Congenital heart disease in adults  is a growing burden for healthcare systems. While infant mortality due to congenital heart disease in the last four decades decreased by almost 3-fold, adult congenital heart disease prevalence increased by more than 2-fold in United States. Adult congenital heart disease prevalence is expected to increase steadily until 2050 in projections. Adult congenital heart disease is a multifaceted problem with many dimensions. This manuscript aims to provide an overview of the common adult congenital heart diseases and summarize important points in management of these diseases with possible problems and complications that the patients and the physicians face. Congenital heart disease in adults [adult congenital heart disease: (ACHD)] is a growing burden for healthcare systems. The definition is the persistence of any structural abnormality present at birth that involves the heart and/or great vessels in adult life i.e. beyond 16 years of age. Arrhythmia and cardiomyopathies are not covered in this definition  2). Con. Con2). Two-dimensional echocardiography (2D-TTE) is the mainstay of diagnosis in ACHD similar to other structural heart diseases. A systematic approach called sequential segmental analysis is recommended for delineating anatomy. Cardiovascular anatomy is defined in 3 segments in this examination protocol: visceral and atrial situs, atrioventricular concordance and the interrelation of great arteries. Subcostal, suprasternal, suprasternal views and modified parasternal views should be utilized liberally. A systematic approach with a standardized examination protocol and a report template allows a common language between clinics and prevents missed diagnosis of associated abnormalities .Three-dimensional transthoracic echocardiography is a promising modality for delineation of complex anatomic abnormalities of the heart. This technique is especially advantageous in distorted chamber geometries in which 2D ejection fraction calculation methods are source of error. Dependence on operator experience and need for familiarity with the software of the specific device, higher cost, larger acoustic window required by bigger probes and need of multi-beat images with breath-hold for high frame-rate images are the main disadvantages .Three-dimensional transesophageal echocardiography (3D-TEE) is particularly valuable during transcatheter occlusion of interatrial andinterventricular septal defects. Significant decrease in radiation exposure was observed with efficient use of 3D-transesophageal echocardiography (3D-TEE) in closure of interatrial communications. Limitations are less-pronounced compared to 3D-TTE . Fusion Left and right ventricular strain imaging are the emerging modalities for assessment of contraction dynamics. Abnormalities in strain patterns often precede overt dysfunction.Usefulness of strain imaging in several ACHD groups, including patients with bicuspid aortic valve, Tetralogy of Fallot (TOF) and operated TOF patients was previously shown ,13,14. SMagnetic resonance imaging (MRI) demonstrates superior performance in volumetric calculations, 3D anatomy, wall characteristics and quantification of mass of ventricles and atria, shunts and shunt fractions, and regurgitant fractions of valvular incompetence and myocardial deformation measures. Magnetic resonance imaging is especially beneficial in assessments of the right heart including right ventricle, pulmonary valve and pulmonary artery. Magnetic resonance imaging is used for the right ventricle diastolic, systolic volume and ejection fraction measurements. The regurgitation fraction of pulmonary valve incompetence can be measured accurately by MRI . Tissue Cardiac computerized tomography is more widely available and cheaper, application is less time-consuming and patient compliance is achieved easier compared to CMR. Nevertheless, due to concerns about ionizing radiation and intravenous contrast administration, we usually prefer CMR unless concurrent imaging for epicardial coronary arteries, pulmonary vascular tree and aorta, or other fistulae or shunts is planned .Cardiopulmonary exercise testing (CPET) evolved to be used in exercise medicine but found wide application in ACHD in recent years. The test provides significant amount of data about hemodynamic response, conduction system and respiratory response to exercise and some parameters are still to be understood. The main advantage of this test would be the thorough information it provides, while the main disadvantage would be the expertise required for performance and interpretation of the test and limited availability. We utilize CPET liberally in our institution in guiding pharmacological, interventional and device therapy, as well as evaluation of the change in postprocedural progression of the diseases. Some examples to important applications of CPET in ACHD are as follows: patients with coarctation of the aorta with borderline clinical findings for reintervention, follow-up of patients with pulmonary hypertension and Eisenmenger syndrome, risk stratification and clinical decision-making in patients with repaired tetralogy of Fallot (TOF) ,18,19. AAtrial septal defect is the most common form of congenital heart disease in the adult. The incidence is about 1-2%. It is not uncommon for an adult cardiologist to detect an ASD in a patient presenting with atypical chest pain or palpitations. Other presenting symptoms include exercise limitation, dyspnea and rarely right-sided heart failure, recurrent pulmonary infections or paradoxical emboli. Secundum-type ASD is the most common form and makes up more than two-third of the defects in the interatrial septum. 3D-TEE guidance and intracardiac echocardiography contributed to already-high procedural success with transcatheter closure, as well as postprocedural assessment of closure devices . A shuntThe main important question to be answered by a cardiologist in an adult patient with ASD today should be suitability for transcatheter closure. Echocardiography is the main modality in deciding for closure. There are several issues to be addressed in management of an ASD patient are as follows:1. Presence of right ventricular failure and/or pulmonary hypertension: Enlargement in right heart chambers is an indicator of a significant ASD. Pulmonary artery systolic pressures should be assessed by echocardiography. Right heart catheterization should be performed, vascular resistance calculations should be made. Reversibility should be performed if significant pulmonary hypertension is detected. Eisenmenger physiology is a contraindication to percutaneous or surgical closure.Concomittant Ebstein’s abnormality should be suspected in case of marked right atrial enlargement. More than 50% of patients with Ebstein’s abnormality have patent foramen ovale or ASD.2. Anatomical properties of the defect: Is the defect secundum, primum or high-venosum? Transesophageal echocardiography is usually recommended and performed for unusual anatomy and poor echocardiographic window.Superior or inferior sinus venosus defects may accompany partial abnormal pulmonary venous return. Pulmonary venous return abnormalities might be difficult to detect with transthoracic echocardiography.3. Systolic or diastolic dysfunction of the left ventricle  might result in postprocedural complications after ASD closure. Flow redirected to right heart through ASD creates a relief for the chronic volume overload on the left ventricle, which has decreased compliance in some patients. Since increasing left ventricular stiffness and diastolic dysfunction is a common finding in the older adult, one should always be careful while proceeding with closure. This might result in reflection of the volume load back into pulmonary vasculature with resultant pulmonary edema in case of transcatheter occlusion.4. Arrhythmias, especially atrial arrhythmias are a problem in patients with ASD. Atrial arrhythmias are more common in patients undergoing delayed transcatheter or surgical correction. Fifteen to twenty percent of patients experience some form of new-onset supraventricular tachyarrhythmia following correction . Antiarr5. Paradoxical emboli: An ASD discovered in a patient presenting with paradoxical emboli prompts intervention regardless of the size, unless other contraindications exist.*  Simple secundum ASD with significant shunt causing enlarged right heart chambers,*  Sufficient rims,*  Normal or slightly increased pulmonary artery pressure, without pulmonary vascular disease or Eisenmenger physiology.Strategies during interventional closureOne of the most important implications of percutaneous closure method, specific for an adult patient with ASD might be the left ventricle diastolic dysfunction. Balloon occlusion test could be used in older patients with suspected diminished left ventricular compliance. The occlusion test could be done with the sizing balloons. Transient inflation of the balloon which blocks the left to right shunt of fifteen minutes duration is preferred method to reveal any hemodynamic disturbance. If there is an abnormal response to balloon occlusion, closure with a fenestrated device could be considered. Another strategy is left ventricle training with drugs to treat the diminished left ventricle compliance for a few weeks. The closure could be possible after this treatment period . Howeverartery to obliterate after birth. Most of the PDAs are diagnosed and closed during childhood. Percutaneous closure again attracts interventional cardiologists.Mild continuous murmur is the main presenting clinical finding in many patients with a PDA. This defect may incidentally be diagnosed during TTE performed for various other reasons. PDA is usually detected in basal sections of parasternal short axis window or distal half of the aortic arch in suprasternal window. Closure of a silent PDA is an ongoing debate today. Some authors suggest that even silent shunts might alter long-term survival and prognosis patterns during follow-up . Most paEisenmenger syndrome may develop at large PDA’s missed during childhood period. Correction is contraindicated in this instance. Endarteritis became less common in recent years. Aneurysm formation is a late complication due to endarteritis.Aortic coarctation (ACo) is defined as focal constriction in descending aorta just distal to aortic attachment of ligamentum arteriosum. There are anatomical variations in extent of stenosis caused by and segments involved. The condition is frequently diagnosed during childhood but the most common clinical presentation in an adult is upper extremity hypertension. It is important to note that ACo is a systemic disease and should not be perceived as a simply mechanical obstruction. Hypertension and the other related vascular consequences might persist or recur during follow-up of patients who undergo correction. Ambulatory blood pressure monitoring (ABPM) and exercise stress testing might be used in follow-up. Recurrence might manifest as a hypertensive response to exercise stress testing or findings in ABPM. Hypertension due to aortic coarctation should