The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy.Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria  and ventricles  were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of “any ECG change” (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression.P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. “Any ECG change,” LA-Wall-PC6 scores, and PTV size were retained in the multivariable model.38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, “any ECG change,” and larger planning target volume (PTV) were significantly associated with higher DR (We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients. We explored associations between all-cause death rate (DR), cardiac radiation doses, and electrocardiographic changes in 78 patients with locally advanced non-small cell lung cancer treated in IDEAL-CRT, a trial of isotoxically escalated concurrent CRT. We found evidence of associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher heart or left atrial wall volumes receiving 63 to 69 Gy.Definitive chemoradiation (CRT) is the standard of care for locally advanced non-small cell lung cancer (NSCLC) Radiation-induced heart disease (RIHD) has been associated with poorer long-term OS in breast and lymphoma survivors In this post-hoc analysis of the prospective data from IDEAL-CRT Data were analyzed for 78 of all 82 patients with stage IIB/III NSCLC who were recruited and treated in IDEAL-CRT, a phase 1/2 trial of isotoxically escalated CRT, which delivered 63 to 73 Gy in 30 fractions over 6 weeks, concurrently with 2 cycles of vinorelbine and cisplatin. Four patients were excluded, 1 because of corrupted radiation therapy planning archival records, 2 because of replanning during treatment, and 1 because of treatment termination after toxicity after 5 fractions resulting in very low heart doses.The ECGs obtained at baseline and 6 months after CRT were assessed by 2 cardiologists (S.R. and A.K.) in a blinded manner for the following characteristics: normal ECG, new rhythm changes compared with baseline , and ischemic or pericarditis-like changes (new or worsening ST and T wave changes compared with baseline). ECG changes between the 2 time points were then scored dichotomously as present or absent (“any ECG change”).Treatment plans were imported into the open-source Computational Environment for Radiotherapy Research (CERR) software written in MATLAB R2012b . Whole-heart contours delineated by physicians at participating centers were checked by DL and SV. The pericardium, right atrium (RA), right ventricle (RV), left atrium (LA), left ventricle (LV), and AV node (AVN) were delineated as individual substructures by SV using a modified version of a validated cardiac atlas www.redjournal.org) Differential dose-volume histograms (dDVH) with 1-Gy dose-bins were constructed for the whole heart and all substructures and were exported to SPSS.23  and R 3.2.3  for further processing. Separate principal components analyses (PCA) were carried out for the whole heart and for each cardiac substructure, representing patients' dDVHs as linear sums of structure-specific orthogonal principal components (PCs) and the population-averaged dDVH  of hazard ratios (HRs) for the all-cause death rate (DR) (measured from the start of treatment) were performed with Cox proportional hazards regression. Factors analyzed for association with DR were as follows: clinical (patient and treatment) characteristics, ECG changes, and scores of the 10 highest-ranked whole-heart dosimetry PCs. Relevant clinical factors, ECG changes, and PCs having www.redjournal.org). The predictive abilities of multivariable models were characterized using Harrell's concordance (C) statistic The false-discovery rate for significant associations after multiple hypothesis testing was controlled using the Benjamini-Hochberg step-up procedure to identify positive discoveries  criterion described in www.redjournal.org) to assess closeness of alignment.Two approaches were used to further localize the associations seen between DR and whole-heart dosimetry to specific cardiac substructures. The first involved UVA/MVA of associations between DR and the scores of individual cardiac substructure PCs (ss-PCs). To avoid excessive multiple testing, we studied only ss-PCs closely aligned with “heart-PCwww.redjournal.org). Binary masks were created from each patient's whole heart and left and right atria and ventricles, and registered to the corresponding masks of a reference patient by affine transformation. 3D dose distributions were mapped to the reference geometry through the same affine transformations, and a threshold was applied to identify the region where dose was associated with the peak in heart-PCmax (as quantified in the Results section) for each patient. These high-dose regions were visualized by taking 2D projections through the reference geometry in each principal anatomic plane , producing images with pixel values representing the percentage of patients for whom the projected high-dose region was present at each point in the plane. Projections were convolved with a Gaussian smoothing kernel (3-mm standard deviation) to avoid identification of features smaller than the typical registration error. This process was carried out for both for the whole heart and for each cardiac substructure, allowing visual localization of the high-dose peak.The second approach was a graphic interrogation of the shapes of the heart dose distributions of all 78 patients, mapped to a single reference geometry using an in-house MATLAB program . However, when analyzed separately, ischemic/pericarditis-like ECG changes and conduction ECG changes were not statistically significantly associated with DR. The presence of an abnormal baseline ECG was not significantly associated with DR (Results from UVA are shown in  with DR  or with P=.009) (Heart-63-69) and 0 to 4 Gy (VHeart-0-4) are, respectively, relatively large and small. Higher DR is more plausibly linked to larger volumes receiving high doses than to smaller volumes receiving low doses—an interpretation supported by a significant association between VHeart-63-69 and DR  but not between VHeart-0-4 and DR . Heart-PC6 was not significantly correlated with PTV size  or with prescribed dose  .Higher DR was significantly associated with larger Heart-PC6 scores (P=.009) . Heart-PP=.009) ; therefoP=.02), “any ECG change” (P=.04), and PTV size (P=.08) as factors associated with DR  was limited to 20% by the Benjamini-Hochberg procedure. The multivariable model judged best according to the AIC retained Heart-PC6  were 4%  and 16% , respectively, compared with 0.3%  and 0%  in the other 58 patients.The hearts of 62 patients received doses in excess of 63 Gy (the lower end of the peak of Heart PC6), and in 82% of these patients ≥1 cmicardium : specifiwww.redjournal.org). Like Heart-PC6, they both had prominent 63- to 69-Gy peaks . LA-Wall-PC6 and Pericardium-PC5 scores were both significantly associated with DR on UVA , presence of “any ECG change” (P=.07), and PTV size (P=.10) as factors associated with higher DR, the LA-Wall-PC6 score superseding Heart-PC6  for patients with less highly irradiated atrial wall volumes. The scale of association between DR and ECG changes is shown in the survival curves split by the presence or absence of any ECG change, also plotted in P=.90, .77, and .44, respectively) .Correlations between “Any ECG change” and scores for Heart-PC6, Pericardium-PC5, and LA-Wall-PC6 were not significant  for α/β = 3 Gy. The scale of associations between DR and heart and substructure volumes receiving 63 Gy was substantial, despite median values of these volumes being low . Given that VHeart-63-69 was not significantly correlated with PTV size or prescribed dose, the association between heart dose and DR is likely independent of these latter 2 factors; indeed, both PTV size and Heart-PC6 are retained in the whole-heart multivariable model judged best by the AIC criterion, whereas prescribed dose is not significantly correlated with DR on univariable analysis.We have found higher DR to be significantly associated with the presence of “any ECG change” 6 months after radiation therapy, and with large PTV size and larger values of Vwww.redjournal.org). On univariable analysis, neither N2/3 disease nor involvement of subcarinal nodes was significantly associated with DR . After the addition of these factors into the multivariable models of P=.03, with very slightly reduced HRs), whereas subcarinal nodal involvement was also retained in the multivariable model judged best on AIC (P=.07). In this dataset, then, there is no indication that nodal N2/3 disease or subcarinal nodal involvement was a confounder of the observed associations between cardiac dosimetry and DR.We have additionally explored the impact on DR of the presence of N2/3 disease, and of subcarinal nodal involvement .Because of the proximity of the heart to lung tumors and nodes, it is difficult to avoid the entire heart when escalating tumor dose. It would therefore be useful to identify specific radiosensitive cardiac substructures to spare preferentially, but few data exist regarding cardiac substructure dosimetry. Although irradiation of the left atrial wall was significantly associated with DR in our study, it was not possible to determine whether this was because damage to this structure was particularly critical, or whether the association simply reflects the strong correlation between whole-heart and left atrial volumes receiving 63 to 69 Gy  meta-analysis, which demonstrated a 7% absolute reduction in 2-year OS and higher rates of non-cancer-related deaths for irradiated compared with nonirradiated NSCLC patients Radiation-induced fibrosis is thought to be a key mechanism in the development of cardiac dysfunction after radiation therapy. In rats, fibrosis accumulation and dose-dependent decreases in end-diastolic diameter were seen 1 month after single fractions of 15 or 20 Gy, and deaths due to cardiac failure occurred after 22.5 Gy Atrial fibrosis is commonly seen in patients with atrial fibrillation (AF) and plays an important role in the pathophysiology of AF Some limitations of our study must be acknowledged. First, although it was a prospective study, our analysis was post hoc and lacked comorbidity or smoking status data, which may be additive risk factors for RIHD. Second, the resting 12-lead ECG has limited value as an indicator of subtle pathologic changes within the heart Third, the study was relatively small, and its findings must consequently be interpreted with caution. Although we found DR to be associated with dosimetry and ECG changes, we could not distinguish truly cardiac-related deaths from cancer-related deaths because there was a lack of cardiac-specific morbidity or mortality data, and all patients with early death experienced tumor relapse. Recording of cause of death is complicated because deaths of radiation therapy patients after cardiac arrest could be scored as cancer related.Fourth, although we found an association between high doses to left atrium and poorer survival, the mechanism remains unclear. Although we used a validated atlas In this small cohort of NSCLC patients we have seen significant associations between all-cause death rate and higher heart volumes receiving 63 to 69 Gy . The observed associations suggest that small volumes of heart receiving high radiation doses may have a negative impact on survival, greater and more acute than that seen in breast cancer and lymphoma patients who are treated with lower radiation doses. Our study is hypothesis generating and requires further work to establish a causal relationship between radiation therapy and mortality. The pathophysiology of acute RIHD needs to be determined in prospective functional imaging studies before we recommend modification of treatment plans on the basis of these initial results, for example, to reduce heart doses receiving ≥63 Gy, particularly if this compromises dosimetric PTV coverage. Our finding of an association between DR and ECG changes at 6 months after treatment does, however, tentatively suggest a link between DR and RT-induced cardiac damage.Given the armory of intensity modulated photon and ion beam radiation therapy technology available, outcomes of dose-escalated NSCLC treatments may be improvable in future by means of cardiac-sparing dose escalation techniques, given greater knowledge of links between survival, cardiac pathophysiology, and whole-heart and substructure dosimetry.


