The use of a large number of cardiovascular biomarkers, meant to complement the use of the electrocardiogram, echocardiography cardiac imaging, and clinical symptom assessment, has become a routine in clinical diagnosis, differential diagnosis, risk stratification, and prognosis and guides the management of patients with suspected cardiovascular diseases. There is a broad consensus that cardiac troponin and natriuretic peptides are the preferred biomarkers in clinical practice for the diagnosis of the acute coronary syndrome and heart failure, respectively, while the roles and possible clinical applications of several other potential biomarkers are still under study. This review mainly focuses on the recent studies of the roles and clinical applications of troponin and natriuretic peptides, which seem to be the best-validated markers in distinguishing and predicting the future cardiac events of patients with suspected cardiovascular diseases. Additionally, the review briefly discusses some of the large number of potential markers that may play a more prominent role in the future. According to the World Health Organization (WHO), cardiovascular disease (CVD) is the number one cause of death globally and is responsible for 45% of all deaths, equating to >4 million deaths per year in Europe . Its higClassically, biomarkers, such as cardiac troponin and the natriuretic peptides (NPs), associated with acute coronary syndromes and heart failure, respectively, play an important role in routine clinical practice. The ideal biomarker for detecting myocardial injury needs to be expressed at relatively high levels within cardiac tissue, with high clinical sensitivity and specificity that is detectable in the blood early after the onset of symptoms, such as chest pain . As therNatriuretic peptides (NPs), composed of three structurally similar peptides, that is, atrial natriuretic peptide (ANP), B-type (or brain) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), play an important role in cardiovascular disease  and are We performed PubMed and Web of Science searches for original studies and screened reference lists to identify possible relevant studies by searching the literature from 2003 to 2019. Search terms were “biomarker,” “new biomarker,” “B-type natriuretic peptide,” “cardiac troponin,” “C-reactive protein,” “copeptin,” “endothelial cell-specific molecule 1,” “interleukin-6,” “inflammatory medium,” “cardiac myosin-binding protein C,” “gene expression biomarkers,” “heart-type fatty acid binding protein,” “platelet related biomarkers,” “transmembrane and soluble isoforms,” “cystatin C,” “microRNA,” “acute coronary disease,” “coronary artery disease,” “heart failure,” “non–ST-elevation acute coronary syndrome,” etc. Studies were included if they were prospective, retrospective, randomized controlled trials or animal models.This article will provide an overview of cardiac biomarkers, mainly focusing on the recent studies of the role and applications of cTn and NPs in the diagnosis, risk stratification, and management of patients with acute coronary syndromes and heart failure. Additionally, this article reviews some biomarkers related to acute coronary syndromes and heart failure that may have potential clinical value in the future.2+, cTnI, which inhibits the ATPase activity of actomyosin, and cTnT, which interacts with actomyosin. cTn mediates the interaction between actin and myosin and thereby regulates cardiomyocyte contraction [The cTn complex is one of the components of the thin filament and it plays a significant role in the regulation of muscle contraction. This complex is composed of three isoforms, namely, cTnC, which binds Catraction . cTnI antraction –18, whictraction . Many retraction . In clintraction –18, 20 btraction . In additraction , 23.cTn is an integral criterion in the diagnosis of AMI. According to the 2015 European Society of Cardiology (ESC) guidelines for NSTE-ACS, the measurement of a biomarker of cardiomyocyte injury, preferably hs-cTn, was mandatory in all patients with suspected NSTE-ACS . An undeOne report has shown that while hs-cTnT and hs-cTnI seem to have comparable diagnostic accuracies, hs-cTnI had greater early diagnostic accuracy . That suBeyond diagnostic utility, cTn levels provide prognostic information in predicting short- and long-term outcomes based on clinical and ECG variables. Numerous studies have demonstrated a strong independent relationship between cTn and prognosis . Meta-anBNP is synthesized and released by cardiac ventricular cells in response to volume or pressure overload . Both acGuidelines recommend the use of BNP or NT-proBNP in the diagnostic algorithm for HF, especially for the patients whose echocardiography was not found to have an important cardiac abnormality , with hiIn addition to their utility in HF diagnosis, the levels of BNP or NT-proBNP are remarkably useful for risk stratification and management of patients with suspected HF. In HF management, the trend of decreasing levels of natriuretic peptide indicates effective management strategies . RecentlBoth cTn and BNP are quantitative markers of cardiac damage and widely applied in clinical diagnosis, risk stratification, and management of patients with or without cardiovascular diseases. BNP, widely used for the diagnosis and risk stratification of patients presenting with suspected heart failure, may sometimes be measured after an ACS in order to identify patients at high risk and low risk of adverse outcomes . In patiIn James and his coworkers' research, they measured BNP in samples obtained three days after the onset of ischemic symptoms in 2525 patients and found that BNP could provide predictive information for use in risk stratification across the spectrum of acute coronary syndromes, such as the risk of new or recurrent myocardial infarction . CTn, coBoth cTn and BNP/NT-proBNP are definitive biomarkers of ACS, but they are not enough. Therefore, it is necessary to explore more markers to facilitate earlier and appropriate diagnosis, risk stratification, and management of patients. Moreover, using one or two biomarkers to define the complex pathophysiology of heart failure is inadequate and novel biomarkers are still required for the diagnosis and management of cardiovascular diseases. However, because the literature on the variety of cardiac biomarkers in clinical practice is too large to summarize in one article, this article only focuses on some useful and routine biomarkers.CRP is a useful prognostic indicator in patients with ACS, as elevated CRP levels are independent predictors of cardiac death, AMI, and congestive heart failure . It is tCopeptin, the c-terminal part of the vasopressin prohormone that is released together with arginine vasopressin (AVP) within 0–4 h after symptom onset , observaIL-6, as well as CRP, is a critical inflammation biomarker that may be implicated in the diagnosis, risk stratification, and prognosis of patients with AMI. IL-6 expression is shown to be elevated in induced myocardial infarction by transcoronary ablation of septal hypertrophy, suggesting its diagnostic role . AdditiosCD40L is a molecule involved in both inflammation and the thrombosis process , and a sGal-3 is a member of the inflammation mediators and is related to the extent of myocardial inflammation and fibrosis, which is also negatively correlated with ventricular ejection fraction . FurtherThe interleukin-37 (IL-37) concentration is highly upregulated in acute coronary syndrome and elevated IL-37 baseline is related to poor outcomes , 92. LipcMyC is one of the three isoforms of myosin-binding protein C expressed in the cardiac tissue whereas the other two isoforms are expressed in the skeletal muscle . FollowihFABP is released from injured myocardium and may serve as a potential biomarker for AMI. The assessment of HFABP at the ED admission adds an incremental value to the initial hs-cTnT. The increase in the sensitivity and negative predictive value for patients with chest pain with noncontributive electrocardiogram could potentially allow safe and early rule-out of AMI without the need for further serial troponin testing . In the Endothelial cell-specific molecule 1 (ESM-1), also known as endocan, is a biomarker for endothelial dysfunction  and may Mean platelet volume (MPV) and beta-thromboglobulin (beta-TG) are two important platelet biomarkers that may increase during platelet activation and have a higher expression in patients with coronary artery diseases . High MPST2 is a member of IL-1 receptor family with two forms, namely, transmembrane (ST2L) and soluble (sST2) isoforms . sST2 haIn addition to MI, sST2 also has a beneficial role in diagnosing heart failure, especially for patients with high IL-33 levels . Also, tcys-C is generated in almost all human nucleated cells and serves as a biomarker for early renal impairment. An elevated cys-C level is related to impaired coronary perfusion and undesirable recovery of cardiac function in STEMI patients undergoing PCI  and predmiRNA-208 and miRNA-499 are solely expressed in cardiomyocytes. AMI patients exhibit significant increases in the concentrations of circulating miRNA-208b and miRNA-499 compared with the health control group –137. In miRNA-1 and miRNA-133a are muscle-specific microRNAs that regulate cardiomyocyte growth and differentiation . They arlncRNAs, as well as miRNAs, are observed to be altered in patients with myocardial infarction and may be beneficial for the diagnosis of myocardial infarction –143. In The SIRT family, comprising seven proteins (SIRT1–SIRT7), attracted attention as stress adaptors and epigenetic enzymes involved in the cellular events controlling aging-related disorders and cardiovascular disease . Among sTREMLs are important effectors of the innate immune system, and polymorphisms within genes encoding them may increase the risk of occurrence of various pathologies including cardiovascular disorders. The analysis of the whole genomic expression in the peripheral blood cell model showed that TREML4 was upregulated in the early stage of the acute coronary syndrome , which iβ (TGF-β) cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Under pathological conditions, GDF-15 can be produced by many cardiovascular and noncardiovascular cell types. Higher circulating GDF-15 levels are associated with increasing cardiometabolic risk factors in individuals without the overt cardiovascular disease [GDF-15 is a member of the transforming growth factor- disease . GDF-15  disease , 154, su disease , 156. GD disease , 158.PAPP-A is a high molecular weight and zinc-binding metalloproteinase, and several studies have demonstrated that PAPP-A plays a role in cardiovascular diseases. PAPP-A is a sensitive, specific, and early marker for ACS diagnosis. Coronary PAPP-A levels were significantly elevated among patients at risk for cardiovascular diseases . In the The class II phosphatidylinositol 3-phosphate kinase (PIK3C2A) and the protein arginine methyltransferase 5 (PRMT5) expression have been verified to be downregulated in the AMI and are independent risk factors , 164. YKCurrently, clinicians typically measure either cTn or BNP/NT-proBNP when encountering patients with suspected acute coronary syndromes or heart failure, based on the guidelines published by the European Society of Cardiology or American Heart Association . Knowing


