Pronounced extracellular acidosis reduces both cardiac contractility and the β-adrenergic response. In the past, this was shown in some studies using animal models. However, few data exist regarding how the human end-stage failing myocardium, in which compensatory mechanisms are exhausted, reacts to acute mild metabolic acidosis. The aim of this study was to investigate the effect of mild metabolic acidosis on contractility and the β-adrenergic response of isolated trabeculae from human end-stage failing hearts.-6 M).Intact isometrically twitching trabeculae isolated from patients with end-stage heart failure were exposed to mild metabolic acidosis (pH 7.20). Trabeculae were stimulated at increasing frequencies and finally exposed to increasing concentrations of isoproterenol  as compared with pH 7.40. Force-frequency relation measurements yielded no further significant differences of twitch force. At the maximal isoproterenol concentration, the force amplitude was comparable in each of the two groups (pH 7.40 versus pH 7.20). However, the half-maximal effective concentration (EC50) was significantly increased in the acidosis group, with an EC50 of 5.834 × 10-8 M , 3.48 × 10-8 to 9.779 × 10-8; n = 9), compared with the control group, which had an EC50 of 1.056 × 10-8 M , indicating an impaired β-adrenergic force response.A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% (12.1 ± 1.9 to 9.0 ± 1.5 mN/mmOur data show that mild metabolic acidosis reduces cardiac contractility and significantly impairs the β-adrenergic force response in human failing myocardium. Thus, our results could contribute to the still-controversial discussion about the therapy regimen of acidosis in patients with critical heart failure. The reset al. [In our experiments, a negative force-frequency relation and an abnormal increase in diastolic tension with increasing stimulation frequencies was observed. Failing human myocardium is well known to show this negative force-frequency relation ,40. Haseet al.  showed tet al. . At highet al. [2+ sensitivity and yields a negative FFR [We found no data in the literature in which the direct effect of acidosis on the FFR was investigated, especially not in the human heart failing myocardium. Morii et al.  showed itive FFR . Our dat1-adrenergic receptors in heart failure [In patients with severe heart failure, a prolonged increase in the activation of the sympathetic nervous system and therefore increased β-adrenergic hormone blood levels leads to a desensitization to adrenergic stimulation . This de failure -46.In our study, we found a delayed response to increasing isoproterenol concentrations under acidotic conditions, whereas the β-adrenergic maximal reached force amplitude did not differ between the two pH groups. Acidosis changes the relative binding affinities of inotropes and vasopressors to adrenergic receptors . A studyThe present study is, to our knowledge, the only series of experiments that has investigated the catecholamine response in end-stage failing human myocardium in the presence of a mild metabolic acidosis. We could show this effect by using isoproterenol. However, to get information about the behavior of other catecholamines, an additional series should follow. .Therefore, this specially modified and extremely fragile myocardium requires greater β-adrenergic stimuli to reach the same force amplitude when the pH is mildly decreased compared with a normal pH.The prolonged use of positive inotropes in patients with chronic heart failure is well known to increase mortality ,49. HencParticularly critical times for heart-failure patients undergoing on-pump cardiac surgery are those during and after weaning from the cardiopulmonary bypass, because a low cardiac-output syndrome can occur. Because of cardiac ischemia, myocardial dysfunction induced by cardioplegia, reperfusion injury, the presence of nonrepaired preexisting cardiac disease, and the activation of coagulation cascades and inflammation, a pharmacologic support can be necessary . It is nin vitro from which we derived direct information about the effects of selective acidosis on myocardial contractility. Therefore, our results should be translated into a clinical situation with cautiousness because acidosis in vivo is a part of a complex process of myocardial impairment during shock conditions and is associated with proinflammatory cytokines and NO generation.This study has several limitations. All hearts were explanted as a result of organ transplantation for end-stage heart failure. Therefore, this patient group is very special, and its incidence in the clinical routine is not common. Normally, cardiac surgery patients have a more moderate form of heart failure in which some compensatory mechanisms still work. Furthermore, we artificially induced acidosis in vivo model followed by a large clinical study.The data are preliminary and should be confirmed in an However, to our knowledge, this is the first investigation that shows that an acute mild metabolic acidosis has already had a negative influence on cardiac contractility and the β-adrenergic response in the isolated myocardium of end-stage heart failure patients.In the end-stage heart failing myocardium, a preexisting acute mild metabolic acidosis with a pH of 7.20 leads to a decrease in contractility and a delayed β-adrenergic response. Our results may contribute to the controversial discussion about the therapy regimen of acidosis, particularly in this special patient group.• The present study shows that clinically relevant low metabolic acidosis impairs myocardial contractility in isolated human failing myocardium.• Low metabolic acidosis delays the β-adrenergic response of human failing myocardium.• From our point of view, it seems to be important to recognize patients with severe heart failure as a special patient group that reacts very sensitively to pH changes because of already exhausted compensatory mechanisms.• Our study should trigger clinical trials to investigate possible treatment strategies for patients with heart failure in the critical situation of metabolic acidosis.1: Angiotensin II receptor: type 1; ATP: adenosine triphosphate; BDM: 2,3-butanedione monoxime; Ca2+: calcium; CaCl2: calcium chloride; CI: confidence interval; Cl-: chloride; CO2: carbon dioxide; EC: excitation-contraction; EC50: half-maximal effective concentration; FFR: force-frequency relation; H3PO4−: phosphoric acid; HCO3−: bicarbonate; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; K+: potassium; KCl: potassium chloride; Mg2+: magnesium; MgCl2: magnesium chloride; Na+: sodium; NaCl: sodium chloride; NaHCO3: sodium hydrogen carbonate; NaH2PO4: monosodium phosphate; Na2SO4: sodium sulfate; NCX: Na+/Ca2+ exchanger; O2: oxygen; pH: negative decimal logarithm of the hydrogen ion activity in a solution; RyR: ryanodine receptor; SEM: standard error of the mean; SERCA: SR Ca2+-ATPase; SIRS: systemic inflammatory response syndrome; SO42−: sulfate; SR: sarcoplasmic reticulum.ATAll authors declare that they have no conflict of interest regarding the present study. The authors have full control of primary data and confirm that in case of interest, the requisite data will be provided.HS performed the experiments, performed the statistical analysis, and wrote the manuscript. KT performed the experiments and coordinated the logistic part of the study. AFP made substantial contributions to heart supply, analysis of data, and helped to draft the manuscript and revision. AR explanted the hearts of terminal heart-failure patients undergoing heart transplantation and helped to draft the manuscript. JDS supplied failing hearts and helped to draft the revision substantially. JG explanted the hearts of terminal heart-failure patients undergoing heart transplantation and helped to draft the manuscript. MQ and MB helped to draft the manuscript and revision. LSM participated in its design and helped to draft the manuscript. SS conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.Dr. Sossalla is funded by the Research Program, Faculty of Medicine, Georg-August-University of Göttingen, Germany. Dr. Maier is funded by the Deutsche Forschungsgemeinschaft (DFG) through the Clinical Research group KFO155 (MA 1982/2-2) and a Heisenberg grant (MA 1982/4-1).


BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of ≤ 15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP > 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role, essentially in the screening proposing criteria for estimating the presence of PH mainly based on tricuspid regurgitation peak velocity and systolic artery pressure (sPAP). The therapy of PAH consists of non-specific drugs including oral anticoagulation and diuretics as well as PAH specific therapy. Diuretics are one of the most important treatment in the setting of PH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5-2.5. Target INR for patients displaying chronic thromboembolic PH is between 2–3. Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for PAH exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids , endothelin receptor antagonists  and phosphodiesterase type 5 inhibitors . This review discusses the current state of art regarding to epidemiologic aspects of PH, diagnostic approaches and the current classification of PH. In addition, currently available specific PAH therapy is discussed as well as future treatments.Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point  revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of  Pulmonary arterial hypertension (PAH) is defined by right-heart catheterization (RHC) showing precapillary pulmonary hypertension with a mean pulmonary artery pressure (mPAP) of >25 mmHg and a normal pulmonary artery wedge pressure (PCWP) of <15 mmHg ,4. In 19In 2008, the fourth World Symposium on PH held in Dana Point  and the consensus of an international group of experts was to revise previous classifications in order to accurately reflect published data, as well as to clarify some areas that were unclear. In 2013, the fifth World Symposium on PH held in Nice (France) and proposed only minor modifications, however, since the definite conclusions of this symposium were not yet published, we presented the Dana Point classification of PH  gene, a member of the transforming growth factor beta (TGF- ß) signaling family, can be detected in about 70% of cases [activin receptor like kinase type 1 (ACVRL1 or ALK1) or endoglin genes, also coding for members of the TGF-ß signaling family, have been identified in patients with PAH, predominantly with coexistent hereditary hemorrhagic telangiectasia. Some authors suggested that mutations of genes encoding for Smads proteins , which are other members of the TGF-ß signaling pathway, or mutations in caveolin-1 gene may predispose to PAH [Idiopathic PAH describes a sporadic disease with neither a family history of PAH nor an identified risk factor. When PAH occurs in a familial context, germline mutations in the of cases ,7. More e to PAH .BMPR2 mutations have also been detected in 11–40% of apparently idiopathic cases with no family history [BMPR2 mutations is artificial, as all patients with a BMPR2 mutation have heritable disease. In addition, BMPR2 mutations were identified in only 70-80% families with PAH. Thus, it was decided to abandon the term “familial PAH” in favor of the term “heritable PAH”, including idiopathic PAH with germline mutations and familial cases with or without identified mutations [ history . Indeed,utations ,14.A number of risk factors for the development of PAH have been individualized in the last European Respiratory Society/ European Society of Cardiology (ERS/ESC) conjoint guidelines of PH  Table 22.Aminorex, fenfluramine derivatives and toxic rapeseed oil represent the only identified “definite” risk factors for PAH ,16. SouzTwo prospective epidemiologic investigations, the SNAP (Surveillance of North American Pulmonary Hypertension) and the SOPHIA (Surveillance of Pulmonary Hypertension in America) study, were conducted in the USA ,19. ThesThe agent benfluorex is structurally and pharmacological related to fenfluramine and may be also considered as an anorectic agent. Frachon and co-workers  showed aThe SOPHIA study examined intake of a variety of nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants and anxiolytics. No increased risk of developing PAH was observed .Amphetamine use represents a “likely” risk factor, although they are frequently used in combination with fenfluramine. A recent retrospective study suggested a relationship with the use of methamphetamine  and the occurrence of PAH . MethampRecently published data from the French registry of pulmonary hypertension suggested that dasatinib, a tyrosine kinsase inhibitor (TKI), may induce precapillary PAH . SeveralPAH associated with connective tissue diseases (CTD) represents an important clinical subgroup, in which systemic sclerosis represents the major cause of CTD associated PAH. The prevalence of PAH has been well established only for systemic sclerosis (SSc). Prospective studies using echocardiography as a screening method and RHC for confirmation found a prevalence of PAH between 7–12% ,25. PH dPAH is a rare complication of HIV infection ,30. HIV-Porto-pulmonary hypertension (POPH) is defined by the development of PAH associated with increased pressure in the portal circulation ,34. ProsA significant proportion of patients with congenital heart disease (CHD), in particular those with systemic-to-pulmonary shunts, will develop PAH if left untreated. Eisenmenger's syndrome is defined as CHD with an initial large systemic-to-pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis ,38. It rIn the Dana Point classification, PH associated with schistosomiasis was included in Group 1. Recently, it has been demonstrated that PH associated with schistosomiasis may have a similar clinical presentation and histological findings as idiopathic PAH ,43. The The chronic hemolytic anemias represent a subcategory of PAH. There has been increasing evidence that PAH is a complication of chronic hereditary and acquired hemolytic anemias, including sickle cell disease ,47, thalPH has been reported most frequently in patients with sickle cell disease, however the prevalence of PAH is not yet clearly established. The prevalence of PH in sickle cell disease is undoubtedly much lower than 32% as suggested by echocardiography . RecentlPVOD and PCH are uncommon conditions, but they are increasingly recognized as causes of PH . A recen2 in patients with PVOD or PCH [Although PVOD and PCH may present similarly to idiopathic PAH, there are a number of important differences. These include the presence of crackles on examination, radiologic abnormalities on high-resolution computed tomography of the chest  -58, hemoLeft-sided ventricular or valvular diseases may produce an increase of left atrial pressure, leading to a backward transmission of the pressure and a passive increase of pulmonary arterial pressure. Left heart disease, probably represents the most frequent cause of PH . In thisIn this group, the predominant cause of PH is alveolar hypoxia as a result of either chronic lung disease, impaired control of breathing, or residence at high altitude. However, the precise prevalence of PH in all these conditions remains largely unknown. In the revised classification, the heading has been modified to reinforce the link with the development of PH. A category of lung disease characterized by a mixed obstructive and restrictive pattern was added, including chronic bronchiectasis, cystic fibrosis and the recently described syndrome of combined pulmonary fibrosis and emphysema in which the prevalence of PH is almost 50% ,67. In PChronic thromboembolic pulmonary hypertension (CTEPH) was included in Group 4. The incidence of CTEPH is uncertain. CTEPH represents however a frequent cause of PH and occurs in up to 4% of patients after an acute pulmonary embolism ,72. In tPH has been reported in chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia ,80. SeveThe second subgroup includes systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis or vasculitis.PH is a well recognized complication of sarcoidosis , with a Pulmonary Langerhans cell histiocytosis is an uncommon cause of infiltrative and destructive lung disease. Severe PH is a common feature in patients with end stage disease  and PH iLymphangioleiomyomatosis is a rare multisystem disorder predominantly affecting women, characterized by cystic lung destruction, lymphatic abnormalities, and abdominal tumors. PH is relatively uncommon in patients with lymphangioleiomyomatosis . RecentlNeurofibromatosis type 1, also known as von Recklinghausen’s disease, is an autosomal-dominant disease. The disease is occasionally complicated by systemic vasculopathy. A series of cases of PH have been reported in the setting of Neurofibromatosis type-1 .PH has been reported in a few cases of type Ia glycogen storage disease, a rare autosomal-recessive disorder caused by a deficiency of glucose-6-phosphatase -95. The Gaucher’s disease is a rare disorder characterized by a deficiency of lysosomal B glucosidase, which results in an accumulation of glucocerebroside in reticuloendothelial cells. In a study of 134 patients with Gaucher’s disease who were systematically screened by echocardiography, PH was not uncommon . In thisThe association between thyroid diseases and PH has been reported in some studies . A prospThe last subgroup includes a number of miscellaneous conditions, including tumoral obstruction, fibrosing mediastinitis or chronic renal failure on dialysis.A progressive obstruction of proximal pulmonary arteries leading to PH may be observed in tumor obstruction when a tumor grows into the central pulmonary arteries with additional thrombosis. Such cases are due principally to pulmonary artery sarcomas, which occur rarely but are usually rapidly fatal -103. TheFibrosing mediastinitis have been mainly reported in sarcoidosis, tuberculosis, histoplasmosis and after radiotherapy. Fibrosing mediastinitis may be associated with severe PH due to compression of both pulmonary arteries and veins.Lastly, PH has been reported in patients with end-stage renal disease maintained on long-term hemodialysis. Based on echocardiographic studies, the prevalence of PH in this patient population is estimated up to 40% . PH in tInformation relative to the natural history of PAH was derived from a national registry conducted in the USA in the early 1980s, which included 187 patients with idiopathic PAH followed for up to 5 years. This study characterized the disease and confirmed its poor prognosis with a median survival of 2.8 years ,106. BetIn France, a national multicenter registry prospectively collected data from 674 adults with PAH from October 2002 to October 2003 and followed these patients during a 3-year period . This prRecent prospective data in consecutive patients with idiopathic, familial or anorexigen-associated PAH patients followed-up for a period of three years  showed better survival rates than historical cohort. For incident cases, estimated survival rates were 85.7%, 69.6% and 54.5% at one, two and three year of follow-up, respectively. In combined mixed population , estimated one, two and three year survival was 82.9%, 67.1% and 58.2%, respectively. Parameters significantly associated to improved survival were female gender, preserved 6-MWD and normal cardiac output on RHC .Data from the REVEAL registry  are similar concerning the one year survival rate estimated to 91%. Variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units, NYHA functional class IV, men older than 60 years and familiy history of PAH .bone morphogenetic protein receptor type 2 gene (BMPR2) [BMPR2 gene encodes for a type 2 receptor member of the transforming growth factor beta (TGF-β) family. Nowadays, germline BMPR2 mutations are detected in 58-74% of PAH patients with a family history of the disease, and in 3.5-40% of so called idiopathic PAH patients [ACVRL1 (Activin A receptor type II-like kinase 1) and ENG (endoglin) genes. Mutations in these two genes are infrequent in PAH but are frequently identified in HHT [BMPR2 gene, ACVRL1, ENG, Smad8, Smad1 and Smad5 genes are encoding proteins which are involved in the TGF-β signaling pathway. More recently, using whole exome sequencing in a large PAH family, Austin et al. demonstrated the involved of mutations in caveolin-1 gene in the development of PAH [caveolin-1 mutation in an unrelated PAH patient. Caveolin-1 protein is necessary for the formation of calveola, which are crucial for joining membrane receptors and initiating cellular signaling cascade such as TGF-β signalling pathway. This supports the hypothesis that mutations in genes involved in the TGF-β signaling pathway may be a trigger for pulmonary vascular remodeling. Moreover, this signaling pathway controls growth, differentiation and apoptosis of various cell types like pulmonary vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Thereby, mutations in genes involved in the TGF-β signaling pathway may be responsible for abnormal proliferation of pulmonary