Heart failure (HF) is a threat to public health. Heterogeneities in aetiology and phenotype complicate the diagnosis and management of HF. This is especially true when considering HF with preserved ejection fraction (HFpEF), which makes up 50% of HF cases. Natriuretic peptides may aid in establishing a working diagnosis in patients suspected of HF, but echocardiography remains the optimal choice for diagnosing HF. Echocardiography provides important prognostic information in both HF with reduced ejection fraction (HFrEF) and HFpEF. Traditionally, emphasis has been put on the left ventricular ejection fraction (LVEF). LVEF is useful for both diagnosis and prognosis in HFrEF. However, echocardiography offers more than this single parameter of systolic function, and for optimal risk assessment in HFrEF, an echocardiogram evaluating systolic, diastolic, left atrial and right ventricular function is beneficial. In this assessment echocardiographic modalities such as global longitudinal strain (GLS) by 2D speckle-tracking may be useful. LVEF offers little value in HFpEF and is neither helpful for diagnosis nor prognosis. Diastolic function quantified by E/e′ and systolic function determined by GLS offer prognostic insight in HFpEF. In HFpEF, other parameters of cardiac performance such as left atrial and right ventricular function evaluated by echocardiography also contribute with prognostic information. Hence, it is important to consider the entire echocardiogram and not focus solely on systolic function. Future research should focus on combining echocardiographic parameters into risk prediction models to adopt a more personalized approach to prognosis instead of identifying yet another echocardiographic biomarker. Chronic heart failure (HF) represents a large societal burden of disease and has recently been characterized as an emerging epidemic . HF is aThe diagnosis of non-acute HF relies on the presence of HF-related symptoms and the subsequent quantification of cardiac dysfunction. Cardinal symptoms include but are not limited to dyspnoea, reduced exercise capacity and peripheral oedema. Comorbidities such as previous myocardial infarction increase the likelihood of a HF diagnosis . Many ofNatriuretic peptides are secreted in response to myocardial wall stress. HFpEF is characterized by a small LV cavity and thickened LV walls . Since tHFrEF is easily diagnosed by echocardiography. The diagnosis of HFrEF, is by definition HF symptoms and left ventricular ejection fraction (LVEF) <40%, usually quantified by the Simpson biplane method (2), LV hypertrophy (left ventricular mass index ≥115 g/m2 for men and ≥95 g/m2 for women) or an E/e′ ≥13  guidelines for assessment of diastolic dysfunction  HF guidelines. This patient group has been termed ‘heart failure with mid-range ejection fraction’ (HFmrEF), and comprises patients with heart failure symptoms, a LVEF of 40–49%, elevated levels of natriuretic peptides and either relevant structural heart disease  enlargement) or diastolic dysfunction . In the In the current guidelines, echocardiography is recommended in the diagnostic workup of suspected HF patients in order to establish a diagnosis of either HFrEF or HFpEF . EchocarHF patients who have undergone echocardiographic examination show better survival rates due to intensified medical treatment and intervention . Many ecEchocardiography is very valuable in the risk stratification of HFrEF patients. In 1962, Folse and Braunwald published results describing how to measure the ‘fraction of LV volume ejected per beat’ . This stReduced systolic function confers an adverse prognosis in HFrEF. LVEF remains the most widely used echocardiographic parameter for quantification of systolic function and is an established predictor of mortality in HFrEF , 38. HowTwo major causes of death in HFrEF are cardiac pump failure and sudden death from malignant ventricular arrhythmias. Device-based therapy such as CRT and CRT-ICD has been shown to reduce mortality and rehospitalization rates and improve prognosis in selected subsets of HFrEF patients . HoweverBeside the geometric assumptions, another significant disadvantage of the LVEF is the lack of ability to quantify regional myocardial function. In mammalian hearts, reentry circuits arise when a wave of electrical activation abnormally reenters the myocardium instead of propagating normally throughout the cardiac tissue to die out in its periphery. Reentry plays a significant role in the pathophysiology underlying life-threatening ventricular arrhythmias such as ventricular tachycardia (VT) or ventricular fibrillation (VF) . ArrhythIt is now apparent that quantification of systolic function offers much prognostic value in HFrEF. However, the high prevalence of atrial fibrillation (AF) in HFrEF represents a challenge to current echocardiographic methods. In AF rhythm, the varying RR-interval and changing loading conditions impairs systolic measurements and thus the usefulness of these to predict outcome . Hence, In HFrEF, much emphasis is put on the quantification of systolic function. Other aspects of cardiac structure and function also contribute with prognostic value. The quantification of LV filling pressure holds prognostic value in HFrEF: A restricted filling pattern by Doppler echocardiography as determined by E/A ratio and deceleration time of the E-wave is highly prognostic in HFrEF , 55. TheThe left side of the heart is not the sole contributor to risk stratification in HFrEF. The right ventricle (RV) holds significant prognostic value in HFrEF. A common misconception – it is thought that RV systolic function is exclusively determined by the afterload posed by decreasing LV function. However, RV ejection fraction and pulmonary artery systolic pressure both independently predict outcome in HFrEF . Thus, tet al. in a study of 1065 HFrEF patients  were important in the risk stratification of their HFrEF cohort et al. inF cohort . They alF cohort .Figure The measurement of BNP to aid in risk stratification of chronic HF patients is recommended in current guidelines (recommendation Class 1A). Hence, BNP assessment is useful for determining risk of adverse outcome in chronic HF . BNP preHFpEF currently represents a substantial clinical conundrum. Although spironolactone has been shown to reduce heart failure hospitalization rates in HFpEF , no therHFpEF was originally thought to result from diastolic dysfunction. This was based on invasive hemodynamic studies displaying increased LV stiffness, impaired diastolic relaxation and increased filling pressure in HFpEF , 69. HowHow LVEF can be preserved, despite the presence of systolic impairment in HFpEF, is not entirely clear. An analysis of the LV fibre and contraction pattern may offer some insight into the conundrum that is HFpEF. The LV muscular wall comprises three overall compartments: the subendocardium, the midmyocardium and the subepicardium . CircumfIn the Candesartan in heart failure - assessment of mortality and morbidity (CHARM) trials, which studied 7599 HF patients with a broad spectrum of LVEFs, LVEF did not accurately discriminate risk of cardiovascular outcome in patients with an LVEF >45% . A similHFpEF is usually characterized by a small LV cavity, hypertrophied LV walls and severe diastolic dysfunction . NaturalAs previously discussed, LA structure and function is a sensitive barometer of LV filling pressure. Chronic exposure of the LA to elevated LV filling pressure causes LA dilatation . LA dilaRV function is closely related to LV diastolic function, since high LV filling pressure will increase pulmonary pressures and cause greater RV afterload. Thus, pulmonary hypertension and RV dysfunction are highly prevalent in HFpEF . PulmonaOnce more, it becomes apparent that not one echocardiographic marker of cardiac structure or function is sufficient in HFpEF. A comprehensive examination is needed and results must be interpreted by the clinician on a personalized basis. We see that LV systolic and diastolic function, LA function and RV function offer prognostic value in HFpEF. As is stated in the current guidelines, the assessment of diastolic function is multifaceted and requires the assessment and interpretation of multiple echocardiographic indices . This isBNP levels are lower in HFpEF than in HFrEF . This isIt is now apparent that many echocardiographic markers hold prognostic value in HF. However, single measures of risk are rarely sufficient for the accurate estimation of prognosis in complex diseases such as HF . The topB-type natriuretic peptides are useful in the exclusion of suspected HF; however, caution is warranted in the morbidly obese suspected of HFpEF. Echocardiography remains an essential procedure in HF. Echocardiography allows for accurate diagnosis and prognosis in both HFrEF and also in HFpEF. Future research should focus on combining echocardiographic prognostic markers into easily applicable prediction models in order to aid clinical decision making. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.Daniel Modin was supported by a scholarship from the Medical Society in Copenhagen during the preparation of this manuscript. Tor Biering-Sørensen was supported by the Fondsbørsvekselerer Henry Hansen og Hustrus Hovedlegat 2016. The sponsors had no role in the study design, data collection, data analysis, data interpretation or writing of the article.