IntroductionCardiac catheterization is widely considered the “gold standard” for the diagnosis of pulmonary hypertension. However, its routine use is limited due to its invasive nature. Therefore, the aim of this study was to evaluate the correlation between pulmonary artery pressures obtained by various parameters of transthoracic echocardiography and cardiac catheterization.MethodsThis study includes 50 consecutive patients with intracardiac shunt lesions diagnosed with severe pulmonary hypertension on echocardiography and admitted for cardiac catheterization at the National Institute of Cardiovascular Diseases (NICVD) in Karachi, Pakistan. Cardiac catheterization and transthoracic echocardiography were performed in all patients simultaneously and systolic (sPAP) and mean pulmonary artery pressure (mPAP) were assessed with both modalities. Correlations and agreement, in terms of Bland-Altman plot, were computed between both modalities for sPAP and mPAP.ResultsOut of 50 patients, 46% (23) were male and mean age was 7.49 ± 4.45 years. On cardiac catheterization, sPAP was 93.92 ± 17.91 mmHg and mPAP was 67.0 ± 14.28 mmHg. Correlation between cardiac catheterization and echocardiography for the assessment of sPAP was 0.917 (p<0.001), and mPAP was 0.832 (p<0.001) for mean gradient of tricuspid regurgitation (PGTRmean), 0.749 (p<0.001) for peak gradient of pulmonary regurgitation (PGPRpeak), 0.691 (p<0.001) for Acceleration time across right ventricular outflow tract (RVOT), and 0.752 (p<0.001) for end gradient of pulmonary regurgitation (PGPRend). Bland-Altman plot showed moderate agreement between two modalities.ConclusionA positive but modest correlation was observed between hemodynamic parameters of transthoracic echocardiography and cardiac catheterization for assessment of pulmonary artery pressures. Transthoracic echocardiography can reliably be used as an initial non-invasive modality for the assessment of pulmonary artery hypertension and can obviate the need of right heart catheterization in some patient especially with mild pulmonary hypertension. Pulmonary hypertension (PH), according to the European Society of Cardiology (ESC) guidelines for diagnosis and treatment of pulmonary hypertension, is defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg at rest assessed by right heart catheterization as gold standard investigation ,2. PulmoCardiac catheterization is widely considered “gold standard” for the diagnosis of pulmonary hypertension . HoweverDifferent studies have compared different parameters of echocardiography for pulmonary artery pressure assessment in pulmonary hypertension patients with cardiac catheterization and found that echocardiographic assessment of peak and mean pulmonary artery pressure (mPAP) is closely related to that assessed by cardiac catheterization . As PH iIn this cross-sectional study, 50 children, aged 1.5 years to 15 years presented at pediatric cardiology department of National Institute of Cardiovascular Diseases Karachi, Pakistan (NICVD) during the study period of January 2018 to July 2018. Patients were selected by using the non-probability consecutive sampling technique. Patients diagnosed with severe pulmonary artery hypertension (PAH) associated with shunt lesion, such as ventricular septal defect (VSD), VSD with atrial septal defects (ASD)/ patent ductus arteriosus (PDA), PDA and PDA with ASD on echocardiography and scheduled for right heart catheterization were included in this study. Consent for the participation and confidentiality was obtained from the parents/guardian of the patients. Patients with cyanotic heart disease, ventricular dysfunction, dysrhythmia, free tricuspid regurgitation (TR), and associated valvular and other cardiac anomalies were excluded from this study. Cardiac catheterization and echocardiography were performed in all patients simultaneously and echocardiography findings such as; peak gradient of tricuspid regurgitation (PGTRpeak), mean gradient of tricuspid regurgitation (PGTRmean), peak gradient of pulmonary regurgitation (PGPRpeak), end gradient of pulmonary regurgitation (PGPRend), right atrial pressure (RAP), and acceleration time across right ventricular outflow tract (RVOT) and right heart catheterization (RHC) finding such as; systolic (sPAP), mean pulmonary artery pressure (mPAP), and mean right atrial pressure (RAP) were recorded on a predefined structural proforma.Echocardiographic examinations were performed by Toshiba Xario 200  ultrasound system with five and six MHZ phased array transducer within a half-hour of cardiac catheterization. Echocardiography was performed by a single experienced sonographer, totally blind to the cardiac catheterization data of the patient. Sweep speed of 100 was kept for the Doppler and an average of three findings were calculated. Assessment of pulmonary artery pressures i.e. systolic and mean, was done by using different parameters including tricuspid valve regurgitation velocity, pulmonary valve regurgitation velocity and acceleration time across right ventricular outflow tract . The macFor Systolic pulmonary artery pressure (sPAP), the tricuspid valve was visualized properly on 2D images in parasternal short axis and the apical four-chamber view and TR jet was obtained by color Doppler. Then, by using continuous-wave Doppler, a satisfactory envelope was obtained. Peak velocity was obtained by tracing the envelope, which was automatically converted to gradient by machine as discussed above. Systolic pulmonary artery pressure was calculated by adding the right atrial pressure to peak gradient .Mean Pulmonary Artery Pressure from tricuspid regurgitation (TR) was calculated by adding right atrial pressure to the mean pressure gradient across the tricuspid valve obtained by tracing TR jet as discussed above. For the calculation of mean pulmonary artery pressure by pulmonary regurgitation (PR), pulmonic valve was visualized properly in the parasternal short axis on 2D images and PR jet was obtained on color Doppler. Then, by using continuous-wave doppler, pulmonary regurgitation wave was obtained, and PRpeak and PRend velocities were measured. These were then converted to gradients as discussed above. Pulmonary artery end-diastolic pressure (PAEDP) was calculated using PAEDP= PGPRend + RAP. The mPAP was calculated from PGPRpeak and PGPRend as mPAP= PGPRpeak + RAP and mPAP = 2PAEDP/3 + systolic PAP/3 respectively ,13.For the calculation of Mean pulmonary artery pressure from RVOT Acceleration Time, RVOT was visualized in the parasternal short axis. Using pulse wave Doppler just proximal to the pulmonic valve, the pulse wave was obtained and acceleration time was measured by taking measurements from the peak to start of the wave. The mean pulmonary artery pressure was then calculated by using mPAP = 90 - (0.62 × ATRVOT) .Cardiac catheterization was performed by an expert cardiologist under conscious sedation on the Toshiba Infinix 800v CFI  machine. Femoral arterial and venous catheterization were done. A Berman Angiographic Catheter or NIH Catheter was used for pressures, and Oxygen saturation of right heart chambers and Pigtail Catheter was used for left-sided chamber pressures and oxygen saturation. Pressures were obtained after proper calibration and zeroing the transducer at mid-chest level.The sample size for the study was calculated using the reported correlation of 0.87 between systolic pulmonary artery pressure (sPAP) assessed by cardiac catheterization and echocardiography [Total of 50 patients were included in this study, out of which 46% (23) were male patients. Mean age of the patients was 7.49 ± 4.45 years (1.5 to 15 years) with 46% (23) patients up to five years of age. In the majority (96%) of the patients , the shunt lesion was VSD. Baseline characteristics of the patients are presented in Table The hypothesis of normality was not rejected for all three measures, namely sPAP and mPAP with Shapiro-Wilk test p-values of ≥ 0.05. On cardiac catheterization, sPAP was 93.92 ± 17.91 mmHg (55 to 140 mmHg) and mPAP was 67.0 ± 14.28 mmHg (30 to 108 mmHg). Assessment of sPAP and mPAP on echocardiography and cardiac catheterization are presented in Table Correlation between sPAP assessed on cardiac catheterization and echocardiography was 0.917 (p<0.001). Similarly mPAP assessed by echocardiography showed correlation of 0.832 (p<0.001) for PGTRmean, 0.749 (p<0.001) for PGPRpeak, 0.691 (p<0.001) for Acceleration time at RVOT and 0.752 (p<0.001) for PGPRend with that assessed by cardiac catheterizationBland-Altman plot for sPAP assessed on cardiac catheterization and echocardiography, presented in Figure Similarly, Bland-Altman plots for mPAP assessed on cardiac catheterization and four parameters of echocardiography showed a strong correlation. Among the four methods for the assessment of mPAP on echocardiography, PGTRmean method showed relatively better agreement with a mean difference of 2.65 mmHg and 95% agreement limits of -13.5 to 18.8 mmHg, as shown in Figure Accurate assessment of pulmonary hypertension (PH) without any invasive modality is quite challenging in clinical practice . TransthSimilarly, Greiner et al. found echocardiographic assessment of sPAP closely related to that assessed by the invasive method. Non-invasive diagnosis of pulmonary hypertension with Doppler echocardiography had a good sensitivity 87%), specificity (79%), and accuracy (85%) for sPAP at cut-off value of 36 mmHg, and area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.91 . It was further reported that Pearson’s correlation coefficient between echocardiography and cardiac catheterization for the assessment of sPAP was 0.87 (P<0.001) [7%, speciFisher et al. conducted a study to assess the utility of the echocardiography as a non-invasive modality for the diagnosis of PH. Despite optimization of the assessment methodology for potential bias, they found significant differences in estimates of pulmonary artery pressures by echocardiography and cardiac catheterization . The BlaResults for our population are not different from other studies. The correlation coefficient was found to be 0.917 (p<0.001) between sPAP assessed on cardiac catheterization and echocardiography. Slightly higher correlation in our study as compared to Greiner et al. can be attributed to the fact that we excluded population with normal PAP due to the ethical concern of invasive procedure (cardiac catheterization) without proper indication . HoweverSimilarly, the correlations between cardiac catheterization and different parameters of echocardiography for the assessment of mPAP were found to be 0.832 (p<0.001), 0.749 (p<0.001), 0.691 (p<0.001), and 0.752 (p<0.001) for PGTRmean, PGPRpeak, Acceleration Time at RVOT, and PGPRend respectively. Bland-Altman plots for mPAP  with pulmonary hypertension, operability depends on pulmonary vascular resistance which is calculated from mean pulmonary artery pressure on cardiac catheterization. Therefore, mean pulmonary artery pressure should be assessed along with systolic pulmonary artery pressure in pulmonary hypertension patient .As PGTRmean and Acceleration Time across RVOT are not in routine use for pulmonary artery pressure assessment, and as the present study shows that tricuspid and /or pulmonary regurgitation was not present in all patients, there is need for a parameter that is not dependant on these factors. As Acceleration time across RVOT showed good correlation with cardiac catheterization for assessment of mPAP, it can be used in situations in which no TR and PR jet are present. Although PGTRmean is not in routine use, our study showed relatively good agreement between mPAP assessed by cardiac catheterization and TTE; therefore, it should be used routinely.A positive but modest correlation was observed between hemodynamic parameters of transthoracic echocardiography and cardiac catheterization for assessment of pulmonary artery pressures. Transthoracic echocardiography can be reliably used as an initial non-invasive modality for the assessment of pulmonary artery hypertension, and can obviate the need of right heart catheterization in some patients, especially those with mild pulmonary hypertension.


