cardiac fibrosis is a common histopathological occurrence with many types of heart diseases , including ischemic heart disease , inherited cardiomyopathy mutations , diabetes , and ageing and is associated with morbidity and mortality . while there are several mechanisms of myocardial fibrosis with acute and chronic etiologies , increased accumulation of extracellular matrix ( ecm ) that impacts cardiac function , is the underlying cause of fibrotic heart disease . besides the disturbances in the mechanical functions of heart , fibrosis mediated scarring and electrical dysfunction often initiates ventricular arrhythmias , which in turn accelerates events towards heart failure and then sudden cardiac death ( 13 ) . myocardial fibrosis presents one of the major challenges clinically not just to improve the survival rate and also the quality of life . cardiac magnetic resonance ( cmr ) has been useful in measuring the extent of diffuse myocardial fibrosis , which is considered as a common pathological pathway that leads to the loss of myocardial function ( 4,5 ) . inasmuch as fibrosis can be reversible ( 6 ) , its quantification using cmr can be useful in changing the way the cardiac fibrosis patients are monitored and treated ( 7 ) . myocardial fibrosis has been demonstrated in the pressure - loaded left ventricle of infants and children with aortic stenosis and coarctation ( 8) . histological studies revealed right ventricular myofiber disorganization and interstitial fibrosis in patients with tetralogy of fallot ( 9 ) . right ventricular fibrosis is not just found in late adult survivors , but actually is already present in infants suffering with this condition ( 10 ) . alterations in myocardial architecture associated with fibrotic remodeling lead to deranged heart function in different ways . thus , in patients after tetralogy of fallot repair , fibrous endocardial thickening of the right ventricular infundibulum is a predictor of poor right ventricular function ( 5 ) . on the other hand , myocardial fibrosis is associated with systolic ventricular dysfunction early in life in patients with tricuspid atresia ( 11 ) . healthy myocardium consists of mostly cardiomyocytes ( ~75% ) , with the remaining partition , the interstitium regions comprising of fibroblasts , endothelial cells , and coronary arteries ( 12 ) . the fibroblasts participate in the continuous formation and degradation of ecm , which is composed of types i and iii collagen fibers , that act as the scaffold for the myocardium . disturbances in the balance between collagen production and degradation in the ecm , that led to expansion of collagens , cause myocardial fibrosis . such derangement occurs either due to the death of cardiomyocytes , or because of stimuli that trigger elevated collagen synthesis ( 13 ) . i ) reactive interstitial fibrosis ( rif ) : this is characterized by an increase in collagen synthesis without much effect on the viability of myocardium ( 14 ) . rif is considered as a type of myocardial remodeling and leads to an increased interstitial compartment volume without any associated changes in myocyte volume . this type of fibrosis is associated with diffused deposition of collagen and occurs in response to increased pressure and/or volume loads as in the cases of hypertension , aortic stenosis , chronic regurgitation , and shunt , ischemia , hyperglycemia , or ageing . rif , which generally presents with a progressive chronic course , is possibly reversible by curtailing the damage causing stimuli or even by targeted therapy . ii ) replacement fibrosis : an increased type i collagen deposition and expansion of ecm , following cardiomyocyte death contributes to this type of fibrosis ( 14 ) . the elevated levels of collagen fibers replace the dead cardiomyocytes , but lack the contractile and electric functionality . acute or chronic conditions that trigger cardiomyocyte death such as myocardial ischemia and events that damage the cardiomyocyte membrane integrity causing cell death , lead to diffused or focal replacement fibrosis . unlike the rif , in replacement fibrosis , the affected myocardium is not viable and thus is unable to recover contractile properties following revascularization or by blocking the damaging process . iii ) infiltrative interstitial fibrosis : this fibrosis is seen in conditions such as amyloidosis or anderson - fabry disease ( 14 ) . inflammatory cell infiltration was proposed to be an important factor underlying the interstitial fibrosis seen in right ventricles of systemic sclerosis - associated pulmonary arterial hypertension ( 15 ) . iv ) endomyocardial fibrosis ( emf ) : emf affects children under age of 2 years in tropical and subtropical regions , and involves the apical endocardium of either or both right and left ventricles . it has been suggested that emf as one of the primary causes of pediatric congestive heart failure , which is often overlooked clinically ( 16 ) . there is no clear etiology for emf , but hypereosinophilia , infections , autoimmunity , genetic factors and nutritional deficiencies may play a role . emf has been described to present in three phases : initial phase of acute carditis with febrile illness and with heart failure in severe cases ; an intermediary subacute phase followed by a chronic burnt - out phase ( 17 ) . notably , emf is identified mostly at late stages of the disease and is not observed in the early phase of the disease . however , following diagnosis , there is rapid onset of associated complications such as atrial fibrillation , thromboembolism and progressive atrioventricular valve regurgitation . emf patients display clinical features of heart