be treated aggressively. Noninvasive and invasive imaging methods should be used for recognition of recoarctation . HyperteAlthough echocardiography is essential as the initial diagnostic modality, definitive diagnosis necessitates computerized tomography/magnetic resonance angiography and/or invasive angiography. Computerized tomography-angiography is the preferred modality unless there is a contraindication . Upper eTranscatheter stent implantation, preferably covered stent, is shown to be safe and efficient in treatment of this disease and was used successfully even in near-atretic coarctation cases. Surgical treatment is reserved for patients who are not eligible for transcatheter intervention due to anatomical or technical reasons. There are a wide variety of surgical techniques for correction of aortic coarctation but the 3 main techniques are: end to end anastomosis, interposition graft and jump graft A subset of patients with previously corrected CHD has a single active pump unit receiving pulmonary venous flow and directing flow to systemic circulation. Fontan procedure, or cavo-pulmonary circulation is surgical bypass of the right ventricle to divert systemic venous blood directly to pulmonary circulation. The procedure, introduced in late 1960s, was suggested in an effort to provide cure for atretic tricuspid valve . The claRhythm disturbances are not rare and mainly consist of atrial arrhythmias and atrial fibrillation. Atrial fibrillation is a major problem with atriopulmonary Fontan patients and increases with duration of follow-up . It is sSystemic congestion and protein-losing enteropathy are other complications. Lack of suction effect from active relaxation of the right ventricle and augmentation of the pulmonary venous flow is held responsible for this . ImpedanTetralogy of Fallot is the most common form of cyanotic congenital heart disease. Most of the patients have been diagnosed and surgically repaired during infancy period. While the palliative approach consists of Blalock-Taussig shunt, Waterston and Potts anastomoses may be needed in patients with anatomy unsuitable for this shunt. The rationale underlying each of these shunts is directing blood from either left subclavian artery-to left main pulmonary artery or ascending aorta-to-right main pulmonary, or descending aortic-to left main pulmonary artery, respectively. These shunts are preferred either until the total correction is performed or when the patient is unamenable for a therapeutic surgical intervention. Definitive treatment of TOF consists of right ventricle outflow tract (RVOT) repair and VSD closure. Right ventricular outflow tract repair could be performed either with simple infundibular resection or transannular patch might be required in patients with more severe outflow obstruction.In patients with a definitive surgical correction there are several issues which demand special attention: pulmonary regurgitation, residual or recurrent RVOT obstruction, and atrial and ventricular arrhythmias.Pulmonary regurgitationPulmonary regurgitation (PR) is more severe and more common in patients with transannular patch repair. Pulmonary regurgitation was found associated with fatal and nonfatal arrhythmias compared to either significant tricuspid regurgitation or pulmonary hypertension . It is vRecurrent right ventricle outflow tract obstructionIncreased right ventricular systolic pressures by echocardiography should always warrant cardiac catheterization. Site of stenosis might be at the level of infundibular, valvar or any other distal site as well. Percutaneous or surgical interventions for distal stenoses might be the treatment of choice. The obstruction should be treated in case of right ventricle systolic pressure exceeding 2/3 of left ventricle systolic pressure.ArrhyhthmiasWide-variety of arrhythmias, ranging from atrial fibrillation to supraventricular tachycardias to ventricular tachycardias may occur during follow-up . ArrhythOf note, an untouched adult TOF patient with an incidental late presentation is still a good candidate for surgical correction provided that there is no severe irreversible pulmonary vascular disease or severe right ventricular dysfunction.Patients with previous arterial switch operations, performed for the relatively common congenital heart disease called transposition of great arteries (d-TGA) is another group worth discussing.There are 2 types of TGA. The first type is called corrected (c-TGA or L-TGA) with discordant atrioventricular and ventriculoarterial association, and these patients might reach adult age without an apparent problem unless there is a concomitant shunt, which is a frequent finding in these patients. The second type is called d-TGA and this defect is incompatible with life unless there is a concomitant left-right shunt. Surgical correction for this disease underwent significant evolution to take its final form, Jatene procedure, which consists of reimplantation of great arteries to their consequent ventricles and reimplantation of coronary arteries to neo-aorta.The previously mentioned segmental analysis is vital in delineating anatomy in patients with transposition. Venoatrial, atrioventricular and ventriculoarterial associations should be carefully assessed by proper imaging techniques and interpreted by experienced imagers.Mustard and Senning procedures formed the basis of surgical correction of d-TGA for about 2 decades and many of these patients are now in their adulthood. These operations are based on the same technique of forming a baffle, directing blood from systemic veins to left ventricle and from pulmonary veins to right ventricle. The only difference is that while Mustard makes use of pericardial tissue, atrial tissue is used in Senning procedure. Although survival after Mustard and Senning procedures improved in the last 2 decades, Jatene procedure seems to provide better outcomes  .Main problems related with these operations are 1.Baffle leak or obstruction: Baffle leaks are restrictive most of the time and become clinically relevant when either the defect is large or is proximal to a baffle obstruction with resultant right-to-left shunting .2. Arrhythmia: Atrial manipulation during these procedures predispose to nodal disease and atrial arrhythmias. Many patients will need a pacemaker. Catheter ablation, although technically demanding might be an effective option. 3. Outflow obstruction might be observed due to relatively thick left ventricular wall in the subpulmonary region. Subvalvular membranes might or might not accompany.4. Right ventricular dysfunction: Right ventricular dysfunction is an important cause of morbidity in patients with TGA and there should be an active ongoing surveillance for early symptoms and signs .Sudden Cardiac Death (SCD) is a catastrophic consequence of ACHD. Congenital heart disease is demonstrated as the cause of SCD in %0.02 of patients in a recent autopsy study . Recent Sudden cardiac death has two main implications in adult congenital heart disease patients. First and maybe the most important one would be risk stratification and primary prevention. Second one would be the technical challenges related with implantable cardioverter defibrillator (ICD) implantation related with insertion of leads in surgically manipulated hearts.QRS duration and dispersion as well as temporal changes in these parameters, left ventricle ejection fraction and subpulmonary ventricular functions were predictors of sudden cardiac death in ACHD patients. QRS prolongation was in the form of nonspecific conduction delay in patients with preserved ventricular functions and in the form of bundle branch block in ACHD patients. QRS prolongation demonstrated a more rapid progression in patients with systemic or subpulmonary ventricular systolic dysfunction .Almost one-third of ACHD patients required reintervention following implantation of a rhythm device with defibrillator capability. Forty-percent of the ICD shocks delivered in these patients were classified as inappropriate .IE is a major concern in ACHD. It is particularly important in patients with residual or untreated left to right shunts. The latest European Society of Cardiology on IE are far more loose compared with the previous guidelines with regard to antibiotic prophylaxis. The patient and disease related factors that necessitate prophylaxis according to these guidelines are:1. The first 6 months following surgical or transcatheter treatment of intracardiac shunts.2. Any residual leak or valvular leak following transcatheter closure of shunts.3. Presence of any type of prosthetic heart valve.4. Any type of cyanotic congenital heart disease.5. Previous history of IE.The procedure related factors are as follows:1. Dental procedures involving gingiva, periapical region or that results in loss of continuity of the oral mucosa will require prophylaxis with proper antibiotic regimen,2. Surgical interventions involving respiratory system, gastrointestinal system, genitourinary system, musculoskeletal system or skin and already require prophylaxis by nature would require IE prophylaxis to cover potential microorganisms. Prophylaxis is required for any type of vascular or cardiac prostheses. Prophylaxis is not recommended for procedures that don’t fit in any of these categories .Reproductive health and contraceptionIt is shown that menarche is significantly delayed in patients with CHD. Primary, secondary amenorrhea and menstrual cycle irregularities were more common in women with CHD. The authors emphasized the role of functional hypothalamic amenorrhea, which could be exacerbated with stress response, hemodynamic disturbances and cachexia due to heart failure . MenstruWomen in reproductive age should be counseled about their disease and the associated pregnancy related risk by a multidisciplinary team. Patients on potentially teratogenic cardiovascular drugs should be warned against risks of pregnancy.Non-hormonal intrauterine devices are the first choice for contraception. When hormone-based methods are preferred, preparations containing estrogen are not recommended due to same reasons discussed above .Pregnancy, delivery and lactationPregnancy poses a significant risk for the fetus and the mother in certain forms of ACHD while others could be well-tolerated with outcomes comparable to general population. Different risk models have been proposed for risk stratification ,47. EuroCardiovascular drugs during pregnancy in patients with ACHD: Pharmacotherapy should be tailored for pregnancy. Classes of cardiovascular drugs used in ACHD patients are: anticoagulants, antiarrhythmic agents, antihypertensive agents and heart failure medications. Unfortunately, hazardous effects of most of these drugs in pregnancy are well known.th and 12th weeks. Discontinuation or continuation of vitamin K antagonist should be decided on an individual basis, weighing the risks and benefits. Selected drug classes used during pregnancy in ACHD patients are summarized in Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are associated with several congenital abnormalities along with oligohydramnios, intrauterine growth retardation, prematurity and renal failure . Beta blMenopause and hormone replacement therapyAs discussed in the previous section, primary and secondary ovarian failure and early menopause seem to be more common in certain ACHD subgroups . HormonaErectile dysfunction is frequent among ACHD patients. Severity of erectile dysfunction does not seem to correlate with the severity of ACHD. Nitrate use should be questioned when phosphodiesterase inhibitors are considered for treatment of erectile dysfunction.ACHD patients face many problems related to their care in many levels. These patients are usually overwhelmed by the frequent physician visits and interventions. Majority have complicated medical records with complicated imaging, intervention and surgery notes . Their mDenial reactions are common in terminal stage patients with CHD. Management of these patients might be challenging for an unexperienced physician. Studies showed that denial is more common in ACHD patients and had impact on adherence to medical therapy .NYHA class is shown to be a significant predictor of QOL in these patients . Mood anPalliative CarePalliative care and end-of-life discussions constitute an extremely important aspect of care when currently available therapy options are already exercised. Symptom relief and treatment of the mood disorders, as well as thorough end-of-life care discussions with involvement of the specialists in the field is very important . Unfortu


Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. Various cells and molecules are involved in this process, providing targets for potential drug therapies. Currently, the main detection methods of myocardial fibrosis rely on serum markers, cardiac magnetic resonance imaging, and endomyocardial biopsy. This review summarizes our current knowledge regarding the pathophysiology, quantitative assessment, and novel therapeutic strategies of myocardial fibrosis. Heart failure (HF) is a malignant and fatal disease, causing medical, and financial burdens worldwide  play pivotal roles in the development of fibrosis by controlling ECM degradation. Diverging from previous viewpoints, recent studies showed that MMPs are not only involved in ECM degradation, but are also implicated in the progression to HF , regulatory T cells (Tregs), and Th17 cells Wei, . Th1 celInflammatory cytokines, reactive oxygen species, TGF-β, and the renin-angiotensin-aldosterone system all regulate the process of myocardial fibrosis  is secreted by inflammatory cells and fibroblasts, and can be degraded by MMPs. Some animal experiments demonstrated that Gal-3 can accelerate myocardial fibrosis in cardiac disease. Moreover, circulating levels of Gal-3 are associated with the degree of myocardial fibrosis and can predict the re-hospitalization and all-cause mortality of HF. In addition, Gal-3 is an excellent marker for the detection of earlier cardiac remodeling without HF  plays a role in suppressing myocardial fibrosis and cardiomyocyte hypertrophy via binding to ST2L, whereas excessive soluble ST2 can attenuate the function of IL-33, leading to myocardial fibrosis and ventricular dysfunction. Many studies indicated that ST2 is associated with all-cause mortality and cardiovascular mortality  are a cluster of short RNAs that can regulate these processes by promoting either the degradation or the translational repression of their target mRNAs, while playing a vital role in myocardial fibrosis  are the carboxy-terminal pro-peptide of pro-collagen type I (PICP) and the amino-terminal pro-peptide of pro-collagen type III . This association was independent of the LVEF and etiology of heart failure (ischemic cardiomyopathies and non-ischemic cardiomyopathies).LGE has provided clinicians with tools to distinguish non-ischemic from ischemic cardiomyopathies and to identify the etiology of non-ischemic cardiomyopathies. In addition, the presence of LGE and its extent in myocardial tissue relates to overall cardiovascular outcomes  is a primary cardiomyopathy of both genetic and non-genetic origin that is characterized by dilation of the ventricle and systolic dysfunction in the absence of coronary artery disease. DCM is the most frequent indication for heart transplantation. Duan et al.  performen = 3067) with HCM, highlighted the relationship between LGE and cardiovascular mortality in HCM. This study further proves that extensive LGE is a promising risk-stratification tool as it significantly predicts SCD risk, cardiac mortality, and all-cause mortality in patients without conventional risk markers. Hence, LGE should be considered a novel risk marker in predicting SCD in HCM. Currently available data support that patients with extensive LGE for primary prevention of SCD should be considered for ICD implantation, even if they are not at high-risk according to the conventional risk markers.HCM is a relatively common genetic disorder of the cardiac sarcomere, characterized by an idiopathic LV hypertrophy and represents the most frequent cause of SCD among young athletes. Traditional risk factors for SCD in patients with HCM such as family history of SCD, personal history of ventricular fibrillation (VF) or ventricular tachycardia (VT), frequent non-sustained VT on 24-ambulatory holter, LV wall thickness >30 mm can sometimes be inconclusive in determining a patient's risk of SCD. Recent studies suggest that the extent of LGE  can play a major role in SCD stratification in this subset of patients . Moravsky et al. explored the association between the extent of LGE at different thresholds and the degree and content of fibrosis in myocardial tissues of patients with HCM. LGE quantified by 5 T1 mapping has prominent advantages to detect diffuse fibrosis, since it assesses the T1 relaxation time of myocardial tissue. Several studies showed that the association of T1 mapping  with CVF in myocardial biopsies of AS , a novel parameter evaluating myocardial fibrosis, is measured from both pre- and post-contrast T1 mapping analyses. In a recent study, Barison et al. found that the myocardial ECV in patients with non-ischemic dilated cardiomyopathy was higher than that in normal individuals, and the extent of ECV was associated with worsening left ventricular function and composite events such as VT. More importantly, ECV could identify early interstitial fibrosis with no apparent LGE, which provides physicians with a valuable way to predict the prognosis of HF patients with non-ischemic dilated cardiomyopathy  and increase the sensitivity of the ligand to the β-AR. Moreover, beta-blockers have certain antiarrhythmic effects, which decrease the risk of SCD. ACE inhibitors target the renin-angiotensin-aldosterone system and inhibit cardiac remodeling. Losartan, an ATin vivo animal experiment discovered that serelaxin could effectively suppress myocardial fibrosis better than the ACE inhibitor, enalapril. Serelaxin has entered phase III clinical trials for HF treatment and has been found to improve dyspnea and the 180-day mortality rate in patients with acute HF  and implantable cardioverter defibrillators have been applied for the treatment of HF. HF can be prevented in part by limiting the occurrence of malignant arrhythmias either directly by using implantable cardioverter defibrillators, or by improving the coordination and contractility of cardiac muscles by CRT. Both interventions can further improve the prognosis of HF with fundamental medical interventions. In 2013, the ACCF and other cardiac organizations issued the Guidelines of Appropriate Use Criteria for Implantable Cardioverter Defibrillators and Cardiac Resynchronization Therapy, which provides clinicians the ability to decide therapeutic schedules in different situations. Some studies showed that CRT can produce reserved remodeling, which is defined as a reduction in LV end-systolic volume at 6 months after CRT Table . FurtherDespite the significant amount of research now addressing myocardial fibrosis, the understanding of its pathogenesis, clinical implications, and its management remain limited. In terms of the pathophysiology of myocardial fibrosis, more governing factors should be further explored to improve diagnostic methods and identify therapeutic targets. Nonetheless, myocardial fibrosis carries clinical prognostic importance. Serum markers can be used to significantly assess myocardial fibrosis, but whether they should be applied in a clinical setting is still a matter of debate. LGE is an established tool to assess the extent of myocardial fibrosis, but there is no specific cut-off value to evaluate its prognosis. Additionally, ECV represents a novel technique that has promising future for diagnosing myocardial fibrosis. CVF, the golden standard for myocardial fibrosis detection, cannot be easily generalized because of its invasive nature. Currently, there is no specific medical targeted therapy to reduce myocardial fibrosis. However, more clinical experiments have been devoted to the known target sites of myocardial fibrosis and the development of myocardial pathogenesis for the discovery of new medical interventions. Future studies should focus on the understanding of the pathophysiological mechanisms underlying myocardial fibrosis, identify targets of potential therapy, and improve intervention strategies.TL and DS select articles about the pathogenesis of mycardial fibrosis, and wrote the review. PZ, JD, and TL were responsible for guiding clinical manifestation and treatment of heart failure. XM and WL contributed to recommend high-quality articles about late gadolinium enhancement and helped to accomplish the write about cardiac magnetic resonance imaging. SL and JL guided writing of the pathogenesis. LZ revised the clinical part of manuscript.This review was supported by the China Natural Science Funding (81101173 and 81470429) and the High Levels of Health Technical Personnel in Beijing City Health System (2013-3-005).