After a silentfirst decade, iron deposits in the cardiac tissue lead to arrhythmias, systolic anddiastolic dysfunction, and congestive heart failure in the second or thirddecade.3 In this casereport, we present an adolescent girl who did not receive regular iron chelationtherapy and had cardiomyopathy, arrhythmia and immobile tricuspid valve secondary tothalassemia major.Thalassemia Major is an inherited disorder caused by impaired synthesis of the Bglobin chain and characterized by ineffective erythropoiesis that requires regular,lifelong transfusion therapy, which creates a state of iron overload.A 14-year-old Syrian girl with Thalassemia Major presented to the emergency roomwith a three-month history of increasing fatigue, dyspnea, and abdominaldistension. Her medical history revealed that she had been diagnosed withThalassemia Major at the age of one year old, and she received irregularerythrocyte transfusion and iron chelation therapy in her country. It waslearned that the compliance for previous blood transfusion and chelation therapywas very poor. On general examination, she was undernourished with short stature and the physical examination revealeddyspnea with a typical facial thalassemic feature without cyanosis.Chest x-ray showed areas of consolidation on both sides of the lungs andincreased cardiothoracic ratio .The eleAfter hospitalization in the intensive care unit, inotropes, diuretics and ironchelation treatment  started as soon aspossible. Cardiac enzymes were sent to screen possible myocarditis, and D-dimerwas sent to detect pulmonary thromboembolism. Results were found to be negative.On the seventh day of hospitalization, the electrocardiogram showed atrialflutter . Therefo4 As iron overload, multiple factors such as chronic anemia,hypersplenism, non-progressive restrictive lung disease also lead to cardiaccomplications in Thalassemia Major.5 Iron is mainly stored in myocytes and other cells in the form offree iron, also ferritin and hemosiderin. Free iron, which is referred to as labilecellular iron, is the most toxic form of iron and also the most accessible form forchelation. The goal of iron chelation therapy is to reduce the iron depositionespecially in plasma and other tissues. In some cases, these heart complicationswere reported as reversible with early detection of iron overload and response toregular iron chelation therapy.6In thalassemia, cardiovascular system involvement is pivotal in the prognosis andquality of life. Iron overload cardiomyopathy is the leading cause of mortalityaccounts up to 67% and 71% in thalassemia.Cardiac magnetic resonance imaging (MRI) is the gold standard for detectingmyocardial iron deposition. In our case, cardiac MRI was not performed due to lackof experienced staff in our hospital. Progressive increase of brain natriureticpeptide assay is highly sensitive and specific in the diagnosis of heart failure. Inour patient, brain natriuretic peptide levels were markedly elevated.7Conventional standard echocardiography exhibits pathologic findings at advancedstages of cardiac involvement. The assessment of the ventricular function involvestwo different phenotypes. The first one is ‘dilated cardiomyopathy’ phenotyperevealed by with left-right ventricular dilatation and reduced contractility, whichcause congestive heart failure. The second one is ‘restrictive cardiomyopathy’phenotype revealed by restrictive left-right ventricular filling resulting inpulmonary hypertension, right ventricular dilatation, and heart failure.8In this report, our patient had impaired cardiac functions similar to both dilatedand restrictive patterns of cardiomyopathy. Right, and left ventricle contractilitywas reduced which led to congestive heart failure. Both ventricle diastolicdimensions were increased. Assessment with pulsed and pulsed tissue Dopplerdemonstrated left and right ventricle diastolic dysfunction. Factors that may causepulmonary hypertension in patients with thalassemia include elevated pulmonaryresistance due to high volume of blood flow, elevated shear forces, hypercoagulablestate secondary to splenectomy and nitric oxide formation after chronic hemolysis.Although right heart failure may develop secondary to pulmonary hypertension, inthalassemic patients, it may also develop in the absence of elevated pulmonaryhypertension.9 In our case in contrast to thecarcinoid tumor, the tricuspid valve did not exhibit very bright echoes secondary tofibrous plaques that are deposited on the endocardium of the leaflets.10 Biogenic amine levels in plasmaand urine samples were found to be in the normal range that excluded diagnosis ofcarcinoid tumor. The related literature indicates similar findings in patients withthalassemia; however, illustration of echocardiograms in children is notsatisfactory. Aessopos et al.6reported valvular involvement including leaflet thickening (48%), endocardialcalcification (20%), and left-sided valve regurgitation in adult patients withthalassemia intermedia.6 In ourcase, the patient had serious dysrhythmias due to endocardial involvement,contraction and relaxation dysfunction due to myocardial involvement, and severeleaflet disorder due to valvular involvement. We herein report an extraordinarythalassemia major patient with immobile and non-stenotic tricuspid valve thatemerges as a part of the terminal phase of the cardiomyopathy.In our case, typical stenotic changes and doming that seen in rheumatic diseases werenot present in the tricuspid leaflet. Uniformly, mildly thickened tricuspid leafletswere present with a relatively fixed valve orifice without stenosis. Cardiaccarcinoid usually affects the right cardiac chamber of the heart and results in asimilar presentation. However, it is not reported in the pediatric age group in theliterature. Nevertheless, carcinoid tumor should also be considered as adifferential diagnosis in isolated advanced tricuspid valve involvement.Thalassemia major patients, especially those who do not receive regular chelationtherapy, are under great risk of cardiac involvement. Early detection and regulartreatment regimen enhance their survival and quality of life. We firstly present animmobile tricuspid valve in an adolescent girl. This very rare case of severecardiac findings due to iron deposition is associated with endocardial, myocardialand valvular involvement. In patients with thalassemia, these end-stagecomplications of the cardiovascular system are irreversible despite treatment.


