. All authors have read and approved the final manuscript.