vascular SMCs and may promote ECs apoptosis, which might lead to the selection of apoptosis resistant cells and formation of plexiform lesions, the hallmark of idiopathic PAH [It is now well known that PAH can be either sporadic or clustered in families -114. In  (BMPR2) ,118. BMPpatients ,119-123.d in HHT ,124-130.t of PAH  They conthic PAH ,132.BMPR2 or an ACVRL1 mutation are younger at diagnosis than patients with idiopathic PAH. In addition, they have more severe hemodynamic parameters at diagnosis [The analysis of clinical, functional and hemodynamic characteristics of PAH patients revealed that patients carriers of a iagnosis ,120. BMPR2 mutations [BMPR2 mutation status [Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. As mentioned, Humbert and co-workers have shown that exposure to fenfluramine derivatives greatly increase the risk of developing severe PAH in patients with utations . Moreoveutations . Finallyn status . To expln status ,136.PAH is a disease which affects small pulmonary arteries. It is characterized by vascular obstruction leading to progressive increase in vascular resistance. This increases right ventricular afterload and consequently results in right ventricular failure. Intima and media proliferation and its consequent pulmonary vascular obstruction are considered to be the key element in the pathogenesis of PAH. Vasoconstriction, vascular remodeling and thrombosis are factors that increase pulmonary vascular resistance in PAH ,137. TheProliferation of smooth muscular cells in the small peripheral pulmonary arteries is a common characteristic in all forms of PAH. In hypoxic models, fibroblasts of the adventitia migrate to the media and intima, where proliferation and production of matrix proteins are observed . NeovascIn response to certain stimuli, endothelial cells abnormally proliferate to form plexiform lesions in several forms of PAH. Plexiform lesions consist of endothelial cells, matrix proteins and fibroblasts and obliterate the vascular lumen . The stiInflammatory mechanisms seems to play an important role in certain forms of PAH such as PAH associated with auto immune diseases or HIV infection . In factThrombosis and platelet dysfunction can be important in the development of PAH. Abnormalities of thrombosis, endothelial cells or platelets can generate or aggravate thrombosis in situ. Elevated plasma concentrations of D-dimers and fibrinopeptides A and B, in certain patients with PAH, are the proof of an abnormal intravascular coagulation process. Elevated plasma concentrations of von-Willebrand factor and plasminogen activator inhibitor type 1 also reflect endothelial dysfunction in PAH. It has been demonstrated that shear stress creates pro-thrombotic vascular lesions in PAH that may lead to thrombosis in situ. But platelet function is not limited to coagulation. In response to certain stimuli, platelets can produce prothrombotic, vasoactive or mitogenic factors, such as thromboxane A2 (TXA2), platelet-derived growth factor (PDGF), serotonin , transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) that participate in vasoconstriction and vascular remodeling ,150.The self-tolerance is controlled in the periphery by a particular population of T-lymphocytes called regulatory T-lymphocytes (Treg). The breakdown of self-tolerance can lead to the development of an autoimmune response (i.e. directed against self antigens) that can finally give rise to an autoimmune disease. Huertas et al.  showed tMany authors consider pulmonary vasoconstriction as an early event in the process of PAH. Vasoconstriction has been associated with an abnormal function or expression of potassium channels and with endothelial dysfunction . EndotheProstacyclin (prostaglandin I2) is a potent pulmonary vasodilator that acts via the cyclic adenosine monophosphate (cAMP) pathway. It inhibits the proliferation of smooth muscle cells and decreases platelet aggregation. Production of prostacyclin is reduced in endothelial cells of patients with PAH . PAH theEndothelin-1 (ET-1) is an endothelially-derived peptide that has two receptor subtypes, designated as endothelin A (ETRA) and endothelin B (ETB), located on smooth muscle cells of pulmonary arteries. By ligating the ETRA, ET-1 intracellular calcium concentrations increase and activates the protein kinase C pathway . ET-1 isIn hypoxic models of PAH, hypoxia inhibits one or several voltage dependant potassium channels of the pulmonary arterial smooth muscle cells. This leads to membrane depolarization and opening of voltage dependant calcium channels with a subsequent increase of the intracellular calcium concentration and cellular contraction. Certain potassium channels are under expressed in pulmonary artery smooth muscle cells of patients with PAH ,160. It In PAH, plasmatic concentrations of serotonin  are elevated . An assoRho proteins regulate fundamental cellular functions such as contraction, migration, proliferation and apoptosis. Several studies have implicated Rho protein A and Rho kinases in the vasoconstriction and vascular remodeling of PAH ,166. RhoHypoxia inducible factor-1 (HIF-1) is a transcription factor that principally regulates cellular adaptation to hypoxia but also regulates several genes implicated in angiogenesis, erythropoiesis, cellular metabolism and survival . In expeIn conclusion, the pathophysiology of PAH is heterogeneous and multifactorial. The genetic mutations found in familial PAH and in a proportion of sporadic PAH are neither necessary nor sufficient for the development of PAH. Therefore, the current hypothesis is that of a genetic predisposition for PAH followed by a superimposed environmental factor . Our understanding of the underlying pathophysiological mechanisms of PAH has lead to the development of new treatments such as prostacyclin analogues, endothelin receptor antagonists and type 5 phosphodiesterase inhibitors. However, future progress is still necessary in order to discover new pathophysiological pathways and to develop new therapeutic strategies in PAH.Vascular remodelling in pulmonary arterial and venous hypertension typically involves the small pulmonary vessels. Muscular arteries of less than 500 μm display a thickening within the intimal, medial and adventitial compartment. When involved, pulmonary veins of the interlobular septa and smallest preseptal venules show fibrous obliteration and / or muscularization. Even the smallest vascular level may be involved: patients with pulmonary venous hypertension frequently present focal proliferation of alveolar capillaries. The different histological pattern is presented here below.This abnormality of the vessel wall can be observed in all subgroups of PAH and may even be encountered in other forms of PH, e.g. in mitral valve stenosis. The lesion corresponds to a smooth muscle cell proliferation and / or recruitment within the tunica media; the histological criterion of hypertrophy / hyperplasia is fulfilled, when the diameter of a single medial layer, delimited by its internal and external elastic lamina, exceeds 10 per cent of the arteries cross-sectional diameter Figure A. IsolatFibrotic lesions of the intimal layer are frequent in PAH-diseased lungs. The intima may be thickened by proliferation and recruitment of fibroblasts, myofibroblasts and other connective tissue cells, and consequently by the interstitial deposition of collagen Figure B, C. In This morphologically conspicuous phenotype of intimal fibrosis is also known as “onion-skin” or “onion-bulb” lesion. Numerous concentrically arranged fibrotic layers occlude the arterial lumen of small (diameter: 100–200 μm) arteries .Signs of right heart failure may be observed in the most severe patients, including venous jugular distension, hepato-jugular reflux, hepatomegaly and hepatalgia. Lower limb edema, ascitis and generalized edema underscore the severity of right heart failure. Cardiac auscultation shows usually a prominent pulmonary component of S2, a systolic murmur of tricuspid regurgitation and more rarely a diastolic murmur of pulmonary regurgitation. Pulmonary auscultation is usually normal and contrasts with the importance of dyspnea. History and clinical examination should also screen for manifestations of extra thoracic diseases, particularly Raynaud’s syndrome which can be found in PAH associated with CTD and particularly in systemic sclerosis.The diagnostic process of PAH requires a series of investigations that are intended to make the diagnosis, to clarify the clinical class of PH and the underlying type of PAH and to evaluate the functional and hemodynamic impairment . The detThe ECG may provide suggestive or supportive evidence of PH by demonstrating right ventricular hypertrophy and strain, and right atrial dilation. Right ventricular hypertrophy and right axis deviation are present in respectively 87% and 79% of patients with idiopathic PAH . UnfortuIn 90% of idiopathic PAH patients, chest radiography is abnormal at the time of diagnosis . FindingPulmonary function tests (PFT) will help to assess underlying lung abnormalities. Forced expiratory volume in one second (FEV1) and total lung capacity (TLC) in idiopathic PAH are usually normal or slightly abnormal. Low diffusing capacity of the lung for carbon monoxide (DLCO) has been reported in PAH patients, but is more pronounced in PVOD patients with often severe reductions under 50% of the predicted value ,184. ResThe normal physiologic response of the pulmonary vasculature to exercise consists of distension of pulmonary arteries and arterioles as well as recruitment of previously unused vascular bed. Thus, in health, pulmonary artery pressure rises minimally in response to increased blood flow and pulmonary vascular resistance decreases because of the remodeled vasculature. These mechanisms are impaired in the course of PH. Cardiopulmonary exercise testing (CPET) has been shown to be useful in assessing the severity and prognosis of PAH ,185. SevTTE is a non-invasive screening test for patients with suspected PH. TTE estimates pulmonary artery systolic pressure (sPAP) and may provide additional information about the cause and consequences of PH. The estimation of PAP is based on the peak velocity of the jet of tricuspid regurgitation. The simplified Bernoulli equation describes the relationship of tricuspid regurgitation velocity and the peak pressure gradient of tricuspid regurgitation = 4 x (tricuspid regurgitation velocity). Estimation of PA systolic pressure require to take into account right atrial pressure . Right atrial pressure cannot be measured and is estimated based on the diameter and respiratory variation of the inferior vena cava . An alteOther echocardiographic variables that might raise or reinforce suspicion of PH independently of tricuspid regurgitation velocity should always be considered. They include an increased velocity of pulmonary valve regurgitation and a short acceleration time of RV ejection into the PA. Increased dimensions of right heart chambers, abnormal shape and function of the interventricular septum, increased RV wall thickness, pericardial effusion and dilated main PA are also suggestive of PH, but these signs are considered to be related to the hemodynamic severity .Besides identification of PH, TTE also allows a differential diagnosis of the possible causes of pulmonary hypertension. TTE can recognize left heart valvular diseases and myocardial diseases responsible for post-capillary PH, and congenital heart diseases with systemic-to-pulmonary shunts. The venous injection of agitated saline can help to identify patent foramen ovale or small sinus venosus type atrial septal defects. Transesophageal echocardiography is rarely required in the setting of PH.Ventilation/perfusion lung scan should be systematically assessed to screen for CTEPH. Indeed, V/Q lung scan is the method of choice to detect CTEPH  and normHigh resolution computed tomography of the chest (HRCT) supplies detailed information about underlying lung parenchyma disease, such as pulmonary emphysema or interstitial lung disease. A number of various pathologic features may be detected on chest HRCT including pericardial effusions and pulmonary artery enlargement, defined by the ratio of the diameter of main pulmonary artery to that of the thoracic aorta >1. In the setting of CTEPH, contrast HRCT of the pulmonary arteries may show changes like complete vessel obstruction, vessel cut-offs, intimal irregularities, incorporated thrombus formations as well as bands and webs . FurtherIn CTEPH, pulmonary angiography may be helpful to determinate surgically accessible form. Typical angiographic findings in CTEPH are complete obstruction, band and webs as well as intimal irregularities . PulmonaCardiac magnetic resonance imaging (MRI) allows non invasive evaluation of right ventricular size, morphology and shape. It provides information on right