The Fontan circulation, a result of a palliative procedure in patients with single systemic ventricles, is defined by chronically elevated pulmonary vascular resistance. When traditional heart failure therapies fail, pharmacological agents that reduce pulmonary artery pressures may be used. These include endothelial-receptor antagonists, prostanoids and phosphodiesterase type 5 inhibitors. We report the first use of macitentan, an endothelin-receptor antagonist, in a patient with a Fontan circulation.We describe the case of a 50 year old female with tricuspid atresia and transposition of the great arteries. Following complex surgery as a child, she subsequently underwent a fenestrated modified atrial pulmonary Fontan operation which was later converted to a total cavopulmonary anastomosis Fontan circulation. Due to failure of various medications to relieve her worsening symptoms, she was commenced on macitentan in April 2016. Few months later, she demonstrated a significant symptomatic improvement and associated increase in her incremental shuttle walking test distance.Macitentan has slower receptor dissociation kinetics compared to other endothelin-receptor antagonists, leading to enhanced pharmacological activity with promising effects in patients with pulmonary arterial hypertension. The patient we report has shown considerable improvement in exercise capacity following introduction of this medication and thus we suggest further randomised trials to establish the role of different endothelin-receptor antagonists in the management of the Fontan circulation. The Fontan circulation results from a palliative surgical procedure, which is performed in patients with a functionally single ventricle cardiac anatomy (i.e. univentricular heart). Venous blood is diverted from the vena cava to the pulmonary artery bypassing the single ventricle. The success of this operation has resulted in an increasing population of adults living longer with congenital heart disease .The Fontan circulation is defined by low cardiac output and elevated central venous pressure. The main limitation of the Fontan circulation is the absence of a sub-pulmonary ventricle. Blood flow through the pulmonary vasculature depends on the gradient between central venous pressure and ventricular end-diastolic pressure, as well as a low resistance to flow across the pulmonary vascular bed (pulmonary vascular resistance) .It remains to be determined whether late deterioration is caused by primarily ventricular failure and increasing end diastolic pressure or if it is due to chronically increased pulmonary vascular resistance resulting in raised end-diastolic pressures and therefore increased systemic venous congestion and reduced cardiac output . There iEventually there is a decrease in exercise capacity, functional status and an increase in heart failure-related hospital admissions with an increase in mortality .Traditional therapies for heart failure directed at improving function/decreasing afterload may not be as relevant in a circulation in which the primary problem is filling as opposed to emptying the ventricle. Treatments aiding ventricular filling in the Fontan circulation may be beneficial.Modulating pulmonary vascular resistance could improve cardiac output. Reducing pulmonary vascular resistance improves blood flow across the pulmonary capillaries, which results in a reduced central venous pressure and improved cardiac output. Various pharmacological agents have shown to reduce pulmonary artery pressures such as endothelial receptor antagonists  prostanoWe describe the case of a 50 year old Caucasian female patient who was born with tricuspid atresia and transposition of the great arteries. At the age of 4, she underwent a modified Glenn procedure followed by a classical left Blalock-Taussig shunt at the age of 16. Since then, she has had two major cardiac operations. In 1990, at the age of 25, she had a fenestrated modified atrial pulmonary Fontan. Following a very difficult pregnancy 18 years later, she underwent conversion to a total cavopulmonary anastomosis Fontan circulation, modified MAZE procedure and implantation of an epicardial defibrillator with biventricular pacemaker system. Cardiac catheterisation at that time showed a ventricular end diastolic pressure of 16 mmHg and a Fontan chamber pressure of 18 mmHg, giving a transpulmonary gradient of 2 mmHg. Her cardiac medical history was further complicated with arrhythmias requiring ablation in 1998 and episodes of non-sustained ventricular tachycardia in 2014.This lady has been under regular follow-up by our team since 2008. Various medications have been trialled over the last 8 years due to her progressive reduction in exercise capacity and exertional dyspnoea. She had initially taken part in a trial to test the safety of bosentan in 2010  and at tUnfortunately, over the course of the next few years, she continued to deteriorate with worsening breathlessness (NYHA III), four-pillow orthopnoea and paroxysmal nocturnal dyspnoea, ventricular function was preserved. She noticed a significant limitation in everyday activities, requiring social care input and a mobility scooter for outdoor travel. Sildenafil was commenced however this was discontinued shortly after due to symptomatic hypotension.Cardiac CT scan confirmed non-restrictive Fontan pathway, and normal ventricular function.In early 2016, bosentan was re-commenced with good symptomatic improvement. Unfortunately on this occasion, this was poorly tolerated with significant side effects  and thus stopped. On the basis of her symptomatic improvement with bosentan we decided to try an alternative endothelin-receptor antagonist, macitentan to alleviate symptoms.Macitentan (10 mg once daily) was initiated in April 2016. At 5-month review, the patient reported symptomatic improvement and this was associated with an increase in her incremental shuttle walking test distance from 160 m pre-treatment (prior to bosentan administration) to 200 m post-treatment with macitentan. She has not reported any significant side effects. Her echocardiogram remained unchanged with normal systemic ventricular internal dimensions and good radial systolic function (ejection fraction 55–60%).This is the first patient with Fontan circulation that has been commenced on macitentan. Macitentan belongs to the family of endothelin-receptor antagonists (ERAs) . MacitenThere is limited published evidence to support the use of pulmonary vasodilator therapy in Fontan circulation failure. A recent systematic review identifed improvements in exercise capacity, exercise haemodynamics and ventricular performance following the administration of bosentan and sildenafil in pulmonary hypertension . The TEMThere remain concerns regarding late liver complications in the Fontan circulation, and ERAs have been reported to cause liver dysfunction in a minority of patients. In our own safety study  and in tIn this case report, both Bosentan and Sildenafil medications were tried, however they had to be discontinued due to intrusive side effects. In view of the promising evidence of the success of macitentan in PAH, this was considered as a potential positive treatment in a patient with Fontan circulation. The patient has shown considerable improvement in exercise capacity following introduction of this medication and thus we suggest further randomised trials to establish the role of ERAs in the management of the Fontan circulation.


Despite the emerging evidence on beneficial effects of probiotics on the cardiovascular system, their impact on the management of ischemic heart diseases and the possible mechanism(s) have not been elucidated.Bifidobacterium breve, Lactobacillus casei, Lactobacillus bulgaricus, and Lactobacillus acidophilus, at the concentrations of 2×106 colony-forming units/ml, were orally administered to the rats daily for 14 days before the induction of infarct-like myocardial injury using isoproterenol. Subsequently, 24 h after myocardial injury, the right carotid artery and the left ventricle were catheterized for recording blood pressure and cardiac parameters. At the end of the experiment, the heart was removed for the evaluation of histopathological and biochemical parameters, as well as tumor necrosis factor-alpha (TNF-α) assay.Four viable probiotics bacterial strains, including P≤0.01) left ventricular (LV) dysfunction, as shown by an increase in LV end-diastolic pressure and a decrease in LV dp/dt max, LV dp/dt min, LV systolic pressure, and blood pressure, as compared with normal rats. Pretreatment with viable probiotics significantly reduced lipid peroxidation and TNF-α level and improved cardiac function (P<0.01).The induction of acute myocardial injury resulted in significant (This study shows that viable probiotics have a cardioprotective effect on infarct-like myocardial injury through suppressing TNF-α and oxidative stress damage in a rat model. Probiotic supplements may be used as a new option for prophylaxis in patients at the risk of ischemic heart disease in future. Rats in the fifth group (n=6) were pretreated with probiotics at the concentration of 2×106 CFUs/mL by gastric gavage daily for 14 days and then received ISO (ISO+probiotics [ISO+P]). After 24 h of the second dose of ISO injection and the induction of acute infarct-like myocardial injury, all rats were anesthetized using sodium thiopental , and the femoral artery and left ventricle of the heart were cannulated for recording blood pressure, hemodynamic parameters, and cardiac function. Two tissue samples of tissue from the apex of the left ventricle were removed immediately for the measurement of biochemical and histological parameters. A known weight of the ventricular tissue was homogenized in 5.0 mL of 0.1 M Tris-HCl buffer (pH 7.4) solution. The homogenate was centrifuged, and the supernatant was used for the estimation of various biochemical parameters such as tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) content, and thiobarbituric acid reactive substances.All 32 animals were randomly divided into five groups. The first group (n=8) included the rats that received saline as sham treatment . The second group was normal rats (n=4) that were given probiotics at a concentration of 2×10Bifidobacterium breve, Lactobacillus casei, Lactobacillus bulgaricus (Lactobacillus delbrueckii subsp. bulgaricus), and Lactobacillus acidophilus with 109 CFU/g colony count, which was prepared in the laboratory scale at Neurophysiology Research Center of Shahid Behest University of Medical Sciences, Tehran, Iran. The 2×106 CFU/mL[In this study, we used a combination of four viable probiotic bacteria strains, such as 06 CFU/mL dosage wAcute myocardial injury, an infarct-like myocardial lesion, was induced with the subcutaneous injection of ISO (85 mg/kg) at 24-h intervals for two consecutive days.At the end of the experiment, under deep anesthesia, tissue from the LV cardiac apex was removed and fixed in 10% buffered formalin solution. Heart tissue sections (5 μm thickness) were cut and stained using hematoxylin-eosin for histopathological examination under a light microscope (200×). The slides were evaluated for necrosis, inflammatory cell infiltration, and edema. A minimum of 10 fields for each slide were examined and graded for the severity of changes as follows: Grade 1 (−): absence of inflammation, edema and