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Left ventricular (LV) remodeling after acute ST-elevation myocardial infarction (STEMI) is an important predictor of mid and long-term prognosis. Pathological cardiac remodeling is associated with the development of LV systolic dysfunction and of congestive heart failure. The role of angiotensin converting enzyme (ACE) inhibitors in preventing cardiac remodeling and LV function improvement is well-known. The aim of our study was to assess the impact of an angiotensin II type 1 receptor antagonist administration instead of ACE inhibitor, in the standardized therapy of STEMI, on LV remodeling and function. Methods: We have studied 34 consecutive patients with STEMI  within 6 hours of symptom onset, who received standard fibrinolytic therapy with 1.5 million IU of streptokinase, followed by unfractionated heparin for at least 48 hours. These patients also received: aspirin (100%), valsartan (100%), statins (94%), beta-blockers (85%) and other drugs according to the physician's choice. Neither of them received ACE inhibitors. An echocardiography was performed at baseline and 6 months after STEMI. Left ventricular end-diastolic diameter (LVEDD) and left ventricular mass corrected to body surface (LVm_BS) were used to assess the remodeling process. Left ventricular ejection fraction (LVEF) and a wall motion index (WMI) based on the analysis of regional contractility of 17 segments were taken into account for the LV systolic function. Changes in these values from baseline to the end of the study were compared using the Wilcoxon statistical test for paired samples.Results: After six months follow-up, there were no significant statistical differences from baseline in LVEDD  and in LVm_BS . There was a significant improvement of WMI  and a significant increase of LVEF . Conclusions: The results of this study suggested that administration of valsartan instead of ACE inhibitor, in consecutive patients with medium-risk STEMI, attenuates pathological LV remodeling and improves LV systolic function. However, as obtained within the first six months after the infarction, these results can not be generalized to the later period after STEMI. ST elevation acute myocardial infarction (STEMI) is an important life-threatening emergency in cardiology. It must not be forgotten that half of the patients with acute STEMI dies during the first two hours, and half of the survivors will die within the next 48 hours. Obviously, MI represents a great therapeutic challenge, also. The main therapeutic goal in the acute phase is represented by the opening as fast as possible the artery responsible for the infarction, which could be done either interventional – by coronary angioplasty, or pharmacologically – by fibrinolytic treatment.The secondary prophylaxis in acute MI starts, practically, within the first 24 hours. After the interventional or pharmacological reperfusion, medical therapy is initiated. Its’ goals are to prevent early and late complications and to enhance the cardiovascular risk profile of the patient. The secondary prophylaxis is based on four classes of drugs whose efficiency has been proved by large, randomized controlled clinical trials. These drugs are the acetylsalicylic acid (aspirin), statins, beta blockers and angiotensin-converting enzyme inhibitors (ACE).However, the replacement of ACE inhibitors with another class of drugs, the angiotensin type 1 receptor blockers (ARBs or sartans) was taken into account.1] and this aspect is more obvious when using low doses [2]. In fact, only 13-15% of this mediator’s production is inhibited, because the rest of 85% is produced by alternative metabolic pathways, especially by the cardiac chymase [1]. Van Katz and coworkers [3] have proved that after circulating angiotensin II production is suppressed, angiotensin II levels in the heart are almost unchanged. These findings could be an explanation for the existence of a subgroup of patients with left ventricular (LV) dysfunction after MI that evolves fast towards congestive heart failure of an III-IV functional class. Even more, it has been proved that high levels of angiotensin II are correlated with increased mortality [4]. Under these conditions it has been postulated that blocking type 1 angiotensin II receptor could be a more efficient therapy; at the same time, a supplementary benefit by vasodilatation, anti-fibrinolytic and antiproliferative effect was expected, as a result of AT2 receptors stimulation.The first reason for this replacement was a theoretical one. While the level of circulating angiotensin II increases 8 times over the normal during STEMI, ACE inhibitors achieves only an incomplete blocking of the angiotensin II production . The patients with past history of another MI, with systolic LV dysfunction or with clinical signs of heart failure have an increased morbidity and mortality. In these patients, ACE inhibitors limit the expansion of the infarction, lower reinfarction rate, lower the incidence of new onset heart failure and represent the state-of-the-art therapy for them [7]. These data were confirmed by the analysis made on 53,853 patients registered in the last 10 years in the German Myocardial Infarction Register (MITRA PLUS). The impact of the treatment with ACE inhibitors over the cardiovascular events, in the 18 months following STEMI has been analyzed in these patients. This analysis have shown that administering ACE inhibitors has no effect at 18 months over the combined end-point: death, re-infarction and the need of revascularization . In a subgroup analysis, ACE inhibitors have been proved a beneficial effect only for the patients with bundle branch blocks, heart failure or diabetes mellitus [8].The third reason is supported by the equivocal therapeutic results in patients aged over 75 years or in those with estimated low cardiovascular risk . The formula we have used is presented below.LVm= 1.04 x [(IVS + PW + LVEDD)^3 – LVEDD^3] – 13.6 where LVm – left ventricle mass, in grams; IVS – thickness of the interventricular septum, in cm;PW – thickness of the posterior wall, in cm;LVEDD – left ventricle end-diastolic diameter, in cm.Table II.For better quantifying the dynamics of the changes we have used a derived measure: the LV mass corrected to the body surface (LVm_BS). This is a common method for correcting LVm, The normal values for these parameters are presented in short axis with two planes – basal  and median , long horizontal axis  and a supplementary view called long apical axis . From the base to the top, the left ventricle is divided into three segments: basal, median and apical. In a short axis view, both the basal plane  and the median plane (of the papillary muscles) divide into six segments, which are as follows, starting clockwise from the atrioventricular groove: the anterior wall, the anterolateral wall, the inferolateral wall, the inferior wall, the inferoseptal wall, and the anteroseptal wall. The apical area is only divided into four segments: anterior, lateral, inferior and septal, at which a small strictly apically located segment is added. In all there are 17 segments. The way the segments are identified in different views is shown in Fig. 2. For the quantification of the segmentary anomalies of wall kinetics, a „target” diagram, presented in Fig. 3, was used.The detection of segmentary wall kinetics abnormalities is based on the fact that the echocardiographic heart „segmentation” is quite well superposed over the coronary arteries’ distribution. The echocardiography has borrowed the nomenclature of these segments from the one used in computer tomography exam. The standard terminology for tomographic sections is: Table III. Based on these regional scores we can obtain a global wall motion index. Ideally, this score equals the sum of individual scores for each segment/17. If for some reason not all segments can be visualized, the wall kinetics index will equal the sum of individual scores for each segment/the number of visualized segments. Obviously, in the presence of a normal myocardial contractility, this index will have the value of 1. Higher values of this score are consistent with more severe local contraction abnormalities.The assessment of endocardic movement was made echocardiographically for every segment. The motility of each segment was described as being hyperkinetic, normal, mildly or severely hypokinetic, akinetic or diskinetic. Each of these descriptions has been scored from 0 to 4 according to the description showed in 11]. The LVEF has been calculated with the following formula [12]:The global left ventricle systolic function has been assessed through the quantitative determination of the ejection fraction (LVEF), through measurements made in the 2-D mode. Unlike the qualitative or the semi-qualitative method through the analysis of segmentary contraction anomalies, which has low reproducibility and it is influenced a lot by the experience and mood of the operator, the quantitative assessment of LVEF has a ± 10% variation limit for a confidence interval of 95% . From the advantages we mention simplicity, brief amount of time required, a good accuracy even for low ejection fractions  and a good reproducibility [15]. The normal values are those above 55%.The main disadvantage of the length-area monoplane method is that it tends to overestimate the LV volumes , where at the 20 months evaluation they registered an increase of the LVEDD of 1.37±2.41 mm. The statistical analysis of the changes in the LVEDD, made through the Wilcoxon test for paired samples, has shown that the median of the differences between the pairs of observations is not statistically significant for the interval 0-6 months .The variation of LVEDD values is presented in Table V. As one could observe in this table, there is a slight decreasing tendency. To evaluate this tendency we have applied the Wilcoxon test for paired samples. The median of the differences between the pairs of observations is not statistically significant for the interval 0-6 months The mass of the LV has been calculated from the measurements of the LV dimensions made in M mode, in the parasternal long axis view. We used the Devereux-Reichek formula corrected with Penn’s convention. The changes of this parameter for our study’s patients are presented in Table VI. A minimal growth, insignificant, can be observed during the follow-up period. This aspect is confirmed by applying the Wilcoxon test for paired samples, with a median of differences between the pairs of observations without statistical significance for the interval 0- 6 months .For a more precise appreciation of the changes we corrected the LVm to the body surface area (BSA). If one can postulate that the patient’s height has stayed constant during the study, the body weight has suffered changes and the BSA changed as a result. The changes, expressed as average values, are not spectacular: immediately post MI, BSA = 1.974±0.207m2 and at 6 months post MI, BSA = 1.966±0.276m2. Apparently, during the 6 months of follow-up the body surface area decreases, and the correction of the LV mass to it is therefore totally justified. The values in dynamics for the LV mass corrected to the BSA are presented in Table VII. A constant tendency of decrease of this parameter can be observed, and the meaning of this decline is that of an improvement in segmentary contractility over time. This tendency has also been confirmed by the statistical analysis with the application of the Wilcoxon test for paired samples. The median of the differences between the pairs of observations is statistically significant and different from 0 for the interval 0-6 months . For the patients in the above- mentioned echocardiographic substudy [17] the decrease is significant for both losartan (p= 0.009) as well as for captopril (p < 0.001), but the decrease is greater for the latter .The evaluation of the regional systolic function was made by the analysis and quantification of the contractility of 17 myocardial segments, followed by the calculation of a global wall motion index (WMI). These values, in dynamics, of the WMI for the 34 patients, are presented in parallel with those of the 252 patients in the echocardiographic OPTIMAAL study, in Table VIII and those of the 428 patients in the VALIANT [16] echocardiography substudy are presented in Table IX. A slight increasing tendency over time could be observed for the LVEF. This tendency has also been confirmed by the statistical analysis with the application of the Wilcoxon test for paired samples. The median of differences between the pairs of observations is statistically significant and different from 0 for the interval 0- 6 months . In the echocardiographic substudy of the VALIANT trial, 20 months later they registered for all the 428 patients an average increase of LVEF of 2.0±7.22% (p < 0.0001). There were no statistically significant differences in the amplitude of the changes of LVEF for each subgroup. The global systolic function has been echocardiographically assessed, by calculating the LV ejection fraction (LVEF) by the monoplane length-area method. The ejection fraction has been determined at the same moments as the WMI was : at 7-10 days and at 6 months after MI. The values of LVEF in dynamics for the studied patients are presented in The linear regression method was applied to verify the extent to which the improvement of the regional contractility, represented by the global wall motion index (WMI), is reflected in the increase of LVEF. The statistical analysis shows that there is an indirect linear relation between the two variables and that the correlation between them is strong and statistically significant, at 6 months after MI .Understanding the physiopathology of the heart failure syndrome is based on the understanding of the process of LV remodeling. Every injury of the LV that results in a diminished systolic function and cardiac output determines, in time, histopathological changes in the myocardium as well as structural changes of the LV cavity.18]. This was the essential experiment for proving the role of Renin- Angiotensin- Aldosterone System (RAAS) in the process of remodeling and progression of cardiac failure. Ventricular remodeling is represented by the alteration of ventricular mass, dimensions and geometry of the chamber due to a myocardial injury, or volume or pressure overload. At cellular level the remodeling is characterized by hypertrophy of the cardiomyocites, fibroblast hyperplasia and an increase of the amount of collagen deposited in the interstice. Even in the non-infarcted myocardium the initiation of these processes induces a progressive remodeling of the LV and, finally, ventricular dysfunction. The roles of angiotensin II in inducing these cellular changes was demonstrated for the first time by Sadoshima & Izumo on isolated rat myocites submitted to a mechanic stress [Evaluation of Losartan In The Elderly) [19], SOLVD (Studies of Left Ventricular Dysfunction), VALIANT  [20], CAPRICORN  and the studies CHARM  [21], -alternative [22], -added [23] and preserved [24] have shown the favorable post MI effects of ACE inhibitors, sartans and beta- blockers over the end-diastolic volume of the LV, the LVEF and over the LV wall motion. These effects correlates well with a significant reduction in morbidity and mortality.Several clinical studies, such as ELITE (27] as well as from the high cardiovascular risk group . Neither the treatment with ACE inhibitors nor the one with sartans change this evolution. No significant changes of LV mass were found in the personal study. Its increase, in the first year at least, is due to the hypertrophy limited to the areas with no infarction and is proportional to the level of the wall tension. This last aspect emphasizes the importance, in the therapy of the survivors after an MI, of drugs which decrease the postload. The LV mass was not assessed in the large post MI trials.Reviewing, we have recorded, in the studied group during the follow-up period, a progressive change in the LVEDD, as an expression of the post MI remodeling process. Without being statistically significant, this type of change has also been found in large international trials who followed post MI patients selected from the intermediate cardiovascular risk group . We must emphasize the precocity of this increase, the increase of LVEF with 4.5% in the above mentioned study, being found after 18 months of treatment [28] The increase with over 4% of the LVEF at 6 months in the patients from this study approach in magnitude to the one in the randomized group with valsartan and beta- blocker in the Val-HeFT trial [We cannot affirm whether the effect of sartan on cardiac remodeling and LV systolic function is better or worse than the one of ACE inhibitors, since this study obviously doesn’t have enough statistical power. A randomized, controlled study would be required in order to do that. Two large trials, OPTIMAAL and VALIANT, have already confirmed that sartans are not inferior to ACE inhibitors from this point of view, in high cardiovascular risk patients.The results of this study suggest that administering valsartan instead of ACE inhibitors, in patients with STEMI from the intermediate cardiovascular risk group, decrease the pathological LV remodeling and improves its systolic function. However these fair results, obtained in the first 6 months after MI, could not be generalized as a long term evolutive model for STEMI.


Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation, requiring frequent surveillance angiography. Though cardiac angiography is the gold standard, it is insensitive in detecting transplant vasculopathy and invasive. Perfusion MRI provides a noninvasive alternative and possibly a useful modality for studying CAV. We sought to compare the accuracy of qualitative perfusion MRI to coronary angiography in detecting CAV.A retrospective analysis was performed in 68 heart transplant recipients who had simultaneous surveillance cardiac MRI and coronary angiogram and who underwent transplantation between 2000 and 2007. We compared results of qualitative MRI to those of the cardiac angiogram. Sensitivity and specificity of MR were calculated.Sixty-eight patients underwent both cardiac MRI and coronary angiogram. 73.5% were male; mean age was 45.37 ± 14 years. Mean duration of heart transplantation was 7.9 ± 5.2 years. The mean ejection fraction was 55% in the patients without CAV and 57.4% in those with CAV. There were 48 normal and 24 abnormal MRI studies. The overall sensitivity was 41% and specificity was 74%.Qualitative assessment of perfusion cardiac MR has low sensitivity and moderate specificity for detecting CAV. The sensitivity of MRI was slightly improved with severity of disease. In the United States, heart failure is an epidemic affecting over 5 000 000 people. It is estimated that between 100 000 and 200 000 people suffer from end-stage heart failure [In comparison to native coronary artery disease, which tends to be focal, CAV is a diffuse process that involves intimal thickening of all of the coronary vessels. As a result, angiography is less sensitive in detecting CAV due to its ability to only measure luminal size and area and its poor discrimination of small arteries . To makeWe performed a retrospective analysis of 72 paired coronary angiograms and perfusion MRIs in 68 heart transplant recipients to determine the sensitivity and specificity of MRI in detecting CAV on angiogram. All heart transplant recipients at our program undergo yearly evaluation for CAV with coronary angiogram during the first 4 years after transplant. After the first 4 years, coronary angiogram is performed every other year alternating with a noninvasive study, either exercise echocardiogram or a thallium study, for the life of the transplant recipient. Between November 2000 and June 2007, patients also underwent simultaneous (within one month) perfusion MRI as part of the heart transplant protocol. Four patients had two sets of MRI-angiogram studies; a total of 72 MRI-angiogram pairs were included in the analysis. We compared the qualitative findings on MRI to the results of the associated angiogram. Each angiogram was evaluated by 2 independent interventional cardiologists. MRIs were read by a single MRI specialist blinded to the results of the angiograms. We compared sensitivity and specificity of MRI in detecting the angiographic evidence of cardiac allograft vasculopathy. This analysis was approved by the Institutional Review Board at the University of Minnesota.A 1.5-T magnetic resonance scanner  and a phase-array body coil were used for imaging. Scout images determined the short- and long-axis views of the heart. Perfusion imaging during rest and adenosine-induced hyperemia was then performed. Adenosine was titrated in three steps to a maximum dose of 140 mg/kg/minute for three minutes. Image acquisition was started 1 minute after the start of the of the maximal infusion rate.Perfusion was determined in three LV short-axis slices using a standard protocol. A single shot gradient-echo sequence with saturation-recovery magnetization preparation for T1 weighting and linear k-spacing was used for imaging. The parameters were set to repetition time/echo time/flip angle of 2.4 ms/1.2 ms/18° and a slice thickness of 10 mm.Temporal resolution allowed acquisition of one image in each of the three selected slices within one heart beat up to a heart rate of 110 beats/minute. Sixty images per slice location were acquired with a spatial resolution of 2 to 3 mm. Three heart beats after initiation of the sequence, a compact bolus of 0.03 mmoL/kg bodyweight gadolinium-DTPA  was injected over an antecubital vein at a rate of 7 mL/s using a power injector . Heart rate, peripheral blood pressure, and oxygen saturation were continuously monitored during the magnetic resonance procedure. Images were analyzed by a single reader who was blinded to the patient’s name, clinical status, and results from the invasive measurements. Perfusion studies were analyzed  via qualitative analysis. Both rest and stress images were acquired. Areas of hypoperfusion were assigned to coronary territories using the American Heart Association coronary arterial segment model.Selective angiography was performed yearly during the first 4 years and every other year as part of the post-transplantation protocol. Coronary angiogram was performed using standard angiography techniques and projections. All angiograms were reviewed in a blinded fashion by 2 interventional cardiologists. Though coronary arteries were assessed for both diffuse and focal lesions, cardiac allograft vasculopathy was defined as a 25% or greater stenosis in a major epicardial artery.Sensitivity and specificity of MRI in detecting cardiac allograft vasculopathy was calculated. In addition, sensitivity and specificity based on severity of CAV was determined.Eventy-four percent of patients were male. The mean age was 46 years (range 13 - 65). No patients who had undergone multi-organ transplant were included. One patient had a second heart transplant at the time the studies were obtained. The mean duration between heart transplant and angiogram/MRI was 8 years (range 1 - 23). The mean ejection fraction was 56%. Thirty-four percent had cardiac allograft vasculopathy by the aforementioned definition. Twenty-four MRIs were classified as abnormal; 10 