The idea of right heart catheterization (RHC) grew in the milieu of modern thinking about the cardiovascular system, influenced by the experiments of William Harvey, which were inspired by the treatises of Greek philosophers like Aristotle and Gallen, who made significant contributions to the subject. RHC was first discovered in the eighteenth century by William Hale and was subsequently systematically improved by outstanding experiments in the field of physiology, led by Cournand and Dickinson Richards, which finally resulted in the implementation of pulmonary artery catheters (PAC) into clinical practice by Jeremy Swan and William Ganz in the early 1970s. Despite its premature euphoric reception, some further analysis seemed not to share the early enthusiasm as far as the safety and effectiveness issues were concerned. Nonetheless, RHC kept its significant role in the diagnosis, prognostic evaluation, and decision-making of pulmonary hypertension and heart failure patients. Its role in the treatment of end-stage heart failure seems not to be fully understood, although it is promising. PAC-guided optimization of the treatment of patients with ventricular assist devices and its beneficial introduction into clinical practice remains a challenge for the near future. To elucidate the state of the art of right heart catheterization, focusing on the background of the initial experiments and its physiological meaning, which leads to its implementation in clinical practice. To indicate potential directions for future research.Right heart catheterization (RHC) has emerged as an invasive procedure with a potent role among the current armory of clinical diagnostic tools, including computed tomography (CT), magnetic resonance imaging (MRI), and genetical immunoassays sampling ,2. The bThe work, containing 17 chapters within 72 pages, irretrievably changed the modern understanding of the blood circulation. It is important to keep in mind that Galen was the first person to make extraordinary contributions to the concepts of physiology and medicine that turned out to be widely accepted paradigms. He believed that the circulatory system consisted of two separated parts: venous, originating from the liver, and arterial, originating from the heart. The idea of two separate, unidirectional systems of distribution rather than a unified system of circulation remained unchallenged for many centuries. Harvey, although heavily influenced by his potent predecessor, unwillingly found himself in the position of a revolutionary antagonizer. Harvey’s way of thinking and analyzing different phenomena was heavily influenced by another ancient Greek philosopher, Aristotle ,5. The A“De motu cordis” was released in Europe during the Thirty Years’ War, described as one of the most destructive and violent periods in human history. This era was characterized by different political, religious, and cultural movements . During these times of overwhelming crime, plagues, and the rising wave of inquisition, the signs of independent thinking, especially when based on evidence and experiments, were unwanted and considered dangerous ,7.As time passed, further attempts to experimentally evaluate the circulatory system were made. In 1711, Stephen Hale reported the measurement of cardiac output (CO) with the use of brass pipes introduced into equine veins and arteries ,9,10,11.The innovative dual-lumen catheter device was designed to simultaneously assess the intracardiac pressures of the left ventricle and the aorta, as well as the atrium and the right ventricle. These experiments discovered the so far unreported phenomena of ventricular pressure curves, isometric phase of ventricular contraction, interventricular synchrony, and the chronology of valve closing. It is worth noting that Marey was also renowned as a pioneer of electrocardiography, with significant contributions in the field made by the discovery of the refractory period in 1875 and the first recording of electrocardiogram with the use of capillary electrometer in 1876 .Le mouvement and Le vol des oiseaux [Remarkably, it was nearly three decades before Willem Einthoven reported his invention, which was about to revolutionize the modern diagnosis and treatment of cardiovascular disorders. In his late years, Marey, being somehow possessed by the idea of a general visualization of the motion of different species present in the environment, turned his professional activity towards chronophotography, which he documented in books entitled  oiseaux .German scientists Fritz Bleichroeder, Ernst Unger, and W. Loeb continued the pathway of right heart catheterization in animals, and performed self-experiments in that field; however, these were scarcely documented . A breakThe denazification process, to which he had been submitted in the late 1940s, did not alter his recognition in the area of right catheterization, for which he was awarded the Nobel Prize in 1956, along with Doctors André Cournand and Dickinson Richards. Remarkably, Doctors Cournand and Richards, during their work at the Department of Physiology of the Bellevue Hospital in New York, made an extraordinary contribution to the refinement of the antecedents techniques; they were the first to report a reliable measurement of CO using the Fick principle .Moreover, they understood the phenomenon of oxygen debt in the setting of “clinical shock”, which they managed to treat successfully with the implementation of a human serum albumin . These oIts monitoring, first demonstrated by Hellems and co-workers, was a fairly safe technique of estimating left atrial pressure in the absence of mitral regurgitation . RemarkaThe preferred access point is the internal jugular vein. Its patency and anatomical conditions are reassured during an ultrasound examination, which is believed to reduce access site complications ,37,38,39The European Society of Cardiology (ESC) and the European Respiratory Society (ERS) recommend performing the zeroing of the transducer at the mid-thoracic line . It After zeroing, the measurements of the right atrium, right ventricle, pulmonary artery, and capillary wedge pressure are performed. The currently accepted and recommended measurement of cardiac output is the thermodilution method, in which a constant amount of saline  is injected into the bloodstream—the difference in the temperature is analyzed by the thermistor and recorded. It is important to collect at least three to five results of CO in order to acquire reliable values, especially given that it affects the decision-making process in the real-life clinical setting . It is noteworthy that inaccurately measured, reduced CO will result in raised pulmonary vascular resistance (PVR), according to the equation (PAPm (PAPm—pulmonary artery pressure mean)—PAWP/CO = PVR). In clinical practice, the assessment of the CO by the use of thermodilution is preferred to the evaluation by the Fick method. The latter, in which the cardiac output is calculated as the quotient of oxygen uptake (O2) and the difference of the arterial and mixed venous oxygen content, is advised in the case of tricuspid regurgitation. The main limitation of the Fick method is caused by the fact that the bedside measurement of oxygen uptake is technically demanding. To see the basic definitions and range of normal values please refer to Since there existed a vital need to monitor the severely ill patients’ pulmonary artery, catheterization has been widely introduced into clinical practice, including pediatrics, cardiac surgery, invasive treatments in different kinds of clinical settings, including a wide variety of shock states originating from the circulatory and/or septic background ,66,67,68These complications had different natures—from relatively mild dissections in the puncture site to serious ones with systemic clinical implications, like tricuspid valve chord rupture or pulmonary hemorrhages. Apparently, the learning curve and equipment imperfections could have been blamed to some extent; however, re-evaluation of this clinical modality of invasive cardiovascular system assessment, according to the evidence-based medicine, rapidly generated interest in the community of intensive care practitioners and physicians ,80,81,82The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) lead by Connors and co-investigators was the first prospective cohort study designed to address the issue of pulmonary artery catheter (PAC) effectiveness and costs . PAC (fop < 0.01). Nevertheless, PAC use was not associated with any survival benefit within a 30-day observation period, even after propensity score-matching analysis. Doshi et al. [n = 8,516,528), or who developed CS  during the index hospitalization. They observed a decline in the use of PAC in patients with HF, from 8 PAC used per 1000 admissions in 2004 to 6 PAC used per 1000 admissions in 2007. Additionally, there has been a constant rise in PAC use to 12 PAC per 1000 admissions in 2014 (p < 0.001). Interestingly, there has been a gradual decline in the use of PAC in patients with CS, from 123 PAC used per 1000 admissions in 2004 to 78 PAC per 1000 admissions in 2014 (p < 0.001). Moreover, patients with PAC had increased hospital costs, length of stay, and mechanical circulatory support use. In patients with HF, PAC use was associated with a higher mortality. In those with CS, PAC was associated with a lower mortality and lower in-hospital cardiac arrest; the paradox was also present after propensity score-matching.RHC is currently often used to monitor patients and guide the therapy to optimize filling pressures and volume overloads. Some centers use it excessively in almost all patients, highlighting the point that this technique is basically less prone to subjective inter-observer variability. The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) 85) investigators assessed the results of using RHC in 433 patients enrolled randomly in either an interventional or conservative arm. Remarkably, RHC was used intentionally to optimize pharmacological treatment, not only for those that did not prove any benefit; additionally, it was associated with a higher risk of adverse events, predominantly PAC infection  investig and co-wi et al.  comparedi et al.  and co-ap < 0.01) [Nevertheless, it should be addressed that PAC-guided therapy improved filling pressures and reduced the rates of atrium/brain natriuretic peptides (ANP/BNP) and patients’ quality of life expressed by trade-off protocol. Moreover, its use did not have any impact on overall mortality and, last but not least, its implementation was not assessed in a triage of patients with cardiogenic shock or eligible for ventricular assist device (VAD)/orthotopic heart transplantation (OHT). On the other hand, Tehrani et al. proposed a different, team-based therapy for CS on the base of RHC data. This approach enabled a significant reduction in mortality from 47% in 2016 to 76.6% in 2018 ( < 0.01) . Ma et a < 0.01) . Their p < 0.01) ,93,94,95 < 0.01) . To see RHC is currently considered a gold standard in the assessment of PH, which by definition is associated with the elevation of PAPm above 25 mmHg at rest ,2,97. ClPre-capillary PH is characterized by PAPm ≥ 25 mmHg, and PAWP ≤ 15 mmHg may occur in clinical groups 1, 3–5, where groups 2 and 5 in special conditions consist of different forms of post-capillary PH, which is characterized by PAPm ≥ 25 mmHg and PAWP > 15 mmHg. It can be further divided into isolated postcapillary PH with DPG (diastolic pressure gradient) < 7 mmHg and/or PVR ≤ 3 Wood Units (WU), or a combined form of either pre–and post-capillary component with DPG ≥ 7 mmHg and/or PVR > 3 WU. It needs to be underlined that the role of DPG in the diagnosis of PH has decreased recently, since it is challenging to prove its influence on a patient’s prognosis ,99. The The performance of vasorecactivity testing is recommended in the arterial form of PH, where it contributes significantly to the choice of the treatment regimen . The encSome experienced heart centers use the vasoreactivity testing in heart failure scenario associated with type 2 PH as a part of the integral stratification prior to OHT. Paradoxically, increased PVR above 2.5 WU was associated with unfavorable prognosis only if it was associated with a decrease in systolic blood pressure below 85 mmHg during vasoreactive testing with sodium nitroprusside ,104. TheRHC, although present in experimental physiology and medicine since the beginning of the seventeenth century, still has safety concerns. These, however, are predominantly related to its depersonalized, randomly assigned utilization, regardless of its risk-to-benefit ratio to the patients. RHC is indispensable in PH diagnosis settlement, treatment monitoring, and decision-making. Moreover, it is imperative prior to OHT to stratify the risk of early post-operative RV failure, which might be useful in the end-stage heart failure group of patients (including VADs) in the optimization of pharmacotherapy.