necrosis; Grade 2 (+): focal areas of inflammation, edema, and necrosis; Grade 3 (++): patchy areas of inflammation, edema, and necrosis; Grade 4 (+++): confluent areas of inflammation, edema, and necrosis; and Grade 5 (++++): massive areas of inflammation, edema, and necrosis. The exaThe supernatants of heart tissue were used for biochemical analyses. The total protein content in the heart tissue homogenate was determined using the Bradford’s method. MDA conTwenty-four hours after the second ISO injection and under thiopental sodium anesthesia, a polyethylene cannula (PE-50) was inserted into the right common carotid artery for recording the heart rate and arterial blood pressure . Then the polyethylene cannula was gently advanced into the LV lumen for the measurement of LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), the maximum rate of LV pressure increase , and the maximum rate of LV pressure decline . These parameters were continuously monitored and recorded using a Power Lab data acquisition system .P<0.05 .For the comparison of the groups regarding LVSP, LVEDP, LV dp/dt min, LV dp/dt max, TNF-α, and oxidative stress biomarkers, one-way ANOVA and Dunnett’s post-hoc test were used. Results were presented as mean±SEM. Differences were considered significant at P≤0.01) was seen in ISO+saline group compared to control groups  improved all these parameters compared with the ISO+saline group. Heart rate was not significantly changed (P>0.05) in the ISO+saline group in comparison to the other groups (P<0.05) attenuated by pretreatment with the probiotics bacteria (P>0.05).After 24 h of ISO-induced myocardial injury, a significant increase in LVEDP and decrease in LV dp/dt max, LV dp/dt min, LVSP, and blood pressure P≤0.0 was seenr groups . The raibacteria . There wThe result of histopathological examinations for the normal  and probiotic-treated normal  groups are shown in P<0.01) decreased the MDA content, as a lipid peroxidation marker, and increased the total antioxidant capacity or FRAP index in the heart tissue  and ISO+In.P rats compared with the normal control . Treatment with probiotics significantly . The hemodynamic and histopathological parameters were also improved significantly.There is little information about the host-microbiome interaction and its influence on the health of the cardiovascular system in humans. For the first time, our study showed that a two-week pretreatment with the combination of four probiotic strains of bacterial groups, such as A widely used model to study the possible protective effects of agents on myocardial infarction is coronary ligation, in which the heart is exposed to a left thoracotomy incision. This model is more complex and has a higher incidence of morbidity and mortality unrelated to myocardial infarction, and a mortality rate of approximately 50%. Therefoet al.[in vitro and in vivo. In addition, they showed that the administration of probiotic bacteria was able to protect rats against doxorubicin-induced oxidative damage in a dose-dependent manner, which further confirms the findings of the present study[L. casei, L. acidophilus, and Bifidobacterium lactis enhance the synthesis and augmentation of enzymes with antioxidant activity via alteration in gene expression levels[ISO-induced myocardial injury is mainly attributed to the production of free radicals, which cause cardiac dysfunction, increased lipid peroxidation, and depletion of endogenous antioxidants. Lipid pet al. have recent study. Our reson levels,21.Recent investigations have indicated that probiotics may inhibit pro-inflammatory cytokines such as TNF-α, stimulate the production of anti-inflammatory cytokine interleukin-10, and activate the anti-apoptotic Akt pathway,23. In tIt has been reported that the activation of pro-inflammatory cytokines such as TNF-α has an important role in worsening ischemic injury following myocardial infarction,27. Our et al.[In addition, in the current study, the effect of inactivated probiotics (heat-killed bacteria) on ISO-induced myocardial injury was investigated. Our findings indicated that there is no difference between ISO-treated  and ISO+In.P in cardiac function, histological assay, and hemodynamic parameters. This interesting result showed that the cardioprotective effects observed in this study are related to viable probiotics. These findings reveled that the viability of probiotics is probably needed for preclinical or clinical benefits. However, this hypothesis requires further exploration. Our data are consistent with other experimental research, showing that viable probiotics are more effective than non-viable probiotics,29. Althet al. reportedet al. and humaIn summary, the current study showed that probiotics have a cardioprotective effect against heart ischemic injury through the attenuation of TNF-α and oxidative stress in a rat model of infarct-like myocardial injury. We suggest that the viable probiotic supplements may be useful in the prevention or management of cardiac injury in patients at risk of myocardial infarction. However, more preclinical and clinical research studies are needed to elucidate the role of probiotics as a new option in the prophylaxis and the management of cardiovascular disease.


Extracellular matrix expansion as measured by extracellular volume fraction (ECV) with cardiac MRI (CMR) is a strong predictor of clinical outcomes. The aim of our study was to evaluate the relationship between EKG parameters and the presence of myocardial expansion as measured by ECV.We studied 90 consecutive patients without myocardial infarctions  referred for CMR with T1 mapping that had a 12 lead EKG within 90 days. Numerous EKG parameters were evaluated visually and electronically  to determine their association with myocardial fibrosis as measured by ECV.There were 40 (44%) patients with an elevated ECV ≥ 29%. Patients with an elevated ECV were more likely to have a history of congestive heart failure , had lower ejection fraction , and had more non-ischemic scar  as noted with late gadolinium enhancement (LGE). In patients with an elevated ECV, QRS Cornell amplitude , and QRS-T angle  were significantly higher, while T wave amplitude  was significantly lower. Multivariate logistic regression revealed that QRS-T angle ≥100°  and T wave amplitude ≤ 170 µV  were highly associated with an elevated ECV after adjustment for clinical covariates .Wide QRS-T angle and low T wave amplitude were independently associated with the presence of myocardial expansion as measured by ECV. Prospective evaluation of these parameters can aid in appropriate CMR referral for patients at risk of myocardial disease.


The development of durable ventricular assist devices (VADs) has improved mortality rates and quality of life in patients with end stage heart failure. While the use of VADs has increased dramatically in recent years, there is limited experience with VAD implantation in patients with complex congenital heart disease (CHD), despite the fact that the number of patients with end stage CHD has grown due to improvements in surgical and medical care. VAD use has been limited in patients with CHD and end stage heart failure due to anatomic  and physiologic constraints (diastolic dysfunction). The total artificial heart (TAH), which has right and left sided pumps that can be arranged in a variety of orientations, can accommodate the anatomic variation present in CHD patients. This review provides an overview of the potential use of the TAH in patients with CHD. Ventricular assist devices (VADs) have been shown to improve mortality and quality of life in adults with refractory heart failure. This has led to a dramatic increase in VAD use among adults over the last decade , AbioCor , and CARMAT . The history of these devices and their clinical use has recently been reviewed  was developed for use in adults with end-stage heart failure who had a contraindication to LVAD or biventricular VAD (BiVAD)  or congenitally corrected transposition of the great arteries (ccTGA) carry a life-long risk of systemic right ventricular dysfunction  but does so with a low CVP, something rarely seen with VADs or even early after transplantation. It is this immediate improvement in cardiac output in the environment of a decongested venous system that may allow recovery of renal  and adolescents who are too small for the 70 cc TAH. Syncardia® has now developed a 50 cc pump which is 30% smaller by volume and is now enrolling children and adults in a bridge to transplant clinical study Figure . The stuThe last few decades have seen a dramatic improvement in clinical outcomes among patients with CHD. These improvements are most pronounced in young children and those with severe CHD (Moons et al., CV provided conception/design of the review, contributed to critical drafting and revision of the manuscript and provided final approval for the manuscript. DM provided conception/design of the review, contributed to critical drafting and revision of the manuscript and provided final approval for the manuscript.DM has served as a consultant for Syncardia. DM is also a consultant for HeartWare and Berlin Heart.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


During the period of 1986–1997 the first 4 publications on the mechanical and metabolic properties of heat acclimated rat's heart were published. The outcome of these studies implied that heat acclimation, sedentary as well as combined with exercise training, confers long lasting protection against ischemic/reperfusion insult. These results promoted a clinical study on patients with coronary artery disease scheduled for elective coronary artery bypass operations aiming to elucidate whether exploitation of environmental stress can be translated into human benefits by improving physiological recovery. During the 1998 study, immediate-post operative chamber stiffness was assessed in patients acclimatized to heat and low intensity training in the desert  vs. patients in colder weather  via echocardiogram acquisition simultaneous with left atrial pressure measurement during fast intravascular fluid bolus administration. We showed that patients undergoing “heat acclimatization combined with exercise training” were less susceptible to ischemic injury, therefore expressing less diastolic dysfunction after cardiopulmonary bypass compared to non-acclimatized patients. This was the first clinical translational study on cardiac patients, while exploiting environmental harsh conditions for human benefits. The original experimental data are described and discussed in view of the past as well as the present knowledge of the protective mechanisms induced by Heat Acclimation Mediated Cross-tolerance. A variety of environmental factors are known to influence cardiovascular morbidity and mortality among which climate and ambient temperature appear to have a considerable effect. Multiple reports from throughout the world suggest a seasonal pattern in the occurrence of acute ischemic syndromes and their complications. Higher environmental temperatures appear to reduce the risk of the occurrence and severity of cardiovascular events  induces structural and biochemical changes in the rat heart. These changes are related to the improved systolic and diastolic function and the increased metabolic efficiency observed in heat-acclimated hearts during normoperfusion  during