ventricular function and allows non-invasive assessment of blood flow including cardiac output, stroke volume, distensibility of pulmonary artery and right ventricular mass ,191. DecAbdominal ultrasound should be performed in all patients if PH is suspected to exclude portal hypertension or liver disease. When portal hypertension is suspected, the diagnosis can be confirmed during RHC by measurement of an increased gradient between the free and occluded hepatic vein pressure .Serological tests for HIV, hepatitis B or C serology should be performed to screen for associated diseases. The thyroid hormone measurement may reveal either hyperthyroid dysfunction or autoimmune thyroiditis, frequently encountered in PAH.Invasive hemodynamic assessment with right heart catheterization is requested to confirm the diagnosis of PH showing a resting mPAP of ≥25 mmHg and a normal PCWP [The assessment of PCWP may allow the distinction between precapillary  and postcapillary PH (PCWP >15 mm Hg). In post-capillary PH, the last guidelines from the 4th World Symposium (Dana Point) proposed a dichotomy between "passive" and "reactive" (out-of-proportion) post-capillary PH based on transpulmonary pressure gradient . Indeed, there is no clear consensus on this definition and the future recommendations arising from the last World Symposium on PH  should propose new definition to define these two entities.Measurement values obtained by RHC are PAP , right atrial pressure (RAP), PCWP, right ventricular pressure and cardiac output (CO) preferably by the thermodilution method. In contrast to the thermodilution method, the Fick method is mandatory in patients with suspected CHD. In experienced centres, RHC procedures have low morbidity and mortality rates . ElevateNYHA functional class at baseline or after initiation of epoprostenol treatment, signs of right heart failure, 6-MWD, peak VO2, echocardiographic parameters, hemodynamic parameters and biological tests  predict prognosis in idiopathic PAH when assessed at baseline.Patients presenting PVOD or PAH associated with CTD (frequently associated with venous involvement) have a worse prognosis than patients with idiopathic PAH . PatientA score has been proposed (REVEAL Registry Risk Score) to evaluate severity of newly diagnosed PAH patients . This scPeripheral vasodilatation or increased cardiac demand will put PAH patient at risk of acute cardiac failure and syncope. Thus, we traditionally advise against extreme physical activity. Patients are taught to stay active while adapting effort according to their symptoms. Nevertheless, the appropriate level of physical activity is difficult to define. To date, only few studies have evaluated to effect of cardio-respiratory rehabilitation in PAH. One of this program involved three weeks of inpatient rehabilitation followed by three month training at home with phone call supervision. No modification on cardiac hemodynamic was observed on echocardiography but 6-MWD and quality of life were improved. As proposed in ERS/ESC guidelines, more data are required before appropriate recommendations can be made .As hypoxic vasoconstriction may be an aggravating factor in PAH, stays at altitude above 1500-2000 meters without supplemented oxygen and air flight in unpressurized cabin should be avoided [The hemodynamic and hormonal modifications occurring during pregnancy and peripartum period can lead to severe, and sometimes fatal, right heart failure ,198. PreHypotension induced by anaesthetic drugs, and hemodynamic insults following surgical and anaesthetic interventions are generally poorly tolerated by PAH patients, with a high procedural morbidity and mortality. Consequently, it is recommended in general that PAH patients avoid unnecessary procedures. When required, these should be highly planned with the multidisciplinary team, either within, or in close liaison with, the expert centers, in order to coordinate surgical and medical interventions .Vasoconstrictors used in cold medication to relieve nasal congestion should be avoided in PAH patients. Beta-blockers have been shown to be deleterious to PAH patients because they prevent the important adaptive physiologic response that allows preservation of adequate cardiac output. To discontinue such drugs in a patient with PAH may lead, by itself, to important clinical and hemodynamic improvement .Diuretics are one of the most important treatments in the setting of PAH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Right ventricular overload is part of clinical symptoms and has been associated with a poor prognosis in PAH . DiuretiPathology specimens from PAH patients may show in situ thrombosis and thrombi recanalisation. Only few studies support anticoagulation treatment in PAH (mostly retrospective or not randomized) ,203. CurDigoxin has been suggested as part of PAH therapy in the past because it produces an acute increase in cardiac output , althougCalcium channel blockers (CCB) are indicated in patients with a positive vasodilatation challenge test after inhaled NO. CCB are vasodilators and were initially introduced in the 1980’s as part of PAH therapy to counteract vasoconstriction that has traditionally been assumed to be a preponderant mechanism in PAH. In the 1990’s, Rich and colleagues showed in an open prospective study that high dose of calcium channel blockers (nifedipine 90 to 240 mg/day or diltiazem 360 to 900 mg/day) significantly improve prognosis in patients with an acute vasodilation response . Sitbon Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for pulmonary arterial hypertension exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. Furthermore, emerging treatments such as tyrosine kinase inhibitors, soluble guanylate cyclase activators (riociguat) and prostacyclin receptor agonists (selexipag) are currently being evaluated in PAH.Endothelium-derived prostaglandin I2 (PGI2), or prostacyclin, is an arachidonic acid produced by endothelial cells. Prostacyclin is a powerful systemic and pulmonary vasodilator and an inhibitor of platelet aggregation through the increase in intracellular cyclic adenosine monophosphate (cAMP) ,207. MorEpoprostenol In the 1980s, intravenous epoprostenol was the first prostanoid evaluated in PAH [d in PAH . As the d in PAH ,210. Thed in PAH ,211 and d in PAH .Barst and colleagues  showed iEpoprostenol had initially been proposed as a bridging therapy for lung transplantation but it is currently regarded as the treatment of choice for patients in NYHA FC IV. If treatment with epoprostenol is necessary, it will be started at low dose of 2-4 ng/kg/min and is gradually increased to 10-16 ng/kg/min according to side effects . TreatmeTreprostinil Due to complications related to the central venous catheter used for the i.v. administration of epoprostenol, other prostacyclin agonists have been developed. Treprostinil is a prostacyclin analogue which benefits from a longer half-life of 58–83 minutes by subcutaneous administration [stration . It is dstration . A multistration . Patientstration . Inhaledstration , but resInhaled Iloprost Iloprost is a prostacyclin analogue administered by inhalation or the intravenous route. The pulmonary vasodilating effects of inhaled iloprost lasts nearly 45 minutes, therefore six to nine inhalations daily are needed, with each of them requiring approximately 30 minutes [ minutes ,224. Com minutes . In the  minutes  conducteEndothelin-1 (ET-1) is a potent vasoconstrictor and therefore plays an important role in the pathogenesis of PAH. In addition, it is responsible for smooth muscle cell proliferation . ElevateBosentan Bosentan is an oral active dual ETRA and ETRB antagonist. Bosentan has been evaluated in PAH  in five RCT’s  that have shown improvement in exercise capacity, functional class, haemodynamic, echocardiographic and Doppler variables, and time to clinical worsening [orsening ,225-228.The BREATHE 1 study confirmed the efficacity of treatment with Bosentan in more than 200 assessed patients in NYHA functional class III or IV compared to placebo in a three month trial. After three months of treatment with bosentan, improvements in NYHA functional class were observed in 42% of patients receiving bosentan compared with 30% in the placebo arm. 6-MWD was improved overall to 44 meters in favor of bosentan. Furthermore, delayed time to clinical worsening was also noted as well as better results in dynpnea scores . One accSubsequently published data of treatment with bosentan suggested persistent improvements in pulmonary hemodynamics, exercise capacity and modified NYHA functional class and possibly survival rate of patients -231. ResAmbrisentan Ambrisentan is a selective ETA receptor antagonist administrated once daily at a dose of 5 mg or 10 mg. Two large RCTs  have demonstrated efficacy on symptoms, haemodynamics and time to clinical worsening of patients with idiopathic PAH and associated to CTD and HIV infection [nfection . An extenfection . They foNO is a potent pulmonary arteries SMC relaxant that disposed vasodilator activity through up-regulation of its associated down-stream signalling molecule, cyclic GMP (cGMP), metabolism of which is dependent on the activation of a number of PDEs . PhosphoSildenafil Sildenafil is an oral PDE-5 inhibitor that is available in Europe since 2005 for PAH patients in functional class II-III whereas this drug is licensed in Canada and the USA for patients in functional class II-IV. Basis for the authorization of this drug in the setting of PAH was a large randomized, placebo-controlled trial in which different doses of sildenafil were assessed in 278 patients presenting with idiopathic PAH, PAH related to CTD or congenital systemic to pulmonary shunts surgically corrected. The majority of study patients were in functional class II-III. After three months of treatment, the mean placebo-adjusted changes in 6-MWD for 20 mg, 40 mg and 80 mg doses of sildenafil were 45 meters, 46 meters and 50 meters, respectively. Furthermore, significant hemodynamic and functional class improvements were noted in every sildenafil group as compared to placebo. Common side effects of treatment with sildenafil include headache, flushing and dyspepsia but no hepatic enzymes increase was noted as compared with endothelin receptor antagonists. Long term extension data from 222 patients who completed one year of sildenafil monotherapy with a dose of 80 mg three times daily showed encouraging results with a gain in 6-MWD, suggesting a durable treatment effect [t effect . HoweverTadalafil Another PDE-5 inhibitor is tadalafil which was granted for use in patients with PAH in Europe and North America in 2009. Galiè and colleagues [lleagues  assessedlleagues . Thus, tlleagues  underlinAnother therapeutic option is to combine drugs with different mechanisms of action, in order to optimize clinical benefit while minimizing side effects. The two possible strategies for combination therapy are either to add a new medication to an ongoing treatment  or in first intention by starting from the beginning with a combination treatment. The BREATHE-2 trial compared the association of i.v. epoprostenol and oral bosentan with i.v. epoprostenol and placebo among 33 patients with severe PAH over a 12 weeks period . ReductiSeveral uncontrolled studies evaluated the efficacy of other associations with encouraging results. The open-label sequential addition of bosentan or sildenafil to epoprostenol, treprostinil or iloprost was shown to be of interest -243. AlsThe best strategy of combination therapy should be discussed in the next world symposium of Pulmonary Hypertension. Current ERS/ESC guidelines propose sequential combination therapy without any recommendation regarding the best way to associate available specific PAH therapies.Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve clinical outcome) [Macitentan, also called ACT-064992, is a novel, highly potent, tissue-targeting dual ET-1 receptor antagonist characterized by a high lipophilicity . Macitenoutcome) . The SerMacitentan has met its primary endpoint, decreasing the risk of a morbidity/mortality event over the treatment period versus placebo. Secondary efficacy endpoints, including change from baseline to month six in 6-MWD, change from baseline to month six in NYHA FC and time – over the whole treatment period - to either death due to PAH or hospitalization due to PAH, also showed a dose-dependent effect. Treatment with macitentan in this study was well tolerated; headache, nausea and vomiting were reported as minor adverse events . The safVardenafil is another PDE5 inhibitor. Recently published data from a prospective, randomised study including 66 patients with PAH suggests improvement in 6-MWD and hemodynamic parameters after 3 months of treatment with vardenafil as compared to placebo. Side effects are not reported and proposed dosage is 5 mg twice daily . Howevervia the activation of the second messenger cGMP. The clinical benefits associated with the PDE-5 inhibitor class has led to interest in testing whether other agents that modulate NO signaling might be similarly beneficial in PAH. Riociguat is a first-in-class drug that augments cGMP biosynthesis through direct stimulation of the enzyme soluble guanylate cyclase (sGC) promoting vasodilatation by direct stimulation of sGC in an NO-independent fashion, and by sensitization of sGC to low endogenous NO levels [Endothelium-derived NO regulates vascular homeostasis through pulmonary arteries SMC relaxation O levels .A phase I randomized placebo-controlled study in 58 healthy male subjects were given riociguat orally was designed to test the safety profile, pharmacokinetics and pharmacodynamics of single oral doses of riociguat (0.25–5 mg). A proof-of-concept study was conducted to investigate oral riociguat in patients with moderate to severe PH in a two-part, non-randomized, open-label, single center trial . RiociguThe Phase III, double-blind, randomized, placebo-controlled PATENT-1 study investigated the efficacy and safety of riociguat in patients with symptomatic PAH . TreatmeSelexipag is an orally active prodrug metabolized to the highly selective prostacyclin IP receptor agonist ACT-333679 (previously known as MRE-269), which has a half-life of over 6 h . With inA phase II study, involving 43 PAH patients showed that treatment with selexipag for 17 weeks conferred significant improvements in PVR (−30.3% versus placebo) compared with placebo . TreatmeA phase III randomized trial GRIPHON  to examiOne of the most promising targets in PAH is platelet-derived growth factor (PDGF). PDGF has been implicated in endothelial cell dysfunction and proliferation and migration of smooth muscle cells. It has been suggested that PDGF may play a role in PAH -265. PulThe presence of a right-left shunt, secondary to congenital cardiac malformation, or a patent foramen oval, among patients with severe PAH, seems to carry a better prognosis . AtrioseLung transplantation was historically the treatment of choice for severe PAH and remains treatment of choice if medical treatments are insufficient . HoweverALK-1: Activin A receptor type II-like kinase-1; BMPR2: Bone morphogenetic protein receptor 2; CCB: Calcium channel blockers; CHD: Congenital heart diseases; Chest HRCT: Chest High resolution computed tomography; CI: Cardiac index; CMR: Cardiac magnetic resonance imaging; CO: Cardiac output; CTD: Connective tissue disease; CPET: Cardiopulmonary exercise testing; CTEPH: Chronic thrombo-embolic pulmonary hypertension; DLCO: Diffusing lung capacity of carbon monoxide; DLCO/VA: Diffusing lung capacity of carbon monoxide/alveolar volume; ESC: European Society of Cardiology; ERS: European Respiratory Society; HHC: Hereditary hemorrhagic telangiectasia; HIV: Human immunodeficiency virus; INR: International Normalized Ratio; NIH: National Institute of Health; NO: Nitric oxide; NYHA: New York Heart Association; PAH: Pulmonary arterial hypertension; PFT: Pulmonary function test; mPAP: Mean pulmonary arterial pressure; PCWP: Pulmonary capillary wedge pressure; PVOD: Pulmonary veno-occlusive disease; PVR: Pulmonary Vascular Resistance; RAP: Right atrial pressure; PaO2: Partial pressure of arterial oxygen; PaCO2: Partial pressure of arterial carbon dioxide; PDGF: Platelet-Derived Growth Factor; RCT: Randomized clinical trial; RHC: Right heart catheterization; SpO2: Pulse arterial oxygen saturation; SR: Sex ratio; SvO2: Mixed venous oxygen saturation; TTE: Transthoracic Doppler-echocardiography; TKI: tyrosine kinsase inhibitor; TLC: Total lung capacity; TPR: Total Pulmonary Resistance; TGF: beta Transforming growth factor beta; VEGF: Vascular endothelial growth factor; 6-MWD: 6-minute walk distance.D Montani, X Jaïs, L Savale, M Humbert, G Simonneau and O Sitbon have been supported by Actelion, Bayer Schering, GlaxoSmithKline, Novartis, Pfizer, Inc., Lilly & Co., and United Therapeutics for consultancy services and as members of their scientific advisory boards. The other authors declare that they have no competing interests.DM, SG, PD, FP, BG, GG, XJ, LS, EAM, LCP, MH, GS, OS participated in drafting the manuscript. All authors read and approved the final manuscript.


Uribe et al 2008)A single-phase 3d steady-state-free precession whole heart approach with respiratory navigator gating and ECG triggering (3d SSFP) is now frequently used for diagnostic imaging in children with congenital heart disease (CHD). However, certain cardiac structures may be better assessed during the systolic and others in the diastolic rest period. Therefore, a previously described dual phase 3d-SSFP whole heart sequence may offer clinical benefit in these patients. . Twelve patients were referred for RVOT assessment. Dimensions were measured at valvar, supravalvar and pre-bifurcation levels. CNR, image quality and RVOT measurements were compared between systole and diastole.50 consecutive children with CHD underwent 3D SSFP dual-phase imaging. All cardiac chambers and great vessels were analyzed for contrast-to-noise ratio (CNR) and image quality (IQ) .50 children  underwent 3d dual-phase SFFP imaging. The mean HR was 90 bpm (56 to 139). Dual phase yielded diagnostic imaging for all chambers and great vessels in 48 cases. Systolic imaging alone was diagnostic in 45 cases and diastolic imaging in 47 cases. CNR (paired t-test) and IQ (Wilcoxon Signed Ranks test) were significantly (p<0.05) higher in systole for the pulmonary veins (figure Dual phase 3D SSFP imaging improved the success rate of diagnostic quality imaging compared to single-phase imaging. Cardiac chambers and pulmonary veins are better imaged in systole possibly due to improved blood exchange. Less blood flow turbulence may have improved branch pulmonary arteries or arterial stenosis imaging in diastole. Our data confirms that under-sizing of RVOT stent-valve would have occurred if diastolic imaging were used to guide intervention.


Bedside echocardiography in emergency room (ER) or in intensive care unit (ICU) is an important tool for managing critically ill patients, to obtain a timely accurate diagnosis and to immediately stratify the risk to the patient’s life.  It may also render invasive monitoring unnecessary. In these patients, contrast echocardiography may improve quality of imaging and also may provide additional information, especially regarding myocardial perfusion in those with suspected coronary artery disease. This article focuses on the principle of contrast echocardiography and the clinical information that can be obtained according to the most frequent presentations in ER and ICU. The evaluation and management of patients who arrive at the emergency department (ER) or intensive care unit (ICU) with acute symptoms and/or worrying clinical condition is a daily challenge. Careful history taking-when it is possible-and clinical examination remain the mandatory first steps. It is of importance to obtain a timely accurate diagnosis and to immediately stratify the risk to the patient’s life. Among the possible investigation tools for a precise diagnosis, imaging modalities are frequently required. Echocardiography is the most versatile method. It is non-invasive, can be performed at the bedside, provides rapid results, and avoids exposure of the patient to radiation. Echocardiography is now available in most ER, allowing immediate, standard transthoracic examination. Bedside echocardiography in the ICU is also an important tool in managing critically ill patients, often rendering invasive monitoring unnecessary .In these patients, contrast echocardiography may improve quality of imaging and also may provide additional information, especially regarding myocardial perfusion in those with suspected coronary artery disease. This article focuses on the principle of contrast echocardiography and the clinical information that can be obtained according to the most frequent presentations in ER and ICU.Contrast on echocardiograms by injecting hand agitated saline solution has been recognized for over 30 years for its ability to opacify vascular structures . The priWhen ultrasound waves encounter a MBB, it alternately compresses and expands the MBB, depending on the applied acoustic pressure. Therefore the MBB becomes symmetrically larger and smaller in response to the oscillations of the pressure caused by the incident wave. The volume expansion of a MBB is maximal at a specific frequency referred to as the natural resonant frequency and is inversely related to its size . At the The influence of the response of the MBB to ultrasound waves has led to different strategies to visualize the MBB in echo images. These techniques, exploiting the harmonics, have been implemented in commercial clinical ultrasound systems. Very briefly, the main strategies used are divided in two main families: the high power and the low power imaging techniques. The latter are technologies developed to examine the nonlinear responses of MBB. Even low amplitude MBB backscatter can be isolated from tissue signals for processing. This allows continuous low power imaging to be performed, with limited bubble destruction, enabling simultaneous assessment of wall motion and perfusion in real time. Combining high power burst of ultrasound followed by low power imaging, permits to follow the replenishment of the myocardium capillaries with the MBB over time. This approach provides an estimate of myocardial blood volume and of myocardial blood flow . This caAThe evaluation of left ventricular function is often required for patients at the ER and ICU: to make the diagnosis or to rule out acute coronary syndromes and stratify the risk, in patients with suspicion of acute heart failure, to clarify the etiology of a shock or for hemodynamic assessment of patients with sepsis. In patients presenting with chest pain and a suspicion of acute coronary syndrome, echocardiography plays a key role for the diagnosis, the risk stratification and the management of the disease. Patients with acute chest pain account for a notable proportion 20–30%) of medical admissions to the emergency department . A vast % of mediet al., ultrasound contrast agents were used for the diagnosis of LV pseudoaneurysm in 19 cases. In thirteen of them, contrast was required to make the diagnosis whereas in other 4 patients, the diagnosis was suspected by noncontrast echocardiography but confirmed by contrast administration. In the two remaing patients, suspected LV pseudoaneurysm was ruled out by contrast echocardiography, thereby preventing unnecessary emergent operations [Once the diagnosis of acute coronary syndrome is established, contrast echocardiography improves the detection of complications and a better risk stratification of these patients. Considering the critical issue of left ventricular rupture (LVR) with pseudoaneurysm formation after ST-elevation acute myocardial infarction (AMI), there are approximately 500,000 ST-elevation AMIs in the U.S. annually, of which 1% to 6% involve LVR . Free waerations . On the erations .Numerous patients, especially the elderly, are admitted to the emergency room for acute decompensated heart failure. Acute cardiogenic pulmonary oedema may result from acute events or from acute deterioration of a chronic disease. The main mechanisms include reduced outflow, reduced inflow or backward flow. Rapid distinction between heart failure due to systolic versus diastolic dysfunction should be obtained since there are significant differences in treatment. Therefore, the evaluation of systolic performance is critical and a good visualisation of the endocardium improves confidence of the operator in these often difficult to image patients. Patients in the intensive care unit also remain in technically challenging to obtain adequate echocardiographic images. The frequent use of mechanical ventilation, presence of chest bandages, and difficulty in positioning the patient, poor lighting conditions are factors that impair image quality. Contrast echocardiography may play an important role in this setting . On the other hand, the precise evaluation of aortic stenosis severity is mandatory and contrast may help to enhance Doppler signal. Finally, in patients with acute heart failure and no previous history of coronary artery disease, myocardial perfusion echocardiography is able to determine the presence coronary artery disease, and so, is able to identify viable myocardium at the bedside without requiring a more cumbersome assessment through SPECT, PET, or magnetic resonance imaging (MRI) .Bet al demonstrated that suboptimal studies have worse reproducibility and a poorer inter-observer variability, with inter-institutional institutional observer agreement as low as 43% for studies with poor image quality [Exercise echocardiography and exercise SPECT have