In developed countries heart failure represents a heavy epidemiological burden, with a prevalence of 1–2% of the adult population, rising to ≥ 10% among people with > 70 years of age . In patiRecommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography are in fact explicit in warning that none of the echocardiographic indices should be used in isolation, as some measurements may fall in the normal range despite the presence of diastolic dysfunction due to the several hemodynamic factors that may affect each signal [HFpEF demands a multi-parametric echocardiographic assessment. In this retrospective analysis of data from a previous observational study on stable hypertensive patients, Del Rios et al. considered a single echocardiographic variable in order to assess concordance of EPs and cardiologists in the diagnosis of diastolic dysfunction: medial/lateral averaged mitral annular tissue doppler (TDI) protodiastolic velocity. Other authors have recently investigated the possibility of diagnosing HFpEF by EPs receiving a dedicated training in cardiac bedside ultrasound , or suggh signal .tau although it is not entirely governed by relaxation [TDI acquisition can be technically challenging. Althought E/E’ is key to assess diastolic dysfunction with good reproducibility and reliability, a series of technical issues can affect the accurate measurement of mitral annular TDI. Protodiastolic mitral annular velocity (TDI E’), the cornerstone of diastolic dysfunction diagnosis, reflects mitral annulus motion that precedes filling; it correlates well with invasive measures of the time constant of myocardial relaxation laxation . There alaxation , 14. AllTDI interpretation conceals several pitfalls that should not be neglected. There are a variety of pathological conditions where TDI E’ could be normal in presence of altered cardiac dynamics: constrictive physiology , patientLimited bedside ultrasound diagnostic tests are accurate in specific patient populations, and only when interpreted in tight conjunction with clinical data. One of the basic assumptions of Focused Cardiac UltraSound (FOCUS)  is that the limited ultrasound exam is sufficiently informative only when it is part of a clinical-ultrasound integrated approach , 19, notCore of HFpEF diagnosis is the demonstration of elevated left atrial pressures. Patients may exhibit diastolic dysfunction  unrelated to their respiratory symptoms, i.e. without having high left atrial pressures and congestive HF. Rather than diastolic dysfunction per se, what matters in the approach to patients with suspected acute heart failure is the finding of positive echocardiographic indices of increased left atrial pressures . These sPreliminary data on the feasibility of a proposed simplified approach to diagnose diastolic dysfunction, “more suitable for the use by emergency physicians (EPs) with limited experience in echocardiography”, have been recently reported on the Critical Ultrasound Journal . AlthougThe application of echocardiography in the assessment of diastolic function and cardiovascular pathophysiology requires advanced competences and skills (compared to FoCUS) to both acquire high-quality pictures and signals and to interpret them in the context of the acute cardiac care setting. A recent meta-analysis showed how despite the application of the guidelines for the diagnosis of diastolic dysfunction  this diaThe inherent limitations of FoCUS in the diagnosis of congestive heart failure in the ER can though be partly circumvented by means of clinically integrated multi-organ ultrasound , 26, 27.One of the pivotal rules in medicine is that the difficult path to diagnosis requires a process of integrative, systematic, acquisition of signs, symptoms and data. This is even more true when a complex operator-dependent tool is applied in critical scenarios. Echocardiography is extremely powerful in the study of cardiovascular pathophysiology, and any message supporting the concept of simplifying a complex diagnosis by studying a single echocardiographic parameter risks to be definitively simplistic and misleading, rather than just hazardous. A comprehensive approach which integrates clinical, biochemical, FoCUS, lung ultrasound, and echocardiographic findings is advised to better approach the suspected diagnosis of diastolic dysfunction causing congestive heart failure.


Obesity is associated with type 2 diabetes mellitus, left ventricular diastolic dysfunction and heart failure but it is unclear to which extent it is related to left ventricular systolic dysfunction. The aim of the study was to explore the effects of overweight and obesity on left ventricular systolic function in patients with type 2 diabetes mellitus and a control group of non-diabetic persons.2, overweight 25–29 kg/m2, and obesity ≥ 30 kg/m2). Echocardiography was performed at the beginning of the study and after 4-years in the patient group.We prospectively investigated 384 patients with type 2 diabetes mellitus, and 184 controls who participated in the CARDIPP and CAREFUL studies. The participants were grouped according to body mass index  all are related to body mass index. The mean and standard deviation of left ventricular ejection fraction and global longitudinal strain values were 57% (8%) vs. − 18.6% (2.3%) for normal weight patients, 53% (8%) vs. − 17.5% (2.3%) for overweight, and 49% (9%) vs. − 16.2% (3.0%) for obese (p < 0.05 vs. p < 0.05). Corresponding results in the control group were 58% (6%) vs. − 22.3% (3.0%), 55% (7%) vs. − 20.8% (3.1%) and 54% (8%) − 19.6% (4.0%) (p < 0.05 vs. p < 0.05). Patients who gained weight from baseline to follow-up changed left ventricular ejection fraction (median and interquartile range) by − 1.0 (9.0) % (n = 187) and patients who lost weight changed left ventricular ejection fraction by 1.0 (10.0) % (n = 179) (p < 0.05).Overweight and obesity impair left ventricular ejection fraction and global longitudinal strain in both patients with type 2 diabetes mellitus and non-diabetic persons.Trial registration ClinicalTrials.gov identifier NCT 01049737 Obesity is associated with conditions that increase cardiovascular morbidity and mortality    but the disease] , but alsdisease] . Abdomindisease] . The extdisease] .Diabetes mellitus type 2 is also associated with hypertension and coronary artery disease and is an independent risk factor for myocardial infarction . LV systThe aim of this study was to assess the relationship between overweight and obesity to the LV remodelling of systolic function in patients with T2DM and a control group of non-diabetic persons. We enrolled 512 consecutive patients who participated in the Cardiovascular Risk factors in Patients with Diabetes—a Prospective study in Primary care (CARDIPP) study . ParticiThe investigation included collection of medical history and ongoing medical therapy data from patient records. Each person underwent an echocardiographic examination at time of enrolment into the study. Height and weight were measured. Blood pressure was measured in supine position at rest using a fully automated oscillometric device . All patients in the CARDIPP study were invited to join an echocardiographic follow-up study 4 years after the initial examination but 112 declined to participate and were therefore excluded. The echocardiographic examinations were performed at the Department of Clinical Physiology, Linköping University Hospital, Linköping, Sweden.Urine and blood specimens were taken in the morning following a 10-h overnight fast. Creatinine, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride concentrations were measured. HbA1c was analysed using a Swedish Mono-S HPLC. Since the control group specifically excluded participants with T2DM, HbA1c was not measured in CAREFUL. Renal glomerular function was assessed by eGFR. Microalbuminuria was defined according to the American Diabetes Association definition, as uACR ≥ 3.0 mg/mmol.Echocardiography was performed using a Vivid 7 Ultrasound System  for assessment of LV morphology, systolic and diastolic function. Left atrial (LA) end-systolic size, left ventricular end-diastolic diameter (LVEDD), end-diastolic thickness of the septum and posterior wall were all measured in the parasternal long axis view using M-mode tracing. The linear method and the parasternal long axis approach were used to calculate LV mass. Apical two- and four-chamber views and the apical long axis view were acquired at a frame rate of > 40 frames/s, and were analysed off-line by one experienced independent operator using 2D speckle tracking . Peak global longitudinal strain was calculated as the mean value from 18 segments of the left ventricle. LV end-diastolic volume (LVEDV) and LVEF were measured using the modified Simpson’s method included in the EPPC software as a manually adjusted semi-automated quantification tool (Auto-EF) . Body suThe clinical aim of the study was to assess the relationship between overweight and obesity, as measured by use of BMI, and LV systolic function in T2DM patients and non-T2DM controls. For statistical analysis, SPSSV.22.0 software  and Statistical Analysis Software, SAS/STAT  were used. The results for categorical variables were presented as numbers and percentages. Continuous variables were presented as median and interquartile ranges and in analysis of variance  as mean and standard deviation (SD).1) that were statistically significantly different from zero together with age and gender were included. Pearson’s correlation analysis was used to examine the associations between BMI and left ventricular function and mass. To analyse the relationship between T2DM and left ventricular function, patients and controls were merged in a final regression analysis. Check for multicollinearity as well as homogeneity of variance was performed.Univariable and multivariable linear regression analysis were used to investigate the relationships between baseline characteristics and LV function. In the multivariable linear regression models, those explanatory variables that had estimates of the regression parameters  analysis, and limits of agreement and