coronary artery bypass surgery imposes severe myocardial ischemia followed by reperfusion. Both ischemia and reperfusion are known causes of diastolic dysfunction. For example, an intraoperative study using transesophageal echocardiography has shown an increase in diastolic chamber stiffness immediately after coronary artery bypass surgery reflecting worsening diastolic dysfunction  to 700 m elevation. To focus on the effects of CPB and coronary revascularization on diastolic function in a clinically homogenous group we excluded patients for the presence of more than mild (grade 1) mitral or aortic regurgitation, any valvular disease requiring valve replacement, echocardiographic evidence of left-ventricular (LV) hypertrophy, and a significantly reduced LV ejection fraction (less than 45%). Eligible patients were divided into two groups: heat acclimatized (study) group and non-acclimatized (control) group.Eight patients were prospectively and consecutively included in the acclimatized study group as they agreed to leave their home and spend 2 to 3 weeks on the Dead-Sea seashore  immediately prior to operation. On location they were accommodated in caravans, devoid of air-conditioning, at an ambient temperature (day-night range) of 17–33°C. These patients exercised twice a day as a group under the supervision of a certified physiotherapist and a physician. An individual training program was developed for each patient. To assess training levels, maximal workload capacity of each patient was determined by a modified “sprint” test  of 6–19°C. These patients' daily routine was not changed by any means prior to operation.Preparation of patients for open-heart surgery, including endotracheal intubation and general anesthesia was carried out using standard methods. The transesophageal probe was placed after the patient was fully anesthetized. At the time of aortic and venous cannulations, a left atrial line was also placed. While the patient was in steady state, a baseline echocardiogram  was recorded simultaneously with mean left atrial pressure (LAP) measurement. Subsequently, 500 to 1,000 cc of fluid was administered as a fast intravascular bolus over 5 to 10 min; this consisted of crystalloid solution (Standard bypass solution: PlasmaLite® with 2% mannitol). The infusion was continued until the LAP was increased by, at least, 5 mmHg over baseline. Echocardiogram acquisition simultaneous with LAP measurement was continuously recorded until fluid administration ceased. Thereafter, surgical routines were continued uninterrupted throughout the bypass period.After discontinuation of CPB but before decannulation, while the patient has been fully warmed-up and has re-achieved steady state , a new baseline echocardiogram was recorded simultaneously with mean LAP measurement. Subsequently, 500 to 1,000 cc of fluid was administered as a fast intravascular bolus over 5 to 10 min; this was likely to consist of whole blood and/or plasma but may have been supplemented by crystalloid solution (Standard bypass solution: PlasmaLite® with 2% mannitol and/or Hemacel). This infusion was continued until the LAP was increased by, at least, 5 mmHg over the new baseline. Echocardiogram acquisition simultaneous with LAP measurement was continuously recorded during volume load. Thereafter, surgical routines were continued as usual for decannulation and closure of chest wall. It is important to note that extreme care was taken to assure that the transesophageal echocardiography probe was kept at precisely the same place between the two echograms.Off-line echocardiographic analysis was performed with the interpreter being blinded to the group a particular patient belonged to. End-diastolic frames of the LV short axis view were identified. The LV area was traced at end-diastole and related to the corresponding LAP. Traced LV areas of 4 to 7 consecutive cardiac cycles were averaged for each increment of LAP to account for respiratory variations in LV size. LAP measurements were plotted against corresponding mean LV area to generate diastolic pressure-area curves from data obtained before and after CPB, one pair of curves for each patient. To assess changes in LV diastolic properties, LV area was compared at similar left atrial pressures (within 1 mmHg) for the range of LAP changes with volume loading. Thus, for a given LAP, a smaller LV area implies a leftward shift of the LV pressure-volume relationship while a larger LV area suggests a rightward shift of the pressure-volume curve.P-value of less than 0.05 was considered statistically significant.In view of the relatively small sample size of both the intervention and control groups of patients, data was expressed as median values and their ranges and non-parametric tests were used for statistical calculations. The Mann-Whitney rank-sum test was used to compare variables between the groups. Proportions were compared by Fisher exact test. The Wilcoxon signed-rank test was utilized in comparing pre- and post-bypass data, with each patient serving as his own control. A Patient characteristics are presented in Table 2).There was no significant difference in baseline LV end-diastolic area (LVA) between the study and the control groups, both before and after volume loading. The ratio of the difference in LAP to the difference in LVA before and after fluid loading is strongly related to the “slope” of the LV pressure-volume curve. This ratio was virtually identical in both the study and control groups, suggesting no difference in baseline (pre-CPB) diastolic function of acclimatized vs. non-acclimatized patients . After fluid loading, at mean left atrial pressure 11.9 mmHg, there was a 1.7 ± 0.6 cm2 decrease in LVA (p = 0.02). Thus, a distinct leftward shift of the diastolic pressure-area curve was noted in non-acclimatized patients (Figure Left ventricular area decreased after CPB in all control patients at comparable preloads. Before fluid loading, at mean left atrial pressure 6.5 mmHg, there was a 1.8 ± 0.3 cmHowever, in patients who underwent heat acclimatization, no change in left ventricular area measured at comparable preloads before and after CPB was noted. Both before and after fluid loading, at mean left atrial pressures of 5 and 10.3 mmHg, respectively, mean left ventricular area pre-bypass was similar to left ventricular area post-bypass. Thus, a virtual overlap of the pre- and post-CPB diastolic pressure-area curves was noted Figure .This study was the first clinical research, which exploited environmental stressor to improve human function/health by establishing controlled clinical setting, using a model of ischemia and reperfusion during coronary artery bypass surgery. We showed that patients undergoing “heat acclimatization combined with exercise training” were less susceptible to ischemic injury, therefore expressing less diastolic dysfunction after CPB compared to non-acclimatized patients. The relative contributions of heat vs. exercise were not studied. However, based on contemporary knowledge, this issue will be discussed. CPB imposes a multi-factorial burden on the myocardium resulting, among other things, in diastolic dysfunction. McKenney et al.  have shoWithout exception, there was a decrease in LV distensibility in each of our control patients immediately after CPB. This is in complete accordance with the previous work cited (McKenney et al., 2 consumption (Horowitz et al., per se on the recovery of diastolic function (Levi et al., 2+ sensitivity, thus the heart is less susceptible to Ca2+ overload (Kodesh et al., 2+ sensitivity, increasing contractile strength and efficiency (Tetievsky et al., Environmental factors can influence the structure and physiological characteristics of the myocardium as well as its ability to withstand ischemia and reperfusion. In animal experiments, heat acclimation with/without exercise proved to have a significant cardioprotection and to enhance recovery from ischemia/reperfusion insults. The beneficial effects were manifested by an improved chamber compliance (Horowitz et al., per se enhances cardiovascular compliance, leading to improved exercise capacity and diastolic function in the ischemic heart.Recently, heat acclimation induced cross tolerance was “navigated” to thermotherapy of vascular diseases. Brunt et al. ,b showedOur recent studies shows that heat acclimation involves epigenetic control of gene expression (Tetievsky and Horowitz, The cross-tolerance between heat acclimation and ischemic injury appears to be a long-lasting effect, for at least 2 to 3 weeks (Cohen O, PhD Thesis, The HU; Eynan M, PhD Thesis, The HU; Horowitz M, personal communication and Arieli et al., Increasing number of studies emphasize the role of exercise training in cardioprotection. However, the knowledge of the impact of exercise training on ventricular diastolic function/dysfunction is rather limited and controversial. Bhella et al.  demonstrper se mitigates diastolic dysfunction following ischemia-reperfusion. This group would be less susceptible to ischemic injury not only because of changes in elasticity, which likely impact on diastolic dysfunction after CPB compared to non-acclimatized patients, but also because of better energy state and large reserves of cytoprotective proteins.We thus postulated that in our patients undergoing “heat acclimatization combined with exercise training” the heat exposure per se is a major contributor to the results obtained.A major limitation of this study is that the control group was assigned to “non-committed" to exercise group, which does not allow unequivocal conclusion regarding the relative contributions of heat and endurance exercise to protect post operation diastolic function. However, the low level of exercise in the acclimatized group, together with recent findings on the impact of sedentary thermotherapy support our conclusion that heat exposure A point of note is the question of whether the slight hyperbaric pressure in the Dead Sea has an impact on cardiac stiffness. Abinader et al. , in a piThis work is too small to assess the importance of heat acclimatization on morbidity/mortality after coronary artery bypass surgery. The extension of the deleterious effect of bypass into the post-operative period supports the assumption that enhancement of diastolic function immediately after bypass may eventually prove to be beneficial to improve operative results.This investigation is the first clinical study supporting the experimental evidence for a protective effect of heat acclimatization combined with modest exercise training against diastolic dysfunction imposed by ischemic/reperfusion insults. Although this study could not distinguish the relative contribution of each factor on the gained benefit, we believe that this effect is real and chronic heat exposure plays a major role in it. Further clinical studies are justified to expand on this preliminary data and evaluate the longevity of this effect as well as its relevance to the clinical outcome of patients undergoing coronary artery bypass surgery.This study was carried out in accordance with the recommendations of Hadassah committee for Human's experimentation with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The study was approved by the Institutional Review Board for human's experimentation of Hadassah University Hospital, Jerusalem, Israel.AP: Ecocardiology, interpretation of the results, drafter the paper and the Figures; GM: coronary by-pass surgery; MH: conception of the study, Interpretation of the results in light of the current knowledge of the topic, drafted the paper; MS: Organization of exercise and physiotherapy; DG: Ecocardiology; YH: Conception of the study, Interpretation of the results.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