been shown to provide comparable short term prognostic information in the triage of chest pain patients, allowing safe early discharge; the negative predictive value was 97% in both methods, but exercise echocardiography is preferable because of a higher positive predictive value . Pharmac quality . Contras quality , 18. Contrast echocardiography for enhancing LV borders in suboptimal studies actually represents the main indication of ultrasound contrast agents and is especially useful in approximately 10% to 20% of routine echocardiographic examinations. During dobutamine echocardiography, the sensitivity of contrast myocardial perfusion echocardiography has also been shown to be higher than that of wall motion at both maximal and intermediate doses of dobutamine for the detection of coronary artery disease and in predicting events -46.C1). More recently, in patients with Tako-Tsubo, the potential use of contrast imaging to better define the variance of typical left ventricular ballooning finding in this condition has been emphasized [Contrast echocardiography also has been of value in the structural assessment of the left and right ventricles, the atria, and the great vessels. Ultrasound contrast agents play a key role in the definition of left ventricular apical abnormalities, in complications of myocardial infarction, and in cases of intracardiac masses -51. It mphasized  and on tphasized -55.D2 [Doppler echocardiographic assessment of blood flow velocities in the heart and the great vessels is a standard part of the cardiac ultrasound examination. Contrast enhancement of the Doppler signal has been shown to be of value when the signal is weak or technically suboptimal. Velocity measurement in patients suspected of aortic stenosis may be enhanced with echocardiographic contrast agents as shown in Fig. 2 .E3).Echocardiography plays a major role in pericardiocentesis to determine the distribution and the depth of the effusion. During the procedure, continuous echocardiography has been proposed, eventually combined to the injection of agitated physiologic serum to generate contrast and define the tip of the needle (Fig. Although ultrasound contrast agents have proven utility in the diagnosis and management of critically ill patients , 57-59, In the acutely ill patients, transthoracic image quality is often a problem and the use of ultrasound contrast agents to enhance left ventricular opacification improves the accuracy of echocardiography by rendering examination interpretable. Consequently, this may have implications in patient management. Moreover, perfusion study with contrast echocardiography may add information for diagnosis and risk stratification in patients presenting at the emergency room or hospitalized in intensive care unit. Although there were several concerns regarding the safety with the use of ultrasound contrast agents in the acutely ill patient, recent studies have provided reassurance about the use of contrast in this setting.


Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian stimulation (COS) as part of assisted reproductive technologies (ART). While the safety and efficacy of ART is well established, physicians should always be aware of the risk of OHSS in patients undergoing COS, as it can be fatal. This article will briefly present the pathophysiology of OHSS, including the key role of vascular endothelial growth factor (VEGF), to provide the foundation for an overview of current techniques for the prevention of OHSS. Risk factors and predictive factors for OHSS will be presented, as recognizing these risk factors and individualizing the COS protocol appropriately is the key to the primary prevention of OHSS, as the benefits and risks of each COS strategy vary among individuals. Individualized COS (iCOS) could effectively eradicate OHSS, and the identification of hormonal, functional and genetic markers of ovarian response will facilitate iCOS. However, if iCOS is not properly applied, various preventive measures can be instituted once COS has begun, including cancelling the cycle, coasting, individualizing the human chorionic gonadotropin trigger dose or using a gonadotropin-releasing hormone (GnRH) agonist (for those using a GnRH antagonist protocol), the use of intravenous fluids at the time of oocyte retrieval, and cryopreserving/vitrifying all embryos for subsequent transfer in an unstimulated cycle. Some of these techniques have been widely adopted, despite the scarcity of data from randomized clinical trials to support their use. There has been a rapid increase in the number of couples receiving treatment for infertility with assisted reproductive technology (ART) in recent years . While tOHSS is an exaggerated response to COS characterized by the shift of protein-rich fluid from the intravascular space to the third space, mainly the abdominal cavity that occurs when the ovaries become enlarged due to follicular stimulation . This shThe clinical manifestations of OHSS reflect the extent of the shift of fluid into the third space and the resulting hemoconcentration due to intravascular volume depletion. Symptoms range from mild abdominal distention due to enlarged ovaries alone or with an accompanying fluid shift into the abdomen, to renal failure and death as a result of hemoconcentration and reduced perfusion of organs such as the kidneys, heart and brain Table  5,8]. I,8. I5,8]OHSS can be “early” or “late” based on the source of hCG. Early OHSS occurs in the luteal phase of COS after the administration of exogenous hCG to induce oocyte maturation. Late OHSS occurs when ART results in pregnancy and is the consequence of an increase in endogenous hCG levels following conception. In most cases, OHSS is self-limiting and resolves spontaneously within several days. However, OHSS may persist, particularly late OHSS due to pregnancy.Several primary and secondary risk factors for OHSS have been identified Table . HoweverThere are a number of well-established primary risk factors for the development of OHSS, including young age, polycystic ovary syndrome (PCOS) – characterized by ultrasound and the ratio of luteinizing hormone (LH) to follicle stimulating hormone (FSH) – and a history of an elevated response to gonadotropins, i.e. prior hyper-response/OHSS ,10,15. SResearch has identified additional hormonal biomarkers that may also predict a patient’s response to COS and determine their risk of OHSS. In the very early follicular phase of the cycle, a number of antral follicles (2–10 mm in size) are present that are easily detected by transvaginal ultrasound as their appearance is marked by the formation of a fluid-filled cavity adjacent to the oocyte (the antrum) ,12. The Basal Anti-Müllerian hormone (AMH) levels prior to COS have also been shown to be predictive for OHSS . Two recActivating mutations in the FSH receptor (FSHR) gene have been shown to confer a higher response to FSH and therefore FSHR genotype may predispose women to OHSS , AlthougTraditionally, high or rapidly rising serum E2 levels on the day of the hCG trigger, denoting oversensitivity to hCG, was used as a predictor of OHSS . HoweverPrevention of OHSS is a multi-stage process. The key to the primary prevention of OHSS during COS is recognizing risk factors and individualizing the ovarian stimulation protocol appropriately using iCOS ,21. iCOSSuch a personalized approach, where even clomiphene citrate with human menopausal gonadotropin or FSH  can haveThe use of AMH, as a biomarker to individualize COS protocols, has been evaluated in a retrospective study of women undergoing ART . The stuin vitro oocyte maturation, coasting, decreasing the hCG trigger dose, and using a gonadotropin-releasing hormone agonist (GnRHa) trigger. However, despite the widespread use of these preventative techniques, supporting evidence is limited.Before initiating iCOS, patients at high risk of OHSS can be identified from their risk/biomarker profile and the stimulation protocol can be tailored to their needs through iCOS. If iCOS is not correctly applied then patients are more likely to experience OHSS. To minimize the risk of severe complications, secondary preventative measures are normally applied. Various preventative protocols have been proposed to reduce or minimize the risk of developing OHSS during COS, including There have been few RCTs that fully evaluate the efficacy and safety of these protocols , with diA recent Cochrane review concluded that there was no evidence to suggest a benefit of coasting to prevent OHSS compared with no coasting or other interventions, but only four of 16 studies included in the review met the RCT inclusion criteria . DespiteDue to its long half-life (65 hours), a single injection of corifollitropin alfa is intended to replace daily gonadotropin injections during the first week of COS ,29. In tMetformin has also been used for the prevention of OHSS. In a meta-analysis of eight randomized controlled trials of women with PCOS, metformin given 2 months before starting COS significantly reduced the risk of severe OHSS  .As OHSS is associated with hCG, terminating the ovulation cycle by cancelling the hCG trigger in the presence of several risk factors for OHSS is the most effective technique to prevent OHSS . hCG indIn vitro oocyte maturation, where immature oocytes are retrieved and matured in vitro before fresh embryo transfer, is also an option in these patients. In 56 patients with high risk of OHSS during the controlled ovarian hyperstimulation cycle, hCG was given when the leading follicle reached 12–14 mm in diameter . Cr. Cr62]. Recently, interest in cryopreservation has increased due to vitrification, an efficient method of cryopreservation that result in better survival after thawing, due to reduced cellular damage compared with traditional cryopreservation techniques . VitrifiIf iCOS is not applied and risk reduction strategies are unsuccessful, measures are required to minimize the effect of OHSS and prevent further morbidity. Mild OHSS, which due to the very nature of COS occurs in most patients, and moderate OHSS with no clinical evidence of ascites or enlarged ovaries are not associated with complications and as a result do not require specific treatment. Mild OHSS and moderate OHSS can be treated symptomatically and patients monitored on an outpatient basis , for exaIn patients with moderate OHSS, aggressive early paracentesis can prevent the progression of disease severity . In addiA recent review of the clinical aspects of OHSS provides detailed recommendations for management according to patient diagnosis and risk .Prevention of OHSS begins with tailoring an individual’s ovarian stimulation protocol based on their risk profile, through iCOS. Selecting one standardized preventative approach for all patients or a large cohort of patients undergoing COS is challenging, because the benefits and risks associated with each strategy vary between individuals. Identification of hormonal, functional and genetic markers of ovarian response will facilitate iCOS. Indeed, if the risk factors and biomarkers for OHSS are recognized and patients are correctly treated with iCOS, OHSS may no longer be an issue. In the meantime, despite the scarcity of data from RCTs to support their use, there are various secondary preventative measures that can be employed to reduce the risk of OHSS once COS has begun, including canceling the cycle, coasting, individualizing the hCG trigger dose or using a GnRH trigger (for those using a GnRH antagonist protocol), the use of IV fluids at the time of oocyte retrieval, and cryopreserving/vitrifying all oocytes.AFC: Antral follicle count; AMH: Anti-Müllerian hormone; ART: Assisted reproductive technology; BMI: Body mass index; BMP-15: Bone morphogenic protein-15; CONSORT: Consistency in r-FSH starting doses for individualized treatment; COS: Controlled ovarian stimulation; Cr: Serum creatinine level; CrCl: Creatinine clearance; E2: Estradiol; FSH: Follicle stimulating hormone; FSHR: Follicle stimulating hormone receptor; GnRH: Gonadotropin-releasing hormone; GnRHa: Gonadotropin-releasing hormone agonist; hCG: Human chorionic gonadotropin; Hct: Hemoconcentration; HES: Hydroxyethyl starch; iCOS: Individualized controlled ovarian stimulation; IV: Intravenous; LH: Luteinizing hormone; LPS: Luteal phase support; OHSS: Ovarian hyperstimulation syndrome; PCOS: Polycystic ovary syndrome; RCTs: Randomized controlled trials; VEGF: Vascular endothelial growth factor; VEGFR-2: Vascular endothelial growth factor receptor 2; WBC: White blood cell count.KF has no competing interests to declare. DE is an employee of Merck Serono S.A. – Geneva, Switzerland .KF and DE contributed to the writing and editing of this manuscript and approved the final version for submission. They are fully and equally responsible for the content of the article. Both authors read and approved the final manuscript.