of the MRIs were false positives. There were 48 normal cardiac perfusion MRI studies; twenty patients with normal MRIs had mild CAV (grade 1 - 3) and four subjects had grade 4 CAV.We evaluated the sensitivity and specificity of MRI in detecting cardiac allograft vasculopathy, defined as 25% or greater lesion. The overall sensitivity was 41% and the specificity was 74%. We further evaluated the sensitivity and specificity by severity of CAV. There was a non-significant biphasic increase in sensitivity and a decrease in specificity with increased severity of CAV. There were 20 studies with normal MRIs and CAV present on angiogram . Of these, 4 had grade four disease. One patient did not receive adenosine and one had no response to adenosine. We compared the angiographic location of disease to patients with grade 4 CAV and abnormal MRIs. Though the numbers are small for comparison, there was a tendency toward significant proximal vasculopathy in those patients with a true positive MRI. Those who had false negative MRIs tended to have diffuse disease on angiogram. Collateralization did not explain the false negative MRIs since both groups had evidence of collateralization.Ten patients were found to have a false positive MRI. The rate of subendocardial ischemia in false positive studies was 60%. We attribute this to the possibility of microcirculatory disease, however are unable to substantiate this without intravascular ultrasound and provocative testing.In our study, perfusion MRI detected cardiac allograft vasculopathy, defined as a stenosis of 25% or greater in a major epicardial artery, with a sensitivity of 41% and specificity of 74%. When severity of CAV was assessed, sensitivity increased slightly and specificity decreased.Current noninvasive methods for evaluating cardiac allograft vasculopathy include echocardiography and radionuclide imaging techniques. Dobutamine stress echocardiogram is perhaps the most widely used noninvasive test for evaluation of CAV. In general, sensitivity and specificity of DSE in heart transplant recipients has been acceptable with sensitivity being reported between 79 - 95% and specificity from 55% to 91% when compared to angiography . FurtherWhile highly specific (77 - 100%), stress ECG has extremely poor sensitivity (0 - 38%). Similarly, thallium scintigraphy is highly specific with moderate to poor sensitivity. Multi-detector computed tomography (MDCT) with adaptive multi-segment reconstruction has been shown to detect CAV with 86% sensitivity and 99% specificity . Major cThere are several limitations to noninvasive testing in heart transplant recipients. Attaining adequate heart rate for exercise studies may be difficult in heart transplant recipients due to medications and limited exercise capacity. Furthermore, the gold standard used for comparison, that is, coronary angiogram, is in itself, insensitive in identifying cardiac allograft vasculopathy. Studies that rely on differences in perfusion may be insensitive in detecting diffuse cardiac allograft vasculopathy.Cardiac perfusion MRI, in contrast to exercise testing, does not rely on achievement of a target heart rate. It provides superior spatial resolution when compared to radioisotope techniques and does not require the use of radiation. Perfusion MRI is greatly enhanced with the use of quantitative techniques. In patients with suspected native coronary artery disease, Al-Saadi et al demonstrated a sensitivity of 90%, specificity of 83% and a diagnostic accuracy of 87% for the detection of native CAD using a myocardial perfusion reserve cutoff of 1.5 . SchwittDiagnosis of cardiac allograft vasculopathy using noninvasive techniques, however, represents a challenge due to the inherent differences between native CAD and CAV and its expression in the vasculature. Significant CAV may be present even in the presence of a non-significant stenosis in the epicardial arteries. Wilson et al demonstrated that discrete coronary lesions producing less than 70% area stenosis and less than 50% diameter stenosis do not produce hemodynamically significant reductions in coronary flow reserve (CFR). Furthermore, there is poor correlation between degree of stenosis and CFR in patients with diffuse coronary artery disease . Heart tOur analysis compared qualitative perfusion MRI to coronary angiogram. We did not incorporate quantitative techniques as these are not widely used and thus would not reflect practice in most clinical settings. In our series, we detected a low sensitivity and moderate specificity that was not comparable to dobutamine stress echocardiogram, which has been reported as having excellent sensitivity and specificity in CAV. In addition, sensitivity appeared to improve with severity of CAV but declined with the most severe disease. One explanation for this decline in sensitivity is the decreased ability to detect relative differences in perfusion in advanced and diffuse coronary disease. Specificity also declined, though not significantly, with severity of disease.Based on the low sensitivity of cardiac perfusion MRI in detecting CAV, we conclude that qualitative MRI assessment alone cannot be recommended as a screening tool for cardiac allograft vasculopathy.There are several limitations to this study that should be noted. In this study we evaluated qualitative MRI without the use of quantitative techniques, however quantitative analyses may have provided a better assessment of subendocardial ischemia and microvascular disease which may precede the development of epicardial disease. Nevertheless, qualitative MRI is widely utilized, thus we believe this approach was an accurate evaluation of actual clinical practice. We acknowledge the limitations of using angiogram as the gold standard. CAV involving subendocardial vessels or diffuse, non-stenotic disease is not easily detected on angiogram. It is possible, however, that these lesions may cause changes in perfusion thus resulting in a “false-positive” result on the MRI. Intravascular ultrasound and functional testing may have improved the invasive detection of CAV and small vessel disease. This may have allowed a better determination of the cause of the false positive MRI results. On the other hand, the false negative rate was 28%, and appeared to be associated with the presence of diffuse disease on angiogram. Thus, having a diagnosis by IVUS may not have necessarily improved the specificity. We did not evaluate sensitivity and specificity by type and location of lesion, which may have provided different results.Qualitative perfusion MRI is insensitive in the detection of cardiac allograft vasculopathy and should not be used as a screening study in the evaluation of heart transplant recipients. Quantitative assessments may enhance the ability of MRI to detect CAV and thus represent a more reliable noninvasive diagnostic tool. Furthermore, in planning future studies to evaluate noninvasive techniques in the diagnosis of CAV, consideration should be given to using intravascular ultrasound as the gold standard.


The hemodynamic changes during the first few breaths after birth are probably the most significant and drastic adaptation in the human life. These changes are critical for a smooth transition of fetal to neonatal circulation. With the cord clamping, lungs take over as the source of oxygenation from placenta. A smooth transition of circulation is a complex mechanism and primarily depends upon the drop in pulmonary vascular resistance (PVR) and increase in systemic vascular resistance (SVR). Understanding the normal transition physiology and the adverse adaptation is of utmost importance to the clinicians looking after neonates. It may have a significant influence on the presentation of congenital heart defects (CHDs) in infants. Bedside echocardiography may help in understanding the transition physiology, especially the hemodynamic changes and shunting across ductus arteriosus and foramen ovale, and it may play an important role in making judicious clinical decisions based upon the altered physiology. The transition from fetal to the neonatal circulation is a complex process. In fact, the hemodynamic changes during the first few breaths after birth are probably the most significant and drastic adaptation in the human life. Following lung expansion there is a significant decrease in pulmonary vascular resistance (PVR), and removal of the placenta results in an increase in systemic vascular resistance (SVR) –4. In maPrematurity has major impact on the transition from fetus to neonatal circulation. The persistence of fetal shunts, high PVR due to increased incidence of respiratory distress syndrome, increased need of mechanical ventilatory support, immature myocardium and increased incidence of metabolic acidosis in the premature infants have major impact on the transition from fetus to neonatal circulation , 8, 9.The phenotypical presentation of the adverse adaptation varies immensely—from mild or no symptoms to a critically ill infant with hypotension and cardiogenic shock. To complicate the matter further, transition of circulation may be affected by the resuscitation manoeuvers, maternal condition, sepsis, medications, thermoregulation, and the interventions infants need in the intensive care setting .Therefore, a good understanding of the cardiovascular transition from fetal to neonatal circulation is of utmost importance to the neonatologists and pediatric cardiologists or intensivists caring for the neonates. It may help the clinicians to choose the appropriate intervention in infants with hemodynamic instability; avoid under- or over-treatment in this vulnerable population cohort, especially preterm infants and critically ill infants with persistent pulmonary hypertension –13.The purpose of this article is to review the changes in cardiovascular physiology during transition from fetal to neonatal circulation, impact of the adverse adaptation on hemodynamics, and how bedside echocardiographic evaluation may help in understanding the clinical relevance and management of the adverse adaptation. For the echocardiographic evaluation of specific condition such as hemodynamic evaluation of patent ductus arteriosus (PDA) is discussed in separately under TINEC research topics in Frontiers in Pediatrics.In an adult, the cardiovascular system is connected in series, hence, the stroke volume of right and left ventricles are equal. The circulatory connections in a fetus are complex and in parallel facilitated by various intracardiac and extracardiac shunting. In a fetus right ventricle receives 65% of the venous return while left ventricle receives about 35% of the total venous return , 14, 15.The placenta allows the fetus to receive oxygenated blood from the maternal circulation. The umbilical arteries bring around 45% of the fetal cardiac output (de-oxygenated blood) to the placenta, and the oxygenated blood is returned to the fetus via umbilical vein. Placenta has a low vascular resistance and hence SVR in fetus is maintained low ;Ductus arteriosus (DA) facilitate diverting most of the right ventricular cardiac output to the descending