BACKGROUND. Failed myocardial reperfusion is common and prognostically important after acute ST-elevation myocardial infarction (STEMI). The purpose of this study was to investigate coronary flow reserve (CFR), a measure of vasodilator capacity, and the index of microvascular resistance  in the culprit artery of STEMI survivors.METHODS. IMR (n = 288) and CFR  were measured acutely using guide wire–based thermodilution. Cardiac MRI disclosed left ventricular pathology, function, and volumes at 2 days (n = 281) and 6 months after STEMI (n = 264). All-cause death or first heart failure hospitalization was independently adjudicated (median follow-up 845 days).RESULTS. Myocardial hemorrhage and microvascular obstruction occurred in 89 (42%) and 114 (54%) patients with evaluable T2*-MRI maps. IMR and CFR were associated with microvascular pathology  , whereas thrombolysis in myocardial infarction blush grade was not. IMR was a multivariable associate of changes in left ventricular end-diastolic volume , whereas CFR was not (P = 0.160). IMR (5 units) was a multivariable associate of all-cause death or heart failure hospitalization , whereas CFR (P = 0.124) and thrombolysis in myocardial infarction blush grade (P = 0.613) were not. IMR had similar prognostic value for these outcomes as <50% ST-segment resolution on the ECG.CONCLUSIONS. IMR is more closely associated with microvascular pathology, left ventricular remodeling, and health outcomes than the angiogram or CFR.TRIAL REGISTRATION. NCT02072850.FUNDING. A British Heart Foundation Project Grant (PG/11/2/28474), the National Health Service, the Chief Scientist Office, a Scottish Funding Council Senior Fellowship, a British Heart Foundation Intermediate Fellowship (FS/12/62/29889), and a nonfinancial research agreement with Siemens Healthcare. The index of microvascular resistance correlates with microvascular pathology and is a diagnostic test of myocardial reperfusion in patients with acute ST-elevation myocardial infarction. Acute ST-elevation myocardial infarction (STEMI) is a major cause of premature death and heart failure acutely and in the longer term , 2. PrimThe improved early survival rates following acute STEMI in the past decade have been associated with a persistently high incidence of heart failure in the long term . One expCardiac MRI is the reference diagnostic test for detection of microvascular pathology; however, MRI is not routinely performed in clinical practice , 3. The Coronary guide wire–based sensor technologies have emerged as new diagnostic tools for the invasive management of coronary artery disease . CoronarThe comparative pathophysiological and prognostic significance of IMR and CFR in patients with acute STEMI is incompletely understood –24. SincWe aimed to measure IMR and CFR in the culprit coronary artery immediately after emergency PCI in a large, relatively unselected population of patients with acute STEMI enrolled during daily practice. The specific aims were to assess (a) the feasibility of routine guide wire–based assessments of microvascular function during routine care; (b) the relationships of IMR and CFR with infarct pathologies, including myocardial hemorrhage and microvascular obstruction, revealed by cardiac MRI; (c) the relationships of IMR and CFR with circulating concentrations of IL-6; and (d) the prognostic relationships of IMR and CFR with prespecified LV surrogate outcomes, as revealed by MRI and N-terminal pro b-type natriuretic peptide (NT-proBNP) concentration at 6 months and all-cause death and heart failure hospitalization and major adverse cardiac events (MACE) in the longer term.We hypothesized that (a) CFR would be more closely associated with microvascular obstruction, a potentially reversible pathology, whereas IMR would be more closely associated with irreversible microvascular damage, as revealed by myocardial hemorrhage; (b) IMR and CFR would be more closely associated with microvascular pathology, as revealed by MRI, than established measures of failed myocardial reperfusion, including the duration of ischaemia, the persistent ST-segment elevation on the surface ECG, and angiographic parameters; and (c) IMR has greatest prognostic significance based on its association with irreversible vascular damage, surrogate outcomes, and all-cause death and heart failure.P value of greater than 0.05 indicates the absence of evidence for a statistically significant effect.Categorical variables are expressed as number and percentage of patients. Most continuous variables followed a normal distribution and are therefore presented as means together with SD. Those variables that did not follow a normal distribution are presented as medians with interquartile range (IQR). Differences between independent groups were assessed using 1-way ANOVA, Kruskal-Wallis tests, or Fisher’s tests where appropriate. Univariable and multivariable logistic regression analyses were performed to identify predictors of intramyocardial hemorrhage and microvascular obstruction. Models were compared using Harrel’s C-statistic. Kaplan-Meier and Cox proportional hazards methods were used to identify potential predictors of (a) all-cause death and heart failure events and (b) MACE. The assumption of proportional hazards was assessed using Schoenfield residuals. All statistical analyses were carried out using R v 2.15.1 or later. A 10.1172/jci.insight.85768DS1) and CFR , a reduced CFR (a CFR < median), or both occurred in 136 (48%), 205 (72%), and 107 (38%) patients, respectively.The MRI findings are described in 213 (97%) patients had T2*-MRI maps and IMR and CFR measurements . MyocardP < 0.001) (P < 0.001) than with microvascular obstruction ; P < 0.001).IMR was higher in patients with myocardial hemorrhage  than in patients without myocardial hemorrhage , including those patients that had microvascular obstruction in the absence of myocardial hemorrhage  . IMR wasThe optimal cut-offs for IMR in predicting myocardial hemorrhage and microvascular obstruction are summarized in P < 0.001)  compared with patients without myocardial hemorrhage (1.7 [1.4–2.5]), including the subset of patients that had microvascular obstruction in the absence of myocardial hemorrhage (1.5 [1.1–1.8]) (< 0.001) .Seventy-eight (28%) patients had persistent ST-segment elevation defined as <50% resolution from the prereperfusion ECG 60 minutes after reperfusion. Of these patients, myocardial hemorrhage occurred in 38  and microvascular obstruction occurred in 54 .Forty (14%) patients had persistent ST-segment elevation defined as <30% resolution from the prereperfusion ECG 60 minutes after reperfusion. Of these patients, myocardial hemorrhage occurred in 17  and microvascular obstruction occurred in 26 .IMR  and 5 anBlood samples had been collected in the subset of STEMI patients who had been enrolled during office hours. IL-6, which is an immune cytokine that reflects endothelial activation, was measured in 121 and 151 patients 1 day and 6 months after STEMI, respectively. The clinical characteristics of these patients, and the associations with IMR and CFR, were similar to those of the main study population .P = 0.008). IMR was associated with log IL-6 at baseline .IMR was positively associated with IL-6. The IMR values in groups of patients categorized by tertiles of IL-6 concentration at baseline were 19  versus 23  versus 30  (P = 0.028). CFR was not associated with log IL-6 at baseline or the within-subject change in IL-6 (data not shown).CFR measured acutely was inversely associated with IL-6 concentration on day 1. The CFR values in groups of patients categorized by tertiles of IL-6 (<5.4 pg/ml vs. 5.4 to ≤8.9 pg/ml vs. >8.9 pg/ml) were 1.6  versus 1.5  versus 1.2 , respectively (n = 41), IMR was associated with the natural log of IL-6 concentration at baseline  and the within-subject change in log IL-6 at 6 months from baseline (n = 25) , whereas no associations were observed in patients without myocardial hemorrhage (n = 59), including in the subgroup of patients (n = 9) with microvascular obstruction.In order to investigate the relationships between IMR and IL-6 and the severity of microvascular pathology, as revealed by cardiac MRI, patients were categorized for the occurrence of microvascular obstruction or myocardial hemorrhage. In patients with myocardial hemorrhage (P = 0.004), independent of LV end-diastolic volume at baseline (P = 0.006), whereas CFR was not (P = 0.726).NT-proBNP results were available in 121 patients at baseline (index admission) and 152 patients at 6-month follow-up. IMR was associated with NT-proBNP at baseline .Both IMR and CFR were associated with NT-proBNP at 6 months after adjustment for LV ejection fraction and LV end-diastolic volume at baseline .IMR was a multivariable associate of changes in LV end-diastolic volume from baseline after adjustment for initial LV end-diastolic volume and clinical characteristics  had long-term follow-up data completed. The median duration of follow-up was of 845 days . Thirty (11%) patients died or experienced a first heart failure event during the index hospitalization or after discharge. These events included 5 cardiovascular deaths, 3 noncardiovascular deaths, and 22 episodes of heart failure (Killip class 3 or 4 heart failure [n = 20] or cardiac device implantation [n = 2 received a defibrillator]). Thirteen (4.5%) patients died or experienced a first heart failure hospitalization after discharge, and 8 (61.5%) of these patients had an elevated IMR at baseline.All patients (P < 0.001) and multivariable  associate of all-cause death or heart failure hospitalization (P < 0.001). An IMR >40 was associated with all-cause death or heart failure . CFR was not a univariable associate of all-cause death or heart failure hospitalization .IMR (per 5-unit difference) was a univariable  and multivariable  associate of MACE, whereas CFR was not (Forty (14%) patients died or experienced a MACE during the index hospitalization or after discharge. IMR (per 5-unit difference) was a univariable  IMR and CFR can be routinely measured in the culprit coronary artery at the end of emergency PCI; (b) IMR and CFR were both associated with microvascular obstruction and myocardial hemorrhage; (c) compared with IMR, CFR was discriminative of microvascular obstruction in patients with less severe myocardial injury, as reflected by the absence of myocardial hemorrhage, whereas IMR was not discriminative in this group ; (d) comIn line with our hypotheses, IMR and CFR measured in the culprit artery at the end of PCI were multivariable associates of microvascular pathology; however, differences between IMR and CFR were also observed. CFR was discriminative of microvascular function in patients with less severe vascular injury , whereasThe threshold for IMR and outcome has varied between studies , 28, 29.The 12-lead surface ECG 60 to 90 minutes after reperfusion is the standard of care diagnostic test for assessing the efficacy of coronary reperfusion . The