failure , with enlargement of both atria with normally functioning ventricles during echocardiography ( 18 ) . currently , the approach to treat emf patients is by surgery , involving targeted endocardial resection combined with valve repair or replacement , as there is no specific medical treatment ( 16 ) . although the biology of cardiomyocyte and its apoptotic or necrotic death have been the focus of several investigations addressing cardiac diseases , increasing evidence suggests cardiac fibroblasts in the pathogenic mechanisms ( 19,20 ) . fibroblasts , which are abundant in the normal myocardium , have a structural function by providing support ( 21 ) . however , when these normally quiescent fibroblasts are activated , they transdifferentiate into myofibroblasts , which appear similar to a hybrid of fibroblast and smooth muscle cells . myofibroblasts are able to effectively secrete and myofibroblasts are absent in healthy heart , they appear within days following a cardiac injury ( 22 ) . myofibroblasts appear as spindle - shaped and possess dendritic - like processes ( 23 ) that protrude from the cell body . characteristic elongated and serrated nuclei , extensive areas of rough endoplasmic reticulum and irregular non - sarcomeric myofibrillar structures are morphological features of myofibroblasts as observed in electron micrographs of pressure - overloaded rat heart cross sections ( 24 ) . specific protein markers of myofibroblasts are mainly the ecm proteins , such as periostin , collagens i and iii and fibronectin ( 25 ) . besides these ecm proteins , myofibroblasts also express smooth muscle -actin , sm22 and caldesmon ( 26,27 ) . of note , most of the myofibroblasts present in the border zone and approximately half of those in the fibrotic lesions of damaged myocardium , express embryonic smooth muscle myosin and -sma but not other smooth muscle markers , which is a major difference from smooth muscle cells ( 28 ) . it has been suggested that there are two stages in the transformation of myofibroblast : in the first stage , there is development of  proto - myofibroblasts from fibroblasts , with the characteristic formation of cytoplasmic actin stress fibers and small adhesion complexes , which facilitate the migration of these cells to the injured myocardium , where these cells secrete collagens and fibronectin and assume physical orientation in order to align themselves with the primary stress axes of the injured tissue ( 25 ) . in the second stage , which starts approximately 2030 h following cardiac injury , the cytokines and mechanical stress convert these proto - myofibroblasts to mature myofibroblasts , which express -sma , which forms the stress fiber network ( 25 ) . with further maturation of the myofibroblast , besides the -sma , cadherin-11 is also secreted and adds to the strength of the stress fiber network ( 29 ) ( fig . 1 ) . normally myofibroblasts have a protective function in the heart by participating acutely in injury repair response . although uninterrupted fibrosis can be dangerous to heart , the function of myofibroblasts is important to maintain functional myocardium following any stress insult . thus , following myocardial infarction , when cardiomyocytes die over several days due to ischemia , myofibroblasts play a major role in the remodeling of a fibrotic scar in the affected myocardium , in order to prevent wall rupture ( 30,31 ) . myofibroblasts eventually disappear , through less understood mechanisms , in many situations of wound healing . one possible mechanism is that following the formation of permanent scar and stabilization of cardiac injury , which may take up to 2 weeks , a significant proportion of the myofibroblasts undergo senescence ( 32 ) and/or apoptosis ( 33 ) . it has also been proposed that some of the myofibroblasts may dedifferentiate back to fibroblast phenotype , even though strong evidence for this is lacking in myocardium . critical for the pathogenesis of cardiac fibrosis is the persistent presence of myofibroblasts in the myocardium , long after the resolution of stress insult ( fig . this is generally either due to concurrent dysregulation of neuroendocrine factors or even mechanical stress , both of which lead to and aggravate chronic cardiac fibrosis and/or hypertrophic scarring ( 34,35 ) . a common example for this is the intermittent ischemia , chronically affecting the heart , creating constant wound healing milieu , which leads to persistent activation and formation of the myofibroblasts and the eventual fibrosis ( 30 ) . it has been proposed that the function of resident fibroblasts is to maintain normal tissue integrity and structure , whereas , acute injury or altered neuroendocrine signaling stimulates fibroblasts from other sources , which ultimately contribute to pathophysiologic fibrosis ( 36,37 ) . a better understanding of the molecular mechanisms involved in cardiac fibrosis and the regulation of the players involved such as myofibroblast formation and activation , is essential for developing effective therapeutics . the most commonly employed techniques in patients with congenital heart disease to assess the fibrotic features of myocardium include stress echocardiography and cmr and also positron emission tomography ( pet ) , which is the reference standard for monitoring myocardial viability . stress echocardiography allows for the assessment of myocardial contractile reserve in patients with adequate acoustic windows . because of this , the main limitation of stress echocardiography is decreased diagnostic accuracy in patients with poor acoustic windows ( 38 ) . pet scan is a nuclear scintigraphy and employs n - labeled