aorta. The high PVR in lungs and low SVR facilitate right to left shunting via ductus arteriosus smoothly. The patency of ductus arteriosus is primarily maintained by the high prostaglandin levels synthesized from the placenta and within the ductal tissue, and increased nitric oxide content. The animal studies demonstrate that up to 90% cardiac output is shunted away from un-aerated lungs via ductus arteriosus, although in human fetus this proportion is thought to be bit lower , 17. PreDuctus venosus plays an important role in directing oxygenated blood from the umbilical vein to the inferior vena cava ; andThe shape of ductus venosus allows oxygenated blood diversion to inferior vena cava, and Eustachian ridge (at the junction of inferior vena cava with right atrium) helps in preferential shunting of oxygenated blood from umbilical vein to left atrium via foramen ovale. This allows more oxygenated blood returning to left ventricle. Hence, coronary arteries and upper part of the body (brain) receive more oxygenated blood than the lower part of the body , 17.The transition physiology, from fetal to neonatal circulation, is complex and accompanied by many drastic physiological changes in the cardiovascular system soon after birth. In a term infant, a successful cardiovascular transition is accomplished by an increase in SVR resistance following removal placenta and drop in PVR after expansion of lungs , 16.The SVR is increased primarily from removal of the low vascular shunt (placenta), but, there are also other important contributing factors such as increase in thromboxane 2 and vasopressin. The drop in PVR is primarily from aeration of lungs, which were filled with amniotic fluid in fetus, and increased production of potent pulmonary arterial vasodilators such as bradykinins, histamine and prostaglandins , 20. In The mechanism for ductus arteriosus (DA) closure is complex and multifactorial: it is primarily facilitated by the direct vasoconstriction of ductal tissue (smooth muscle) in response to oxygenated blood from left to right shunt via DA, and a drop in prostaglandins after removal of placenta and increased degradation of prostaglandins in the lungs. In a term infant, the functional closure of DA occurs within 24–48 h after birth while anatomical closure may take up to 10–14 days .The closure of fetal shunts  and removal of placenta result lead to change in the cardiovascular connections: from parallel in the fetus to in series connections. This accomplishes a successful adaptation of transitional circulation leading to equal left and right ventricular output (Qp:Qs ratio of 1).The physiological response to transition in preterm infants is even more complex, and a detailed description is beyond the scope of this review article. However, this is briefly discussed later in the section on adverse adaptation.Overall placental-umbilical blood flow increases with gestational age, and it is estimated that placenta receives around 100–125 ml/kg/min (around 40% of the combined biventricular output in fetus) at term). The placenta is thought to hold 30–50% of the fetal circulating volume at any one time. Following immediate cord clamping the estimated mean blood volume of a term infant is approximately 80 ml/Kg , 23.The studies have demonstrated that a term infant may receive an additional 20–35 m//Kg of blood from placental transfusion when clamping of the umbilical cord is delayed for up to 5 min . The mosIn the fetus, the left ventricular preload primarily depends upon the umbilical blood flow via foramen ovale while soon after clamping of the umbilical cord it primarily depends upon the pulmonary venous return. When umbilical cord is clamped before establishment of lung expansion, it may lead to a significant drop in LV preload and systemic cardiac output. This may look less relevant in a well term infant with smooth transition physiology but it becomes more important in the compromised term infant and in the preterm infants—the maintenance of adequate LV preload is essential for sustaining an adequate LV output .There is good evidence showing benefits of delaying cord clamping for 1–3 min. A recent meta-analysis by Fogarty et al., studied 18 randomized controlled trials involving more than 2,300 patients, concluded that delayed cord clamping decrease mortality, improve hemodynamic stability and increase hematocrit values leading to decreased need of blood transfusions in the neonates . The othNormal transitional physiology may be altered by many conditions including prematurity, underlying congenital heart defect, infection, perinatal asphyxia, meconium aspiration syndrome (MAS), congenital pneumonia, chest infection, congenital diaphragmatic hernia, and pneumothorax to name a few. While detailed discussion is beyond the scope of this article we will discuss adverse cardiovascular adaptation from persistent high vascular resistance leading to persistent pulmonary hypertension or from increased pulmonary blood from shunting, especially in the premature infants.The most immediate and adverse adaptation of transitional circulation occurs from persistent high PVR leading to continued right to left or bidirectional shunting across ductus arteriosus and/or via foramen ovale. Because of the increased PVR, PBF is decreased leading low oxygen saturation levels, increased oxygen requirement and ventilator support. This leads to decreased pulmonary venous return, and hence, decreased LV preload and low systemic blood flow (LV cardiac output). The decrease in perfusion of organs leads to increase in lactate, acidosis and hypoxia which are the most potent pulmonary vasoconstrictors. This further increases PVR, and it becomes a vicious cycle leading to acute pulmonary hypertension (commonly referred as persistent pulmonary hypertension of newborn or PPHN) , 10 Fig.The increase in RV afterload from persistently increased PVR  results in right ventricular hypertrophy and/or dilatation and if this process continues then it may lead to RV dysfunction or RV failure. The right ventricle dysfunction and bowing of interventricular septum toward LV, due to increased RV pressure, further compromises LV preload and LV function leading to biventricular dysfunction (ventricular interdependence). The decreased LV preload and LV dysfunction result in low systemic blood pressure (hypotension) which often needs cardiovascular support . BedsideThere is a high incidence of persistent PDA in the preterm infants, and its incidence is directly related to the gestation age—lower the gestation age higher the incidence of PDA . The shuThe signs and symptoms of persistent PDA not only depend upon the size of ductus arteriosus but also on the magnitude of the shunt and the ability of myocardium to adapt to the extra shunt volume. This may explain why signs and symptoms vary in patients with a similar size of ductus arteriosus. Therefore, a thorough hemodynamic assessment is critical in evaluation of PDA and a bedside echocardiography can help in determining ductal characteristics, degree of pulmonary hyperperfusion  and systemic hypoperfusion  .The other common adverse adaptation of transitional circulation occurs in the setting of perinatal asphyxia. Essentially similar mechanisms as explained above leads to adverse adaptation of transition leading to high PVR, poor cardiac function from direct cardiac compromise and often these infants have associated PPHN from associated or underlying conditions. The therapeutic hypothermia, which is a standard of care for infants with moderate to severe hypoxic-ischaemic encephalopathy, may further affect the transition—it leads to high PVR, high SVR, sinus bradycardia associated with low cardiac output and it may further deteriorate cardiac function from increased afterload , 30. A dAs discussed above, the diagnosis of congenital heart defects (CHDs) may be challenging during transitional circulation. Similarly, the presence of congenital heart defect may affect the cardiovascular physiology and it's critical to understand this impact while managing infants with CHDs. A classification of the CHDs based upon the post-natal transition is summarized in Table The hemodynamic changes due to CHDs are different during fetal life than those occurring after birth. Moreover, even after birth these changes are dynamic depending upon changes in SVR, PVR, shunt magnitude, and disease pathology. It is well known that early fetal obstruction of a ventricular outflow (right or left) tract may result in progressive underlined ventricular hypoplasia. Moreover, altered blood flow and oxygen content may affect pulmonary vascular bed and cerebral development. Most CHDs are well tolerated during the fetal life because oxygenation is primarily dependent upon placenta and fetal shunts allowing the fetal circulation to adapt. Nevertheless, CHD induce profound changes in the fetal hemodynamics that may alter post-natal adaptation .The impact of CHD varies from benign with no repercussion after birth to serious with profound hemodynamic disturbances in the early post-natal life. Transposition of the great arteries (TGA), right and left heart obstructive lesions, and obstructed total anomalous pulmonary venous return (TAPVR) are serious conditions carrying a high early mortality. Those CHDs are poorly tolerated during the transitional phase where the function of oxygenation is transferred from the placenta to the lungs with subsequent decline in PVR, increase in SVR, closure of the ductus arteriosus and closure of the foramen ovale. When untreated, they can progress to severe acidosis, shock and/or cyanosis , 33.Left heart obstructive lesions require an open ductus arteriosus to maintain the systemic circulation. When the ductus arteriosus closes, the SVR decreases, the systemic perfusion falls, the pulses become weak and the newborn develops progressive acidosis and shock . ProstagRight heart obstructive lesions require an open ductus arteriosus to maintain pulmonary circulation. When the ductus arteriosus closes, the pulmonary perfusion falls and the newborn develops progressive cyanosis with no response to oxygen administration. The administration of oxygen will further induce constriction of the ductus arteriosus. Because the fetal physiology is adapted to chronic hypoxia, those babies can tolerate cyanosis better than the older child until acidosis develops . ProstagTransposition of the great arteries with intact ventricular septum (TGA/IVS) can be considered as a duct-dependent lesion, although an atrial septal defect (ASD) or a patent foramen ovale (PFO) is crucial to allow for mixing between the pulmonary and systemic circulations Figure , image BTAPVR requires mixing of the pulmonary and systemic circulation at the atrial level , truncus arteriosus communis (TAC)] and right-to-left shunt through a ventricular septal defect (VSD) may present mild cyanosis. The degree of cyanosis will depend on the severity of the pulmonary stenosis. TGA with VSD can present with mild cyanosis, and it is usually not a duct-dependent lesion due to the mixing of the pulmonary and systemic circulations across the VSD. If