coefficient of variation. A p value < 0.05 was considered to indicate a statistically significant result.To assess the risk for LV systolic dysfunction in patients with overweight and obesity, odds ratios and 95 percent confidence intervals were calculated for LVEF categorized as normal or impaired  vs.  but not in the final estimated models using multivariable linear regression analyses when the two groups were merged. The odds ratio between LVEF  explanatory variables showed that the only variable that had any impact on LVEF was BMI. The odds ratio for an abnormal LVEF in patients with overweight was 2.2 (95% CI 1.6–3.0) and obesity 4.8 (95% CI 2.6–9.2). Correspondingly, the odds ratio for an abnormal LVEF in controls with overweight was 2.1 (95% CI 1.0–4.4) and obesity 2.1 (95% CI 0.8–5.7).Univariable linear regression analysis showed that BMI was associated with LV mass, LVEF, GLS and E/é in patients and LVEF, GLS and E/è in controls Tables , 4 Fig.. MultivaTo investigate the association between weight expressed as BMI and remodelling in terms of LV size and function, the participants were divided into three groups according to BMI Table . There wOverall, LVEDV and the E/é ratio increased from baseline to follow-up but on average, there was no change in LV mass or systolic function Table . PatientInter-observer variability in assessing left ventricle systolic function was determined towards a second, experienced echocardiographer, in 20 consecutive patients. The intraclass correlation (ICC), of LVEF was 0.86, MAPSE 0.95 and GLS 0.83. The coefficient of variation for LVEF was 5.0%, MAPSE 4.0% and GLS 6.9%. Interobserver bias and limits of agreement were 0.45 (− 4.79 to 5.69) for LVEF, − 0.01 (− 0.93 to 0.91) for MAPSE and 0.94 (− 1.46 to 3.34) for GLS.The results of this long-term, observational study of middle-aged to elderly patients with T2DM and non-T2DM controls indicates that overweight and obesity are associated with impaired LV systolic function. Participants with overweight and obesity had increased LV mass, inferior LV systolic and diastolic function, as measured using LVEF, GLS and E/é, compared with the leaner participants. From both the univariable and multivariable regression analyses, we found that, irrespective of T2DM or other explanatory variables, overweight/obesity was the major risk factor for LV systolic dysfunction. Worsening LV systolic function was present at 4 years follow-up in the patients who had increased their BMI. These results are unique because they indicate the presence of an association between overweight/obesity and impaired LV systolic function, as measured by LVEF and GLS, in both a defined population with T2DM and a non T2DM control group.Overweight and obesity were found to be associated with increased LV wall mass and the E/é ratio. This is consistent with the results of previous reports where obesity contributed to LV dilatation, hypertrophy, impaired relaxation, and diastolic dysfunction , 8, 10. Obesity is an established predictor of heart failure, but the extent to which it is associated with impaired LV systolic function is unclear. Previous studies have shown that it is associated with LV structural remodelling, LV diastolic dysfunction and lower longitudinal myocardial deformation, but not with reduced LVEF –8, 24. OThe study design is crucial for what outcome can be expected. The association between obesity and LV systolic function demonstrated here may be different from what has been shown in other cohorts or in studies that excluded patients with known cardiovascular disease or reduced LVEF , 10, 24.What is the clinical relevance of impaired LV systolic function among persons with overweight and obesity in our study? Patients with T2DM and obesity had approximately 8% lower LVEF and controls with obesity about 4% lower LVEF than the normal weight participants. Corresponding figures for GLS were 2.4% vs 2.7%. Symptoms of heart failure are often nonspecific, but a reduction in LVEF is associated with increased comorbidity and mortality . TherefoHow valid are the LVEF results in our study? The speckle-tracking based Auto-EF method has been demonstrated to be reliable compared with MRI. It was also faster and had lower inter- and intra-observer variability than manual assessment by the use of the modified Simpson’s rule . The intWe propose that, compared with normal weight persons, individuals with overweight or obesity are more prone to develop LV systolic dysfunction as measured by use of LVEF and GLS.LV end-diastolic volumes and E/é values increased 4 years after the initial assessment, indicating the presence of elevated filling pressures to the left ventricle and progressive LV diastolic dysfunction. LVEF decreased in participants who increased in weight from baseline to follow-up which further supports our finding of an association between obesity and LV systolic dysfunction. This study was designed as an observational study. We did not intend to improve the already appropriate medical care of the participants and could not identify a subgroup of patients that improved cardiac function. However, better glycaemic control may contribute to regression of LV hypertrophy in patents with T2DM .Our study had some limitations. There were fewer women than men in the patient population. Men with obesity are more likely to be affected by concentric cardiac hypertrophy than eccentric hypertrophy while women with obesity experience both types of hypertrophy . The difOverweight and obesity were associated with LV structural remodeling and dysfunction in middle-aged to elderly patients with T2DM as well as in their non-diabetic controls. Compared to participants with normal weight, individuals with overweight and obesity had impaired LV systolic function as measured by both LVEF and GLS. Progression in LV remodelling was seen at the 4-year follow-up in T2DM patients who had further gained weight and increased their BMI. Our study reveals that overweight and obesity are major risk factors for impaired LV systolic function.


Takotsubo cardiomyopathy (TCM) has gained global recognition as a unique cardiovascular disease that mimics acute myocardial infarction. Since its initial description, more than three decades ago, we have significantly advanced our understanding of diagnosing, treating, and prognosticating this reversible cardiovascular phenomenon. However, the pathophysiological explanation behind its selective involvement of the left ventricle (LV), predominantly the LV apex in poorly understood. In this brief review on differential distribution of the adrenergic nerve (AN) and cholinergic nerve (CN) in the normal human heart, we try to extrapolate an idea of poor CN distribution in the LV apex as an associated factor augmenting microcirculatory dysfunction due to an unopposed AN activity from the catecholamine surge, as a plausible explanation for this characteristic phenomenon. Since 1990, after describing the term tako-tsubo-like left ventricular dysfunction, several concepts have been put forth to individually explain the unique contractile dysfunction seen in Takotsubo cardiomyopathy (TCM) . In partAdditionally, there is increasing evidence of microcirculatory dysfunction occurring predominantly during the acute phase of TCM -12; as dMicrocirculation dysfunction theory in addition to a few notable pathophysiological mechanisms like; multi-vessel epicardial spasm -17, tranKawano et al. examined six autopsied hearts of people who died of non-cardiac cause. Using differential staining for tyrosine hydroxylase and acetylcholinesterase, the authors demonstrated a disparity in the regional distribution of the adrenergic (sympathetic) and cholinergic (parasympathetic) nerves, respectively . AlthougAtria had the highest concentration of CN in the heart, while ventricles were dominated by AN. Among ventricles (right versus left), there was no significant variation in the distribution of AN. Therefore, heterogeneous CN distribution between the ventricles significantly affects its regional microvascular blood flow by way of its vasodilatory mechanism. The left ventricle (LV) base and apex had a lower concentration of CN when compared to the concordant site in the right ventricle (RV), and in particular, LV apex had the lowest concentration of CN among all sub-regions of the heart Figure . MyocardAmong TCM patients, an antecedent physical or emotionally stressful event causes a sudden surge in catecholamine level, which augments the AN activity causing intense coronary vasospasm . This vaLyon et al. proposed that during the catecholamine surge, norepinephrine causes a stimulating effect on the myocardial β1-adrenoreceptors (β1-ARs), resulting in increased contractility at the LV base. While epinephrine causes stimulation of β2-AR, leading to a switch from G(s) to G(i) protein pathway, causing a negative inotropic effect at the LV apex . This thGiven that TCM is a constellation of mismatch between vasoconstriction and vasodilatory response, adenosine challenge during the acute phase of TCM causes a reversal of myocardial perfusion defect, increase in myocardial contractility and significant improvement in the ejection fraction when compared to a patient with ST-elevation MI who have a flow-limiting lesion . AdenosiAlthough this hypothesis complements previously published the theory of coronary microvascular dysfunction . Our theTakotsuko cardiomyopathy is a constellation of catecholamine surge with hypokinetic LV apex and functional hyperkinetic LV base, predominantly noted in older women with a preceding stressful event. The existence of poor CN distribution in the LV apex leading to a lack in the counteractive vasoconstriction in the cardiac microvascular caused by catecholamine surge via AN pathway can explain the phenomenon seen in TCM. Although this theory is based on the findings from the autopsied heart of healthy individuals, due to ethical and logistic reason this is difficult to prove with certainty in TCM patients. Further research is needed to non-invasively assess parasympathetic (CN distribution) activity in the heart among TCM patients.