ammonia , which a marker for coronary perfusion and f - fluorodeoxyglucose , a glucose surrogate , for monitoring myocardial metabolism . a mismatch between the imaging of coronary perfusion and metabolism is indicative of nonviable tissue with the possibility of replacement fibrosis . however , pet scanner availability is limited and its usage requires an on - site cyclotron , and pet is not sensitive enough to detect interstitial fibrosis ( 39 ) . cmr is able to provide much better spatial resolution and visualization of all myocardial segments , in the absence of any contaminating / interfering metallic particles , and this technique is used extensively for the quantitative assessment of ventricular size and systolic function . there are two major cmr approaches for assessing myocardial fibrosis : late gadolinium enhancement ( lge ) imaging and t1 mapping / ecv fraction calculation . lge identifies areas of discrete replacement fibrosis , with high sensitivity and specificity ( 13 ) . in the normal healthy heart , collagen network , which contributes to ecm and maintains myocardial architecture as well as chamber geometry , also provides tensile strength and elasticity , the necessary factors for normal systolic and diastolic function of ventricles ( 40 ) . several local and hormonal systems , such as renin - angiotensin - aldosterone system ( raas ) , regulate the dynamic collagen turnover , and disturbances in these systems lead to an imbalance between collagen synthesis and degradation with the resultant accumulation of collagen , the underlying factor of cardiac fibrosis , followed by deranged myocardial architecture ( 41 ) . thus it has been shown that pharmacological intervention of raas could prevent this process of fibrosis and at times even reverse the damage caused ( 42 ) . thus , aldosterone antagonism with spironolactone has been found to lower collagen levels in hearts , ex vivo ( 43 ) , improve diastolic function ( 44 ) , decrease left ventricular size and ejection fraction ( 45 ) , and also mortality ( fig . 2 ) ( 46 ) . there is ample evidence indicating increased expression of transforming growth factor- ( tgf- ) in response to injury and tgf- is known to play an important role during fibroblast activation and myofibroblast differentiation , and also fibrosis ( fig . 2 ) ( 47,48 ) . tgf- acts via binding to its cell surface receptor , activin linked kinase 5 ( alk5 ) , which phosphorylates smad2 and 3 . phospho - smad2 and 3 bind to smad4 , which translocates into the nucleus , leading to the activation of target gene transcription . it has been shown that inhibitors of alk5 signaling block certain steps of fibrosis process and thus there is a potential that alk5 can be a therapeutic target for cardiac fibrosis ( 49 ) . even though neutralizing antibodies against tgf- have been tried in some studies ( 50 ) , because of involvement of tgf- in several different cellular functions , such approach proved to be not appropriate ( 51 ) and alk5 antagonists are much better choice ( 52 ) . angiotensin ii has been shown to function in concert with tgf- in the signaling pathways that lead to cardiac fibrosis ( 53,54 ) . blockade of angiotensin receptor with inhibitors like losartan is effective in decreasing cardiac fibrosis in animal models and also in humans and this approach of angiotensin - ii inhibitors seems to be better than blocking tgf- ( 55 ) . similarly , antagonism of endothelin-1 , which induces ecm production and myofibroblast transformation ( 56 ) was found to reduce cardiac fibrosis . other possible therapeutic targets include platelet derived growth factor and connective tissue growth factor , ccn2 , but further work is needed to ascertain this possibility ( 57 ) . cardiac fibrosis , which is seen in many types of heart diseases , involves increased accumulation of ecm , mediated by the activated myofibroblasts , arising from cardiac fibroblasts . renin - angiotensin - ii - aldosterone system , tgf- signaling and alk5 have been found useful as therapeutic targets . however , because of the importance of these pathways in many other physiological functions , their therapeutic targeting needs to be approached with caution .
cardiac fibrosis is a common phenomenon in different types of heart diseases , such as ischemic heart disease , inherited cardiomyopathy mutations , diabetes , and ageing and is associated with morbidity and mortality . 
 increased accumulation of extracellular matrix ( ecm ) that impacts cardiac function , is the underlying cause of fibrotic heart disease . 
 there are four different types of cardiac fibrosis , including , reactive interstitial fibrosis , replacement fibrosis , infiltrative interstitial fibrosis and endomyocardial fibrosis . 
 they are involved in the activation and transformation of cardiac fibroblasts to myofibroblasts , which participate in ecm production and fibrotic process and several inflammatory pathways . besides the ecm proteins 
 , myofibroblasts also express smooth muscle -actin , sm22 and caldesmon and other markers related to fibrotic process . 
 most commonly employed techniques to assess myocardial fibrosis include stress echocardiography , cardiac magnetic resonance imaging and positron emission tomography . because of the involvement of renin - angiotensin - ii - aldosterone system , transforming growth factor- signaling and activin - linked kinase 5 in the mechanisms of cardiac fibrosis , these pathways and the involved proteins are useful as therapeutic targets . however , because of the importance of these pathways in many other physiological functions , their therapeutic targeting needs to be approached with caution .