CMR is a recognized method of assessing global RV function in patients with pulmonary arterial hypertension (PAH). Unfortunately, assessment of regional myocardial motion with MRI remains challenging due to the thin RV wall. One solution may be tissue phase mapping (TPM) in which motion can be encoded at a higher spatial resolution. However, one problem is the need for respiratory navigation due to long scan times. We have therefore implemented a novel self-gated golden-angle spiral TPM technique that can acquire high-resolution data efficiently during free breathing in healthy volunteers and in patients with PAH.TPM was performed using a rotating golden-angle spiral acquisition. Reconstruction of real-time images allowed creation of an image-based respiratory navigator, which was used to select expiratory spiral interleaves. Expiratory data was retrospectively cardiac-gated using data binning. TPM of a mid-ventricular slice was acquired in 18 PAH patients and 10 healthy volunteers. Post-processing of TPM data was performed on in-house software developed on the open source OsiriX platform by manually defining endocardial and epicardial ventricular borders. Longitudinal and radial myocardial velocities were calculated from the RV free wall and the LV lateral wall.The self-gated sequence was successful in all patients with excellent image quality. Visualization of the motion vectors demonstrated obvious abnormalities in septal motion Figure . QuantifIn patients with PAH, RV contraction was also significantly prolonged compared to LV contraction, both radially  and longitudinally . There was no difference between RV and LV contraction times in normal volunteers (p > 0.35). Importantly, the prolongation of RV contraction significantly correlated with the degree of septal curvature .We have shown that it is possible to comprehensively assess RV myocardial motion using a novel free-breathing, golden-angle spiral TPM sequence. Using this technique we have shown in PAH that s-wave and e-wave velocities are reduced while a-wave velocities are increased, consistent with reduced RV systolic and diastolic function. Furthermore, we have shown that RV contraction time is prolonged in PAH and this correlated with septal curvature, implying a causal relationship. Thus, we believe that our novel TPM sequence is more fully able to assess ventricular dysfunction in PAH and may be an important tool in diagnosing PAH and monitoring response to therapy.Drs. Daniel Knight and Vivek Muthurangu are funded by the British Heart Foundation (BHF).


The fiber architecture adaption in physiological hypertrophy of the althete heart is still delusive. We aimed to use diffusion tensor cardiac MR (DT-CMR) to evaluate the tissue property and fiber architecture of elite athlete heart.Eight elite athletes of Marathon runner (endurance-training type), 8 of weight-lifter (strength-training type) and 8 ordinary style  were enrolled. Each subject received a CMR study on a 1.5 T scanner including 1. cine SSPF of a stack of LV short axis for LV mass and function; 2 DT-CMR, ECG-gated stimulated echo diffuse EPI on three levels of LV. Diffuse tensor composed of 6 directions and b value = 300 mm2/sec. 3. phase-contrast flow measurement at ascending aorta for stroke volume. The data were compared between groups and correlated between the parameters.The myocardium showed no difference of mean diffusivity (MD) and fractional anisotropy between the groups. Weight lifter showed increase of stroke volume / BSA and LV mass / BSA as compared to runner and ordinary groups. The fiber architecture showed an increased proportion of right-handed helical fibers  in runner and lifter equally, as compared to ordinary group. Putting all 24 subjects together, there was a linear regression between the proportion of right-handed helical fiber and LV mass .DT-CMR revealed the physiological hypertrophy of athlete heart was mainly due to right-handed helical fibers. This underscores the important role of subendocardial fiber on the LV function.N/A


Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy, myofibre disarray as well as interstitial and replacement fibrosis. These characteristics are likely the underlying cause of reduced ventricular compliance and cardiac arrhythmias which subsequently impact on quality of life and outcome.Cardiac magnetic resonance (CMR) based late gadolinium imaging (LGE) has emerged as a prognosticator in multiple cardiac myopathies, including HCM, and is able to demonstrate a type of myocardial scarring that has been likened to replacement fibrosis. CMR based T1 mapping techniques on the other hand are thought to be able to also detect a more diffuse increase in collagen volume fraction of myocardial tissue (i.e. diffuse fibrosis). It has been argued that the latter type of fibrosis may be reversible up to a certain stage. However, even in the physiologically unlikely scenario that both fibrotic processes were independent of each other above mentioned CMR based technologies are not.We therefore sought to investigate the relationship between LV mass (LVM), LGE imaging, using multiple cut-off points for signal differences to normal myocardium, and T1 mapping in order to gain a better understanding of myocardial tissue characteristics (i.e scar volume/diffuse fibrosis) as well as the interconnection of LVM, LGE and T1 mapping as currently applied.Twenty-one consecutive HCM patients attending for clinically indicated scans  underwent T1 mapping pre- and 10 minutes post gadolinium contrast using a modified look locker inversion recovery (MOLLI) sequence  for Osirix . LGE images were acquired immediately after post-contrast T1 mapping using an inversion recovery gradient echo sequence and analysed with thresholds of 2 and 6 standard deviations (SD) and the full width half maximum (FWHM) method . Statistical analysis was performed using SPSS version 19.0.Fourteen patients were male, mean age 54±16 years. Mean left ventricular mass (LVM) was 163.4±57.0g. Mean focal fibrosis masses (MFF) were 29.5±20.7g using FWHM, 65.7±32.1g using 2 SD threshold and 19.6±15.5g using 6 SD threshold. Mean pre-contrast T1 mapping time was 1217±110ms compared with post-contrast of 421±73.8ms. Mean difference between pre and post T1 mapping times (T1Diff) was 797±137sms. Age did not show a significant relationship with LVM, MFF or T1Diff. There was a significant correlation between LVM and MFF . T1Diff was inversely correlated with MFF using FWHM threshold are also inversely correlated.Nothing to disclose.


A cardiac-tailored framework for 3D Diffusion Tensor MRI tractography is developed and used to characterize myofiber architecture in normal and remodeled myocardium. We show that myofibers in the subepicardium of the remote infarct zone become less oblique  as the heart dilates and remodels. This fiber realignment may play an important role in the loss of contractile function in the remote zone over time.Large infarctions cause the left ventricle (LV) to dilate and remodel, ultimately leading to a global decrease in LV function. While the impact of infarction on fiber architecture in the infarct zone is well understood, the impact of remodeling on fiber architecture in the remote zone is not. Diffusion Tensor Imaging (DTI) has contributed greatly to the study of cardiac structure and organization, but the majority of these studies employed 2D datasets ,2. Here 2; voxel-size=2x2x2mm3; TR/TE=8430/96ms. Fiber tracking was performed with a fourth-order Runge-Kutta approach. Myofibers were classified by their median helix angle (HA) and limited in length to half the LV circumference. Histograms of fiber HA were used to compare myofiber architecture in normal and remodeled myocardium.Excised human (n=5) and sheep (n=5) hearts were studied. Large anteroseptal infarctions were produced in the sheep 3 months prior to imaging. DTI of the hearts was performed on a 3T scanner  using 6 gradient-encoding directions, b-value=2000s/mmDTI tractograms in the lateral wall of a normal human heart Figure  and sheeThe developed DTI tractographic framework allows myofibers be to classified as continuous entities and shows that fibers in the subepicardium of the remote zone lose their oblique orientation. This microstructural change likely contributes significantly to the loss of function seen in the remote zone over time.R01 HL093038 (Sosnovik), NCRR P41RR14075 (Martinos Center) and MGH-ECOR (Mekkaoui).