diaTIMI coronary flow grades before but not after PCI were associated with IMR  and micrOverall, IMR was more closely associated with severe irreversible infarct pathology, i.e., myocardial hemorrhage and subsequent adverse LV and clinical outcomes, than other tests of myocardial reperfusion. In clinical practice involving patients with acute STEMI, microvascular obstruction and myocardial hemorrhage routinely pass undetected, despite having proven prognostic value. We think that IMR has potential to address this disparity in diagnosis. The high negative predictive value of an IMR >27 for myocardial hemorrhage points to its potential value as an early rule-out test for failed myocardial reperfusion. On the other hand, we do not propose IMR as an alternative for CMR, which is performed subsequently downstream in the care pathway as a test for LV function, pathology, and viability , 3.In STEMI patients with less severe vascular injury, as revealed by the absence of myocardial hemorrhage, CFR was associated with microvascular obstruction, which is a potentially reversible pathology , 31. Thin = 27–45)  , 33, 34 = 27–45) , 33, 34.Cuculi et al. recently reported that CFR and IMR are modifiable . They foThe study population included 21 patients initially treated with thrombolysis, and 14 of these patients had rescue PCI. The main results of our study were unchanged when these patients were removed (data not shown), and myocardial hemorrhage was similar in patients treated by primary PCI versus thrombolysis. We conclude that guide wire–based assessment of coronary microvascular function is of diagnostic value in patients treated with thrombolysis.n = 281 with both CFR and IMR); however, evaluable T2*maps were not evaluable in all of these subjects due to cardiorespiratory motion and breath-holding problems in acutely ill patients. Enrollment in our study took place 24/7; however, blood sample handling for NT-proBNP and IL-6 was not feasible outside of collection hours. The clinical characteristics of the patients in whom blood samples were obtained were similar to the whole population .We performed a single-center natural history study involving prospective enrollment of patients with acute STEMI. We did not enroll consecutive patients . CoronarThe limited number of adverse events constrained the number of variables and statistical power in the Cox models. Our study builds on previous investigations in smaller patient cohorts. Although our study does not include a validation cohort, the prognostic importance of IMR is consistent with previous studies involving IMR in STEMI patients . Our anaOur results support the feasibility and pathophysiological validity of IMR, over CFR and the ECG, as a routine diagnostic test for failed myocardial reperfusion in patients with acute STEMI. Routine measurement of IMR has potential clinical utility for immediate stratification of patients with acute STEMI following coronary reperfusion, and further research is warranted.2. Acute STEMI management followed contemporary guidelines  for measurement of IL-6 and NT-proBNP, a biochemical measure of LV wall stress. Patients were eligible if they had an indication for primary PCI or thrombolysis for acute STEMI due to a history of symptoms consistent with acute myocardial ischemia and with supporting changes on the ECG   was used to measure IMR and CFR in the culprit coronary artery at the end of primary or rescue PCI. The guide wire was calibrated outside the body, equalized with aortic pressure at the ostium of the guide catheter, and then advanced to the distal third of the culprit artery. CFR is defined as the mean transit time at rest divided by the mean transit time during hyperemia. IMR is defined as the distal coronary pressure multiplied by the mean transit time of 3 sequential manual bolus injections of saline (3 ml) at room temperature during maximal coronary hyperemia, measured simultaneously (mmHg × s or units) , 28, 33.P < 0.001), with a mean difference between IMR measurements of 0.01   .MRI was performed on a Siemens MAGNETOM Avanto 1.5-Tesla scanner with a 12-element phased array cardiac surface coil . The imaT2 maps were acquired in contiguous short-axis slices covering the whole ventricle, using an investigational prototype T2-prepared TrueFisp sequence , 38 Sup. The hypMyocardial hemorrhage was detected using an investigational prototype T2* map sequence acquired in 3 short-axis slices . Typical imaging parameters were as follows: bandwidth, approximately 814 (×8) Hz/pixel; flip angle, 18°; matrix, 256 × 115; spatial resolution, 2.6 × 1.6 × 10 mm; and slice thickness, 8 mm. This method became available for use after 25 patients had been enrolled.2+-DOTA, Dotarem, Guerbet S.A.) using segmented phase-sensitive inversion recovery turbo fast low-angle shot sequence .Early gadolinium enhancement (EGE) imaging was acquired 1, 3, 5, and 7 minutes after contrast injection using a TrueFISP readout and a fixed inversion time of 440 ms. Late gadolinium enhancement images covering the entire LV were acquired 10 to 15 minutes after i.v. injection of 0.15 mmol/kg of gadoterate meglumine . All of the images were reviewed by an experienced MRI cardiologist (C. Berry). LV dimensions, volumes, and ejection fractions were quantified using computer-assisted planimetry . The late gadolinium enhancement images were analyzed for infarct size and microvascular obstruction by observers  who were blinded to all of the other data. In healthy volunteers, the absence of late gadolinium enhancement was determined qualitatively by visual assessment.In STEMI patients, myocardial T2/T2* values were segmented spatially and regions of interest were defined as (a) remote myocardium, (b) injured myocardium, and (c) infarct core. The regions of interest were planimetered to include the entire area of interest, with distinct margins of separation from tissue interfaces to avoid partial volume averaging. The remote myocardium region of interest was defined as myocardium 180° from the affected zone with no visible evidence of infarction, edema, or wall motion abnormalities . The infarct zone region of interest was defined as myocardium with pixel values (T2) >2 SD from remote myocardium on T2-weighted MRI , 38. TheThe presence of acute infarction was established based on abnormalities in cine wall motion, rest first-pass myocardial perfusion, and delayed-enhancement imaging in two imaging planes. In addition, supporting changes on the ECG and coronary angiogram were also required. Acute infarction was considered present only if late gadolinium enhancement was confirmed on both the axial and long-axis acquisitions. The myocardial mass of late gadolinium (grams) was quantified using computer-assisted planimetry, and the territory of infarction was delineated using a signal intensity threshold of >5 SDs above a remote reference region and expressed as a percentage of total LV mass . InfarctMicrovascular obstruction was defined as a dark zone on EGE imaging 1, 3, 5, and 7 minutes after contrast injection that remained present within an area of large gadolinium enhancement at 15 minutes. Identification of microvascular obstruction was performed independently by I. Mordi and N. Ahmed.The extent of myocardial edema representing the jeopardized area at risk was defined as LV myocardium with pixel values (T2) >2 SDs from remote myocardium , 41–44. On the T2* maps, a region of reduced signal intensity within the infarcted area with a T2* value of <20 ms –48 was cA 12-lead ECG was obtained before coronary reperfusion and 60 minutes afterwards. The extent of ST-segment resolution on the ECG assessed 60 minutes after reperfusion compared to the baseline ECG before reperfusion  was exprSerial systemic blood samples were obtained immediately after reperfusion in the cardiac catheterization laboratory and subsequently on the first day (0600–0700 hours) during the initial in-patient stay in the Coronary Care Unit.CRP was measured in an NHS hospital biochemistry laboratory using a particle-enhanced immunoturbimetric assay method Cobas C501, Roche) and the manufacturer’s calibrators and quality control material, as a biochemical measure of inflammation. The high-sensitivity CRP assay measurement range was 0.1–250 mg/l. The expected CRP values in a healthy adult are <5 mg/l, and the reference range in our hospital is 0–10 mg/l. IL-6 was measured using a high-sensitivity ELISA (R&D Systems)  for the reliability of CFR and IMR values measured independently by 2 observers in 12 randomly selected patients from the cohort. In addition, ICC was measured for the reliability of infarct core T2* values measured independently by 2 observers in 20 randomly selected patients from the cohort.Categorical variables are expressed as number and percentage of patients. Most continuous variables followed a normal distribution and are therefore presented as means together with SD. Those variables that did not follow a normal distribution are presented as medians with IQR. Differences in continuous variables between groups were assessed by 2-tailed Student’s Univariable and multivariable linear regression methods to identify associates of CFR and IMR values for infarct pathology revealed by MRI  and circulating cytokines  are described in the Receiver operating curve, Kaplan-Meier, and Cox proportional hazards methods were used to identify potential clinical predictors of all-cause death/heart failure events, including patient characteristics, MRI findings, and IMR/CFR.P values were 2 sided, and P > 0.05 indicates the absence of a statistically significant effect. Statistical analyses were performed using R v 2.15.1 or SAS v 9.3 or higher versions of these programs.All The study was approved by the UK National Research Ethics Service (reference 10-S0703-28). All of the participants provided witnessed informed assent at the time of the acute procedure followed by written informed consent on the ward.DC coordinated the study, obtained informed consent from all of the participants, and coordinated and analyzed the MRI scans. He collected the clinical data, participated in the statistical analyses, interpreted the results, and drafted the manuscript. MM, MCP, HE, ML, SW, and SH obtained informed assent, collected data, interpreted the results, and contributed to the manuscript. CH and IF contributed to study design, analyzed and interpreted the data, and contributed to the manuscript. AM assessed the source data for serious adverse events during follow-up that were potentially relevant to the prespecified health outcomes. IM, NA, SMOR, and AR contributed to the analysis of the MRI scans in STEMI patients and in healthy volunteers and contributed to the manuscript. PM analyzed the ECGs. JC and VTYM undertook quantitative coronary analysis of the angiograms. PW and NS undertook the analysis of blood samples for NT-proBNP and IL-6 and contributed to the manuscript. KGO helped to conceive the idea for the study, collected data, interpreted the results, and contributed to the manuscript. CB is PI for the British Heart Foundation project grant and chief investigator for the clinical study. CB conceived the idea for the study and obtained the funding and IRB approvals. He participated in patient recruitment, collected clinical data, interpreted the results, and jointly wrote the manuscript. CB takes responsibility for the manuscript.