the VSD is small and the foramen ovale is restrictive or intact, prostaglandin E1/E2 infusion may be necessary; and an urgent atrial septostomy should be performed , 34.The infants with systemic-to-pulmonary communications  are usually unremarkable soon after birth because the fall in PVR is progressive, and it takes at least 2 weeks to be complete, even longer in babies with those CHDs. In the early post-natal period, the amount of left-to-right shunt is low and does not cause any symptoms. With the progressive fall in PVR, the amount of left-to-right shunt will increase according to the size of the systemic-to-pulmonary communication, and it results in increased PBF. The left ventricular output increases accordingly to maintain adequate systemic blood flow. The increase in left atrial pressure may lead to pulmonary edema, respiratory distress and poor weight gain , 36.Bedside echocardiography may play an important role in understanding the normal cardiovascular transition physiology and its adverse adaptation. The echocardiographic assessment during a normal smooth transition process, and during the most common adverse adaptations  are discussed below:The echocardiographic assessment during normal transition physiology may show presence of PDA, patent foramen ovale and right ventricular dominance if it is performed soon after birth or in presence of delayed adaptation to transition Figure .The shunt across foramen ovale is either left to right or bidirectional but never purely right to left. A pure right to left shunt across foramen ovale should raise suspicion of underlying CHDs  , 35, 36.The shunt across ductus arteriosus changes to bidirectional or left to right soon after birth Figures . A pure The echocardiographic assessment during adverse adaptation should include a thorough structural assessment to rule out underlying congenital heart defect, assessment of cardiac function and hemodynamic evaluation. In conjunction with other clinical parameters, a bedside functional echocardiography may provide immediate anatomical and physiological information in real time to help in understanding the pathophysiology leading to adverse adaptation and in targeting the specific intervention based upon altered physiology. While the detailed assessment of the individual specific conditions is discussed in other TINEC research articles published in Frontiers in Pediatrics, an approach to echocardiographic assessment to common conditions associated with adverse adaptation of transitional circulation is discussed below:As discussed above, increased PVR is the hallmark of altered transition physiology in persistent pulmonary hypertension. The direct assessment of PVR may be difficult to assess on bedside echocardiography but a detailed assessment of the severity of pulmonary hypertension, cardiac function and hemodynamic assessment may be helpful in managing the adverse adaptation in patients with high PVR or pulmonary hypertension.A persistent high PVR (RV afterload) may lead to right ventricular hypertrophy or even RV dysfunction with or without RV dilatation. The severity of pulmonary hypertension is best assessed by measuring pulmonary artery pressure. It can also be indirectly assessed by assessing interventricular septum and LV shape. The shunt across PDA may be bidirectional or purely right to left depending upon the pulmonary artery pressure in relation to systemic pressure. The shunt across foramen ovale is often bidirectional. The RV cardiac output may be decreased in presence of high PVR and RV dysfunction, and LV cardiac output may be decreased from decreased LV preload (decreased pulmonary venous return) and LV dysfunction . A thoro- Recognition of RV hypertrophy with or without RV dilatation- Estimation of pulmonary artery pressure- Assessment of shunt across ductus arteriosus and foramen ovale- Assessment of interventricular septum and LV shape- Evaluation of RV and LV function- Cardiac filling (preload assessment)- Measurement of RV and LV cardiac output.Like the term infants, most of the mature preterm infants may have a smooth transition. However, this process may be more challenging for the extremely low birth weight (ELBW) infants under 28 weeks of gestation. There are certain specific factors related to prematurity that may affect the transition process in preterm infants: (1) higher incidence of persistent PDA and foramen ovale; shunting across PDA may play an important role in the disease pathology; (2) impaired myocardial performance due to immature myocardium possessing inefficient contractile mechanism leading to inherited impaired systolic and diastolic cardiac function in ELBW infants; (3) faster heart rate with possibly increased cardiac demand and less time spent in diastole limiting the ability to increase stroke output; and (4) higher incidence of respiratory conditions needing mechanical ventilation and affecting cardiovascular dynamics , 38, 39.Therefore, understanding the cardiovascular physiology may be even more important in ELBW infants while making a careful decision regarding fluid therapy and inotropes during adverse adaptation. A persistent large left to right shunt across PDA in ELBW infants may lead to significant hemodynamic changes: systemic hypoperfusion  and pulmonary hyperperfusion. The summary of the echocardiographic assessment of PDA and its hemodynamic evaluation is demonstrated in Figures Perinatal asphyxia refers to oxygen deprivation before or around the time of birth and it may results in hypoxia-ischemia (HI) induced brain damage or hypoxic-ischemic encephalopathy (HIE). The cardiovascular instability is common in patients with HIE and the causes are multifactorial. In fact, transient myocardial ischemia and myocardial dysfunction occurs in two-thirds of the infants with moderate to severe perinatal asphyxia , 44.The effects of perinatal asphyxia on the cardiovascular transition are complex. Myocardial ischaemia may be a direct effect of perinatal asphyxia or it may be further caused by the ongoing redistribution of blood flow leading to reduced myocardial perfusion, especially in the sub-endocardial tissue and papillary muscles –45. ThisIn addition, therapeutic hypothermia also increases PVR and SVR , which cBedside echocardiography can help in assessing the cardiac function and hemodynamic changes in real time. The assessment of preload, cardiac output and cardiac function may help in making a logical choice of therapy in patients with moderate to severe HIE to optimize the end-organ blood flow.As discussed above, the infants with CHDs may have an effect on the transitional physiology such as increased left to right shunt may lead to increased PBF. When shunt is significant it may contribute to worsening of respiratory symptoms such as tachypnoea and increased work of breathing requiring oxygen and/or respiratory support. A persistently increased PBF may contribute to development of pulmonary hypertension in children , 9.Similarly, hypoxia from decreased blood flow may affect the normal transition process. These children often have associated conditions leading to decreased blood flow (such as right ventricular outflow obstruction) which may lead to ventricular hypertrophy, impaired diastolic and systolic functions. The effects of the CHDs can be even more complex to understand in presence of multiple defects or complex association with varying effects on cardiovascular physiology , 47. A cThe other neonatal conditions may have an impact on the cardiovascular transitional process such as neonatal sepsis. It may have direct effect on the myocardial performance leading to cardiac dysfunction or may affect the vasomotor permeability leading the change in SVR. Unlike adults with warm septic shock leading to drop in SVR, neonates may have a complex response to shock. SVR may be increased, especially during early sepsis (cold shock) or it may be decreased (warm shock). The studies have reported that sepsis may have deleterious effect on the myocardial function—both direct effect on myocardium or via cytokine induced pathway. The troponin levels in non-survivors of neonatal sepsis have been reported significantly higher than survivors , 48. SimTransitional physiology is complex and it may be altered by multifactorial causes. The adverse adaptation of transition physiology may lead to persistent pulmonary hypertension, pulmonary hyper- or hypo-perfusion and systemic hypoperfusion. In conjunction with a meticulous clinical examination and routine bedside monitoring, the use of new technologies such as functional echocardiography, non-invasive assessment of cardiac output and end-organ perfusion assessment by using near infra-red spectroscopy (NIRS) may provide invaluable information in the infants with altered transitional physiology. While the role of other techniques is being established, bedside echocardiography may provide anatomical and physiological information in real time helping to make judicious clinical decisions in the intensive care setting.CT is a pediatric cardiologist trained at the University Hospital of Geneva, Switzerland and in Denver, Colorado, USA. CT has been working as an attending pediatric cardiologist at the Children's Hospital of Geneva (HUG) until recently and is now working in the Pediatric Center at Clinique des Grangettes, Switzerland. YS is a consultant in neonatology and pediatric cardiology at Addenbrooke's Hospital in Cambridge, UK and he is a course director for echocardiography in Cambridge. CT and YS have special interest in functional echocardiography and hemodynamic assessment in children. They both belong to the NPE (Neonatologist Performed Echocardiography) group form the ESPR (European Society of Pediatric Research) and are chairing the POCUS (Point-of-Care Ultrasound) working group from the ESPNIC . They belong to the organizing committee of TINEC , a course on functional echocardiography taking place every year in Switzerland since 2016.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 75-year-old woman was presented to our emergency department because her pulse had become slow during physiotherapy exercises. She had a history of bypass surgery for severe triple vessel disease and severe left ventricular dysfunction. Furthermore, one month before presentation, she had been hospitalised with progressive heart failure presumed to have been caused by a high ventricular rate during an episode of atrial fibrillation. In order to achieve rate control, she was treated with digoxin and bisoprolol. She recovered well from this episode of decompensated heart failure.What is your electrocardiographic diagnosis?What is the most likely mechanism?On presentation she had a two-day history of dizziness and light-headedness. On clinical examination her pulse rate was 30 bpm and blood pressure was 160/45 mm Hg. There were no clinical signs of heart failure or dehydration. The electrolyte panel was normal. However, her renal function worsened to an estimated MDRD-GFR of 22 ml/min compared with 37 ml/min one month earlier. The ECG at presentation is shown in Fig. You will find the answer elsewhere in this issue.