It is unknown that dysglycemia in obese adolescents has effects on myocardial deformation that are more pronounced when compared to obesity alone. We hypothesized that obesity associated abnormal glucose tolerance (dysglycemia) would have adverse effects on two-dimensional speckle tracking echocardiography derived longitudinal, radial and circumferential strain  compared to age and gender lean controls. We also examined if changes in deformation would be reflected in abnormal ventricular vascular coupling indices (VVI).In a prospective cross-sectional design 39 obese adolescents  were compared to age and gender matched lean controls . Based on results from an oral glucose tolerance test (OGTT), obese adolescents were categorized as obese normoglycemic  or obese dysglycemic . Left ventricular (LV) global and average LS, CS, RS and strain rate were measured. LV ejection fraction and mass index were measured and VVI approximated as ratio of arterial elasticity (Ea) and end-systolic elastance (Ees).Adolescents with ODG had significantly (P = 0.005) impaired global LS (− 20.98% ± 2.8%) compared to controls (− 23.01% ± 2.3%). A similar (P = 0.0027) reduction was observed in average LS for adolescents with ODG (18.87% ± 2.5%) compared to controls (20.49% ± 2%). Global CS was also decreased (P = 0.03) in ODG (− 23.95%) compared to ONG (− 25.80). A similar trend was observed in average CS after multivariate regression for BMI and blood pressure. CS correlated with HbA1c in both groups (P = 0.05). VVI had a negative correlation with both LS  and CS rate .Myocardial strain and strain rate were significantly altered in obese adolescents. Unfavorable subclinical reductions in global and average CS were more pronounced in adolescents with dysglycemia compared to obese adolescents with normoglycemia and controls. These data indicate progressive worsening of subendocardial function across the spectrum of glucose tolerance. Strain rate was predictive of VVI in obese adolescents, suggesting strain rate may be a sensitive marker for cardiac remodeling in abnormal glucose homeostasis states. The pediatric obesity epidemic had resulted in an exponential rise of Type-2 diabetes mellitus (T2DM). It is well established that in children and adolescents with obesity, ventricular chamber size, left ventricular (LV) wall thickness, and LV mass are elevated compared with lean pears despite no significant changes in ejection fraction (EF) . FurtherIn states of abnormal glucose tolerance (prediabetes) and/or T2DM, myocardial deformational changes are worsened due to the hyperglycemia, increased fatty acid acids, activation of the renin angiotensin system, microangiopathy and increased oxidative stress. In the context of obese adolescents with abnormal glucose tolerance (dysglycemia), LV mass, systolic blood pressure, and resting heart rate are observed to be elevated when compared to lean peers. The study of obese adolescents who have glucose dysregulation (dysglycemia) merits investigation of subclinical myocardial changes in the context of pediatric obesity , 7. Howe2D-STE and 3D-STE have recently emerged as reliable techniques for quantification of myocardial deformation in multiple imaging planes due to its angle independence and high interobserver reliability , 9. HighTo our knowledge, no studies have investigated myocardial strain and strain rate in adolescents with prediabetes, and few studies have demonstrated changes in LV GLS in T2DM . The objA total of 39 obese adolescents with BMI ≥ 95th percentile were recruited for this observational cross-sectional study, as previously reported . All subKey inclusion criteria were: (1) age 12–18 years and (2) Tanner stage II or above. Key exclusion criteria were: (1) Use of medications known to affect insulin sensitivity such as high-dose inhaled glucocorticoids, thiazolidinediones and atypical antipsychotics, (2) medications for treatment of dyslipidemia such as statin therapy, bile acids and fibrates, (3) pregnancy, (4) significant psychiatric illness, (5) blood pressure over 90% for height (6) renal insufficiency based on Schwartz equation as > 0.55 for females and males > 0.7 ages 13–18 years and (7) nonalcoholic fatty liver  and obese dysglycemia . Abnormal glucose tolerance was defined as either (1) impaired fasting glucose (fasting glucose level ≥ 100 mg/dl) or (2) impaired glucose tolerance . None of the adolescents who underwent the OGTT were diagnosed with T2DM after the OGTT.Adolescents diagnosed with T2DM did not undergo an OGTT and were categorized as ODG. The adolescents with T2DM were treated with metformin and/or insulin. Those on metformin were asked to stop metformin 72 h prior to their study day as metformin can affect vascular studies (flow mediated dilatation), which were performed during the study visit, previously reported .Healthy age and sex-matched controls were derived from the Pediatric Cardiology program at the collaborating center, as part of a registry collecting normative data of strain parameters. The control group consisted of children and adolescents who responded to an institutional IRB approved advertisement for participation. In the control group, 2D-STE was performed for research purposes. The control inclusion criteria included: (1) age 1 to 18 years; (2) no history of heart disease, hypertension, or any other systemic disease. Age appropriate assents were signed by the adolescents with parental consent. Data collected at the time of 2D-STE included gender, date of birth, height, weight, heart rate, and systemic blood pressure. BSA was calculated using the Haycock formula. All participants in the control group had no history of congenital heart disease and were lean BMI < 85% with no signs of glucose intolerance. Males were observed to be heavier in the control cohort . Glycemic status was not established in the control using a glucose tolerance test though there was no history of polyuria or polydipsia elicited by the adolescents.2.7. Parameters of diastolic function were measured, including mitral valve inflow E & A wave peak velocities, tissue Doppler imaging (TDI) of the mitral valve medial and lateral annulus e′ and a′ wave peak velocities, pulsed Doppler measurements of the right upper pulmonary vein S, D, and A wave peak velocities, and the left atrial volume by biplane Simpson’s method [2.7 was considered to be dilated. MV E/e′ ratio > 8 was considered to be abnormal diastolic function. Due to the limited dataset, diastolic dysfunction was defined by an abnormality in any of these parameters. Studies were de-identified and stored on a Siemens SyngoDynamics DICOM system .Transthoracic echocardiography images were obtained by an experienced sonographer on a Philips iE33 ultrasound imaging system with a 5 MHz probe . Standard echocardiography acquisition included two-dimensional, color flow Doppler, pulsed Doppler, and continuous wave Doppler. 3–5 cardiac cycles were acquired for each measurement with the patient in supine and left lateral decubitus positions per routine clinical protocol. Two dimensional apical 4 chamber and 2 chamber views, as well as parasternal short axis views, were acquired for strain and strain rate analysis. Left ventricular mass was calculated via Devereux’s formula and by 5/6 area-length methods . LV masss method , 46. MV 0 is the theoretical volume of the unloaded ventricle, determined as the intercept o the linear ESP-ESV relation. End systolic pressure was approximated from systolic blood pressure as, ESP = 0.9 × SBP18. Effective arterial elasticity was approximated as,Ventricular vascular coupling index (VVI) was estimated in a manner similar to that presented by Sanz et al. . Briefly−1). S and SR were obtained using standard 2D multiform B-mode grayscale LV images acquired in the apical four, two, and three (3CV) chamber views. S and SR were also obtained in the parasternal short-axis views of the LV at three levels, namely the basal, mid, and apical LV, corresponding to LV short axis sections at the mitral valve (MV), papillary muscles (PM) and LV apex (AP), respectively. A frame rate > 60 Hz was used for all analyses. Five consecutive cardiac cycles at the same heart rate triggered to the R wave of ECG complex were digitally stored in a cine-loop format for offline analysis. Five values were obtained for each strain index (S and SR) and averaged. The timing of aortic valve closure and mitral valve opening with respect to peak S and SR was ascertained from manual inspection of a single PW or CW Doppler from the LV outflow tract. All LV images in the apical and short axis views were obtained at the same heart rate. A region-of-interest width and when necessary was automatically acquired, which was manually adjusted to include the entire myocardial wall. The tracking algorithm followed speckles in the myocardium throughout the cardiac cycle. Results from the tracking algorithm were confirmed by visual inspection, and the number of LV myocardial segments was maximized. By convention, the myocardial strain is obtained from three planes in the LV, namely longitudinal, circumferential, and radial. The corresponding strain indices that were determined include longitudinal strain (LS), longitudinal strain rate (LSR), circumferential strain (CS), circumferential strain rate (CSR), radial strain (RS), and radial strain rate (RSR). All strains were reported as dimensionless percentages (%). LS was calculated as the % change in LV length, which was determined for three individual apical long axis views, namely the 4CV, 3CV, and 2CV. Global longitudinal strain (GLS) was calculated as the average of LS and LSR from all considered views. CS and RS were calculated as the % change in LV circumference and wall thickness, respectively. Both CS and RS were assessed from the LV short axis view at three levels, namely basal (MV), mid ventricular (PM), and distal LV at the apex (AP). Regional CS and RS were obtained from six segments in three parasternal short axis views of the LV, which were averaged to obtain global CS and RS. The software automatically divided the LV short axis views into six segments, namely the anteroseptal, anterior, lateral, posterior, inferior, and sepal segments, as per standard guidelines [−1 was obtained at the peak temporal spread of the strain rate acquisition at systole. The peak systolic SR was obtained for each cardiac segment from the same views as strain, discussed in detail above.Analysis to derive left ventricular longitudinal, circumferential and radial deformation and strain by offline post processing  was performed on two-dimensional DICOM image datasets, described elsewhere , 20. Briidelines . SR, thet test or the Wilcoxon rank-sum test for normally and non-normally distributed continuous variables, respectively. Differences between categorical variables were assessed using Fisher’s exact test. Logistic regression was used to assess the univariate associations between presence of strain parameters and study variables. Linear regression was used to illustrate the correlation between average LSR/CSR and VVI  for normally distributed continuous variables, and median and IQR for continuous data with a skewed distribution. Differences between groups were assessed using the unpaired VVI Fig. , 2. MultTable The Mitral E/A ratio was significantly different P = 0.0025) between ONG and ODG groups, while no significant differences were observed in index LA volume. E/e′ ratio of lateral and medial mitral valve annulus were not significantly different between the two groups. While only male in ONG had evidence of LA dilatation, five adolescents in ODG had signs of LA dilatation-two (mild); one (moderate) and one adolescents (severe). These results are summarized in Table 5 betweenAs previously discussed, ESP was different between both ONG and ODG groups Table . Mean VVTable Table Subjects in the ODG group were further partitioned into ODG with prediabetes (IFG and/or IGT) and T2DM and compared with ONG subjects. A total of 8 subjects were classified as ODG with prediabetes and 6 subjects as ODG with T2DM. Significant differences (P = 0.01) were observed in global LS between ONG subjects (− 21%), ODG with prediabetes (− 19.71%), and ODG with T2DM (− 19.1%). A similar trend was observed in average LS, in which significant differences (P = 0.04) were observed between ONG subjects (− 19%), ODG with prediabetes (− 18.6%), and ODG with T2DM (− 17.5%). In addition to significant differences in HbA1c, previously discussed, a positive correlation was observed between HbA1c and average CS . Glucose and insulin for time points 0, 3, 5, 10, 30, 60, 90, 120 min during the OGTT were measured. No correlation was observed between time points for both glucose, insulin, mean glucose, mean insulin, and myocardial strain parameters, suggesting that the glycemic status was not related to myocardial deformation independent of obesity.ICAM was observed to be significantly different between ONG and ODG groups (P = 0.023). Furthermore, a negative correlation was observed between average longitudinal strain rate (LSR) and anti-inflammatory adiponectin  in obese adolescents.Our study demonstrates that dysglycemia worsens changes in myocardial deformation parameters as noted in obese adolescents. Despite the observed changes in myocardial deformation, ventricular vascular coupling appears to be preserved in our cohort of obese, insulin resistant adolescents. Thus, clinically, our study highlights that subtle changes in myocardial function are manifest in adolescents with dysglycemia and may be useful for predicting adverse cardiovascular outcomes. “Traditional” diastolic parameters may not be sensitive to detect early stages of diastolic dysfunction. Left atrial enlargement is a reliable diastolic parameter but requires some degree of chronicity of left ventricular diastolic dysfunction to manifest. Image quality in these obese patients may limit the reliability of some of these diastolic parameters.In our comparative cross-sectional study design, diastolic dysfunction was found to significantly higher in adolescents with dysglycemia when compared to their normoglycemic counterparts. We found significant impairments in global and average LS when compared to lean age matched controls. Furthermore, we observed that this impairment in global and average LS parameters were exaggerated in obese adolescents with dysglycemia compared to their normoglycemic counterparts. Of note in this study distinctive differences were observed in CS in dysglycemic states, implying greater abnormalities in myocardial deformation in dysglycemia than previously appreciated. This defects in CS has not been previously reported in obese insulin resistant adolescents.Myocardial strain is well known to reflect ventricular vascular coupling, as diminished myocardial strain is known to decrease myocardial efficiency. However, in our study despite the observed changes in myocardial strain, VVI was observed to preserved. Nonetheless, VVI was additionally observed to correlate with circumferential strain rate, a load independent index of LV peak elastance and diastolic ventricular filling. Clinically, VVI is a known prognostic marker and indicator of aortic compliance, LV function, and LV performance. Together with current information regarding the prognostic value of VVI, our results suggest that ventricular efficiency is intimately dependent on diastolic ventricular function and may be a subclinical marker for changes in LV function later in life.Prior studies have shown that in obese adolescents, insulin resistance alters myocardial substrate utilization and increases sympathetic tone, preload, and fatty acid metabolism, which ultimately results in impaired LV contractility and may lead to clinical heart failure in later life . AdditioStudies of adults with T2DM have shown that cumulative effect of diabetes exposure (those with diabetes diagnosis in childhood and/or early adulthood) and BMI had greatest impact on the adverse LV remodeling , 26. BjoSerum biomarkers of inflammation, namely adipokines and leptins, have been associated myocardial deformational change . AdiponePreviously, Li et al. reported that LS at the cardiac apex correlated with VVI in adults with T2DM with either normal or depressed ejection fraction. Our study demonstrated similar findings. However, Li et al. demonstrated abnormal VVI (1.55 ± 0.53), indicating impaired ventricular-vascular coupling, a finding not observed in our cohort. We speculate that changes in VVI in pediatric populations likely are less pronounced compared to adult populations due to lack of other known comorbidities that abnormally alter ventricular-vascular coupling.Of note is the correlation observed in our study between VVI and circumferential strain rate, a proxy for LV peak elastance. To our knowledge, this is the first study to have correlated VVI, an index of mechanical efficiency and myocardial deformation, namely circumferential strain rate. In the broader context of myocardial mechanics and function, strain rate is a load independent marker of myocardial deformation and can be utilized for clinical assessment of regional wall motion abnormalities –39. WhilOur study has several limitations. Due to the cross-sectional design, causal relationships cannot be established among the observed associations. Additionally, the predominance of Hispanic subjects, about 60% of the cohort, limits generalizability of the findings. However, the study presented simultaneously provides novel data in for pediatric Hispanic subjects, a population known to be a high risk for diabetes. The reduced sample size in this study reduced power required to detect differences between groups based on OGTT results. Though we had age and gender matched control group, we recognize that the control group was predominantly Caucasian.Obese adolescents especially those with dysglycemia demonstrated greater abnormalities in myocardial deformation than previously appreciated in the literature. Furthermore, significant differences in strain in the context of dysglycemia and observed correlations between strain rate and HbA1c suggest that strain rate may be a reliable marker to predict adverse cardiac remodeling in overt diabetes. In conclusion, our study highlights that subtle functional changes are manifest in adolescents with dysglycemia and may be useful for predicting adverse cardiovascular outcomes much earlier compared to their lean contemporary peers.


The benefit of revascularization of chronic total occlusion (CTO) in percutaneous coronary intervention (PCI) is controversial. On the other hand, left ventricular (LV) global longitudinal strain (GLS) is a more sensitive marker of LV myocardial ischemia and LV function than LV ejection fraction (EF). The purpose of this study was to investigate the impact of revascularization of CTO on LV function using LV GLS. A total of 70 consecutive patients  with CTO who had a positive functional ischemia and underwent PCI, were included in this study. Echocardiography was performed before and 9 months after the procedure with conventional assessment including LV end-diastolic and end-systolic volume , LVEF, and with 2DSTE analysis of GLS. Successful PCI was obtained in 60 patients (86%). There were no stent thromboses during follow-up. GLS showed a significant improvement 9 months after successful PCI , whereas in failed PCI group that did not change significantly . LVEF, LVEDV and LVESV did not change significantly during follow-up in both successful and failed groups. Successful PCI for CTO improved LV function, assessed by LV GLS. Chronic total occlusions (CTO) are defined as lesions with TIMI  grade 0 flow for more than three months. CTO lesions are identified in 18.4% in patients undergoing elective percutaneous coronary intervention (PCI) in the absence of previous coronary artery bypass surgery or those presenting with acute myocardial infarction , 3. HoweWe conducted a retrospective study in a cohort of 70 consecutive patients with CTO who had attempted PCI at Himeji Cardiovascular Center between May 2009 and February 2014. All patients had single vessel coronary artery disease with CTO and had a positive functional ischemia study. We excluded patients who had an anticipated noncompliance with dual antiplatelet treatment for at least 12 months, the history of coronary artery bypass surgery, severe valvular disease, other co-morbid systemic disease and atrial fibrillation. CTO was defined as a coronary artery obstruction with thrombolysis in myocardial infarction (TIMI) grade 0 and all patients had a native vessel occlusion estimated to be of at least 3 months duration based on the time from diagnosis made on coronary angiography . PCI andAll of the patients underwent an extensive baseline clinical history taking and physical examination, 12-lead electrocardiography, and transthoracic echocardiography. This study was approved by the research ethics committee of Himeji Cardiovascular Center and carried out in accordance with approved guidelines. Written informed consent was obtained from all patients.Echocardiography was performed before and 9 months after the procedure . ComprehThe LV GLS was obtained by using 2DST software . The endocardial border was traced manually in the end-diastolic frame. The software automatically tracked the myocardium throughout the cardiac cycle. The peak values of segmental longitudinal strain were obtained from greyscale-recorded images in the apical four-chamber, two-chamber, and long-axis views with a frame rate between 50 and 70 frames per second, and GLS was obtained by averaging the peak values  Fig 2)..Fig 2). Data are expressed as mean ± standard deviation for continuous variables, and median and interquartile range for non-normally distributed continuous variables. Data from the successful and failed PCI groups were compared by using the Student’s t-test and one-way analysis of variance (ANOVA) for normally distributed continuous variables, the Wilcoxon–Mann–Whitney test for non-normally distributed continuous variables, and the χ2 test or Fisher’s exact test for categorical variables. Changes in the LVEDV, LVESV, LVEF and GLS data between the before and the 9 months after the procedure were assessed by ANOVA. A value of p <0.05 were considered statistically significant. MedCalc Version 12.7.8  was used for all analyses.Between January 2009 and December 2013, a total of 70 CTO lesions (in 70 patients) were targeted, and 60 lesions were successfully revascularized with PCI, and 10 lesions were failed . No procBaseline characteristics are shown in Echocardiographic parameters are shown in In this study, we investigated the impact of revascularization of CTO on LV function using LV GLS. Successful PCI for CTO improved LV function assessed by LV GLS. To the best of our knowledge, this is the first study to demonstrate the comparison with successful and failed CTO-PCI patients with a positive functional ischemia before PCI, according to LV function evaluated with LV GLS before and after 9 month PCI.CTO is common, being reported in 30% of patients undergoing coronary angiography , 20. HowSeveral investigators reported the effect of revascularization of CTO on LV function. Henriques et al. reported that they did not find an overall benefit for CTO-PCI in terms of LVEF or LVEDV . MashayeGLS assessed with 2DSTE is a new echocardiographic technique for the evaluation of global myocardial function. This method is based on tracking the characteristics speckle patters created by interference of ultrasound beams in the myocardium. Its accuracy has been confirmed using CMR  and it dIn this study, we studied of preserved LVEF patients with positive functional ischemia of CTO lesion before PCI, and assessed the effect of revascularization of CTO on LV function using GLS assessed by 2DSTE before and 9months after procedure. GLS showed a significant improvement 9 months after successful PCI, whereas that in failed PCI group did not change significantly. These results indicated that CTO revascularization improves LV function.This study is limited by the fact that it was a single center, retrospective study and had a small sample size, which might diminish the power of the drawn statistical inference. A further study with a large scale prospective, multicenter design is thus required to confirm our results. An additional limitation to this study is that radial and circumferential strain were not explored. However, it has been recently reported that longitudinal deformation may be a more sensitive marker of cardiac function compared with radial and circumferential strain, especially in chronic ischemic patients , so not Successful PCI for CTO improved LV function, assessed by LV GLS.