Furthermore, the burden of right ventricular non-compaction and papillary muscle abnormality in this condition was highlighted for the first time, which corresponds to findings from the largest pathology study conducted thus far.6It is important to note that currently, the only dedicated left ventricular non-compaction clinic in the southern hemisphere is based at the Chris Hani Baragwanath Hospital, where patients have now been followed up for up to 40 months. This centre has dealt with both national and international referrals, and offers echocardiographic techniques and CMR to aid diagnosis. In addition to standard medical therapy, patients with isolated left ventricular non-compaction have been treated with biventricular pacing and internal cardiac defibrillators in cases of refractory heart failure.Isolated left ventricular myocardium is a condition encountered in clinical practice in Africa and needs to be identified and distinguished from acquired causes of left ventricular non-compaction. Long-term outcome and follow up have not been documented among patients of African origin and is the subject of future research initiatives.


To assess the ability of ShMOLLI T1-mapping in detecting acute myocardial injury in patients with chest pain, positive troponins and non-obstructive coronary arteries.To diagnose acute myocardial injury of varying etiologies, cardiovascular magnetic resonance (CMR) techniques must be sensitive to global and focal changes. ShMOLLI T1-mapping permits quantitative myocardial characterization without contrast agents or reference regions. We compare ShMOLLI T1-mapping against traditional CMR imaging modalities.16 patients  with acute chest pain, Troponin I >1.0 ug/L and non-obstructive coronary arteries underwent 1.5T CMR imaging within 7 days of presentation (median 3 days). CMR protocol included Shortened Modified Look-Locker inversion recovery (ShMOLLI) for T1-mapping, T2-STIR and late gadolinium enhancement (LGE) imaging. Regional wall motion was assessed with SSFP cines. Volumetric fractions of injured myocardium were quantified by (1) T2 signal intensity (SI) of myocardium:skeletal muscle >1.9:1; (2) T1>110% of normal myocardial T1; and (3) LGE SI>2SD of remote myocardium SI.Table2=0.45)  Fig..Patients with Takotsubo cardiomyopathy (mean EF=54±7%) had the highest average T1 values . Except for one with global myocarditis, patients with myocarditis and MI were without significant LVEF impairment with focal injury. Accordingly, average T1 values in these subgroups were not statistically different from normal.Fig.2=0.59; T2-STIR R2=0.18, LGE R2=0.1).On a regional level, compared to segments with normal wall motion, segments with abnormal wall motion had significantly increased T1 values  Fig., larger ShMOLLI cardiac T1-mapping objectively detects acute global and focal myocardial injury of non-ischaemic and ischaemic etiologies. It is a promising method for acute CMR imaging with potential to offer adjunctive information in the characterization of acute myocardial injury.


Lateral wall infarction on DE-CMR, independent of papillary muscle involvement, confers increased risk for ischemic mitral regurgitation.The mitral apparatus contains two myocardial components - papillary muscles and the adjacent left ventricular (LV) wall. Delayed enhancement CMR (DE-CMR) enables in-vivo study of potential contributions of LV wall and papillary muscle infarction (PMI) to MR. This study examined the relative impact of papillary muscle and LV wall infarction on mitral regurgitation (MR) following ST elevation MI (STEMI).Multimodality imaging was prospectively performed among patients with first STEMI: DE-CMR  was used to assess LV infarct pattern - including PMI  and LV wall infarction . Cine-CMR (SSFP) was analyzed for cardiac function and geometry - including LV chamber size, regional wall motion (5 point score/segment), and mitral annular diameter. Echocardiography (echo) was used to quantify MR (0-4+ grade) using established consensus criteria. Each imaging modality was read independently.153 patients  with first STEMI were studied. Echo and CMR (1.5T) were performed within 1 day in all patients (27±8 days post STEMI). 42% had MR . MR severity was similar among patients with and without PMI (p=0.35; Figure Lateral wall injury - whether assessed by infarct size or contractile dysfunction - confers increased risk for MR following STEMI, even after controlling for both mitral annular and LV chamber geometry. Neither presence nor location of PMI independently impacts severity of post-STEMI MR.K23 HL102249-01, Lantheus Medical Imaging, Doris Duke Clinical Scientist Development Award.


Clinical studies implementing late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) studies suggest that the peri-infarct zone (PIZ) contains a mixture of viable and non-viable myocytes, and is associated with greater susceptibility to ventricular tachycardia induction and adverse cardiac outcomes. However, CMR data assessing the temporal formation and functional remodeling characteristics of this complex region are limited. We intended to characterize early temporal changes in scar morphology and regional function in the PIZ.p = 0.04). The size of infarct scar expanded by 14% and thinned by 56% from day 3 to 12 weeks . LVEDV increased from 34.7. ± 2.2 ml to 47.8 ± 3.0 ml . At 30 days post-MI, regional circumferential strain was increased between the infarct scar and the PIZ .CMR studies were performed at six time points up to 90 days after induction of myocardial infarction (MI) in eight minipigs with reperfused, anterior-septal infarcts. Custom signal density threshold algorithms, based on the remote myocardium, were applied to define the infarct core and PIZ region for each time point. After the initial post-MI edema subsided, the PIZ decreased by 54% from day 10 to day 90 (The PIZ is dynamic and decreases in mass following reperfused MI. Tensile forces in the PIZ undergo changes following MI. Remodeling characteristics of the PIZ may provide mechanistic insights into the development of life-threatening arrhythmias and sudden cardiac death post-MI. Despite substantial progress in risk stratification to identify susceptible patients and therapeutical advances, the risk of sudden death remains the highest in the first 30 days after myocardial infarction (MI) ,2. EstimRecent studies employing late gadolinium enhancement (LGE) CMR suggest that a mixture of viable and non-viable cells can be identified as the peri-infarct zone (PIZ), due to an intermediate CMR intensity level between normal (black) and infracted (white) myocardium. Although the detection of the PIZ is contributed to the partial volume effect in CMR acquisitions ,6, this However, PIZ data correlating tissue, substrate-specific characteristics of the temporal formation and functional remodeling of the PIZ, which occur concurrently with structural LV chamber remodeling, do not exist. The purpose of this study was to test the hypothesis that the peri-infarct zone undergoes spatial and functional changes over time in parallel with structural ventricular remodeling following reperfused MI.All animal studies were approved by the Johns Hopkins University Institutional Animal Care and Use Committee and comply with the "Guide for the Care and Use of Laboratory Animals" . Fourteen female Göttingen minipigs, at 15 ± 1 months of age, were purchased from Marshall BioResources . Myocardial infarcts were created in a closed chest approach by 120 minutes balloon occlusion of the left anterior descending artery, followed by restoration of flow, as described in detail previously . We demonstrate that the PIZ--assessed by LGE-CMR imaging-- undergoes significant changes early after MI as well. Until day 10, the PIZ decreases rapidly in mass and the PIZ mass stabilizes thereafter. Our data suggests that after 4 weeks post- MI, the PIZ can reliably evaluate structural remodeling. Additional information for regional strain analysis was acquired, which provides valuable information about the tensile forces working on the scar tissue and in the PIZ.et al. showed that enhanced PIZ function, defined as greater Ecc and earlier time to peak Ecc, was associated with inducibility in patients with post MI heart failure [et al. reported the highest inducibility in a porcine model, 30 days after MI-induction [et al. and our findings suggest that the underlying pathophysiology (of post-MI VT) can be elucidated with imaging techniques.Recently, Fernandes  failure . In our  failure ,29. Tens failure . Until n failure . Howevernduction . This isThe most significant limitation in this animal study was the inability to perform serial VT inducibilty studies with programmed stimulation. Having this data would help to determine the relationship between the imaged tissue substrate and susceptibility to VT. Another limitation was that all of the infarcts were created in the LAD territory, and were transmural. Strain patterns in the PIZ for non-transmural infarcts are expected to be very different from those in transmural infarcts, but our research did not explore this theory. Further, we did not acquire T2-weighted CMR images to quantify the post-MI edema, nor did we use any medications that are currently administered to patients in the post-MI period.The PIZ is a complex tissue substrate that changes its composition and decreases in mass, following reperfused MI. The difference in tensile strain forces, between the infarct scar and the PIZ, is reached approximately 30 days after MI. After this time, the underlying tissue substrate is mainly composed of viable myocytes and clear defined collagen tissue. Myocardial strain characteristics, combined with the PIZ for the assessment of LGE-CMR images, may provide important clinical information for the development of life-threatening arrhythmias, as well as sudden cardiac death post-MI.BSN: Baseline; CMR: Cardiovascular magnetic resonance; CURE: Circumferential strain uniformity ratio estimate; Ecc: Circumferential strain; Err: Radial strain; FWHM: Full-width half max; LGE: Late gadolinium enhancement; LV: Left ventricle/ventricular; LVEDV: Left ventricular end-diastolic volume; LVESV: Left ventricular end-systolic volume; LVEF: Left ventricular ejection fraction; LVSV: Left ventricular systolic volume; MI: Myocardial infarction; PIZ: Peri-infarct zone; RE: Remote myocardium; VT: Ventricular tachycardia.The authors declare that they have no competing interests.KHS, planned, and performed experiments, supervised CMR acquisitions, analyzed data and images, and wrote the manuscript. MC planned, and performed experiments. KSE and AZ performed imaging analysis. RE acquired CMR data. JACL edited the manuscript. ACL supervised imaging analysis, and edited the manuscript. All authors read and approved the final manuscript.