We compared heart deformation analysis (HDA) of SSFP images and cine Displacement Encoding with Stimulated Echoes (DENSE) for the assessment of global and segmental circumferential strain (Ecc) and derivative indices in healthy volunteers and heart failure (HF) patients with left bundle branch block (LBBB).Post-processing methods have been developed to quantify myocardial strain from steady-state free-precession (SSFP) cine images. In the left ventricle (LV), global strain measurements from SSFP in healthy volunteers3,4. The mean and standard deviation of global Ecc were compared and the correlation between HDA and cine DENSE was assessed. The circumferential uniformity ratio estimate computed with singular value decomposition (CURE-SVD) is a quantitative index of mechanical dyssynchrony based on segmental Ecc, where values near 1 indicate synchrony and lower values indicate dyssynchrony5. CURE-SVD was computed for all subjects using HDA and DENSEImaging was performed on a 1.5T Siemens Avanto MR system in 3 short-axis planes in 6 volunteers and 29 patients with HF-LBBB. Ecc was computed from SSFP images using HDA  and from cine DENSE using previously described methods2 = 0.29, p = 0.002) than HDA , Fig. Fig. HDA and cine DENSE show good agreement for global Ecc. For regional Ecc, HDA shows greater variability including apparent false-positive segmental dysfunction in some volunteers. While HDA measurements of dyssynchrony can discriminate HF-LBBB from healthy volunteers (p < 0.01), it underestimates the degree of synchrony in volunteers and the degree of dyssynchrony in patients compared to cine DENSE. CURE-SVD by cine DENSE has a better correlation to LV remodeling compared to HDA.


Impairment of left ventricular (LV) longitudinal function has an important role in hypertrophic cardiomyopathy (HCM). This research investigated an association between the longitudinal strain of different myocardial layers, longitudinal rotation and the LV systolic function of HCM patients.The research was performed on 36 HCM patients and 36 healthy subjects. The peak systolic longitudinal strain of the subendocardial, midmyocardial, and subepicardial layers was measured using 2-dimensional speckle tracking echocardiography (2D–STE). The apical long-axis and 4- and 2- chamber views were acquired via 2D Doppler echocardiography. The curve of the longitudinal rotation was traced at 17 timepoints in the analysis of 2 cardiac cycles.Compared with healthy subjects, in HCM patients regional LV peak systolic longitudinal strain was less, not only in hypertrophied LV myocardium, but also in non-hypertrophied myocardium. The rotational degrees of the midmyocardial-septal, apex, and lateral wall of HCM patients were significantly different from that of normal subjects, as follows. In HCM patients, clockwise longitudinal rotation was found. The interventricular septum thickness at end-diastole positively correlated with the peak longitudinal systolic strain of the subendocardial, the midmyocardial, and the subepicardial layers. The area under ROC curve values for subendocardial, midmyocardial and subepicardial layers in HCM patients were 0.923, 0.938, 0.948.In HCM patients, the longitudinal function was damaged, even with normal LV ejection fraction. The peak longitudinal systolic strain of the subendocardial, midmyocardial, and subepicardial layers, and the longitudinal rotation detected by 2D–STE, are very sensitive predictors of systolic function in patients with HCM. Hypertrophic cardiomyopathy (HCM) is a common clinical heart disease. It is a genetic disorder of the myocardium caused by mutations in cardiac sarcomeric proteins, with asymmetric hypertrophy of the left ventricle, right ventricle, or both –3. The iWith the development of various imaging techniques, especially echocardiography, the discovery and diagnosis of HCM by conventional 2-dimensional ultrasound is becoming more easy and convenient. While the LV ejection fraction (LVEF) can sometimes reflect the systolic function of the left ventricle, it is not reliable, as the LVEF of most HCM patients is normal. Tissue Doppler imaging detects velocity and strain and is one of the most used echocardiography methods , 10, butTo evaluate the changes in LV longitudinal systolic function in HCM patients, the following are innovations of the present study: The anatomy of normal myocardium consists of subendocardial, middle wall and subepicardial myocardial fibers, Using multilayer strain to analysis the LV function is a new method, so the first aim is to measure the peak systolic longitudinal strain of the subendocardial, midmyocardial, and subepicardial layers in patients with HCM; Longitudinal rotation as a new marker has received little attention. The LR means the rotational motion in the long axis of heart, but the origin of LR is still unclear, so the second aim is to Phase a hypothesis that there was longitudinal rotation of the cardiac in HCM patients, measure the longitudinal rotation in HCM patients; and tracing the curve of the LV longitudinal rotation motion in HCM patients by 2D–STE, and then to verify the hypothesis. Last to assess the changes in LV longitudinal systolic function in HCM patients.The Human Subjects Committee of Changzhou No. 2 People’s Hospital approved this study. Written informed consent was obtained from the each couple enrolled in the study.Thirty-six HCM patients and 36 age-and gender-matched healthy  subjects were enrolled. The diagnosis of HCM was based on the following M-mode and 2D echocardiographic evidence of wall thickness ≥ 15 mm in one or more LV myocardial segments and non-dilated left ventricle (LV). In addition to the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident in patients with HCM, such as the valve diseases valve stenosis, hypertensive heart diseases, and coronary heart disease. Apical HCM patients were excluded for the study. If the ECG showed LBBB, HCM patients were excluded for the study. All enrolled HCM patients were non-obstructive, based on the degree of LV outflow tract obstruction, there was no obstruction at rest or provocation (peak gradient <30 mmHg). All enrolled HCM patients were had septal wall hypertrophy and with/without other LV walls hypertrophy.The normal control subjects had no evidence or family history of HCM, hypertension, diabetes mellitus, or any other disease; all of the physical examination tests, the electrocardiogram, and the echocardiograph were normal. Recruitment to the study followed a full explanation of our methods, including that there was no risk of harm.All 36 HCM patients and 36 normal subjects underwent conventional 2D Doppler echocardiography . Left atrial diameter, interventricular septum thickness at end-diastole (IVSD), and LV posterior wall thickness in end-diastole (LVPWD) were measured in the parasternal long axis view of the LV by M-mode. Simpson’s biplane method was used to measure the LVEF. The peak early and late diastolic mitral annular velocities  were measured by pulsed-wave Doppler, and the ratio of early diastolic inflow-to-late diastolic flow at the mitral valve (Ve/Va) was calculated.In each group, ECG leads were connected to each individual. For offline analysis, the following were acquired: hold on the breath, standard high frame rate (60–90/s) of the apical long-axis, and 4 and 2-chamber views of 3 consecutive cycles.We analyzed the apical long-axis and 4- and 2- chamber views using 2D–STE software . Each of the LAX, A4C, and A2C options were used to sketch the LV subendocardial layer. The aortic valve closure time in the apical long-axis view was confirmed. The software then automatically created a region of interest (ROI) which contained the subendocardial, midmyocardial, and subepicardial layers. The ROI was adjusted to include the myocardial as well. In the ROI, the software divided the LV into 6 segments. The peak systolic longitudinal strain of the subendocardial, midmyocardial, and subepicardial layers were calculated.We defined longitudinal rotation as the global rotation of the LV cross section. The subendocardium layer was displayed by using the SAX-MV of the Echopac in the apical 4-chamber view. The software automatically created a ROI that included the subendocardial, midmyocardial, and subepicardial layers. The ROI was adjusted to include the subendocardial and subepicardial layers. The LV region was divided into five segments: base-septal, midmyocardial-septal, apex, midmyocardial-lateral and base-lateral. The segmental longitudinal rotation of the LV was assessed in the same view via 2D–STE.The longitudinal rotational degrees in the apical 4-chamber views were measured at 17 timepoints in the analysis of 2 cardiac cycles (each measured from onset-to-onset of the QRS wave): onset of QRS wave; mitral valve closure; mid-isovolumic contraction; aortic valve opening; 25%, 50%, and 75% of ejection phase; aortic valve closure; mid-isovolumic relaxation; mitral valve opening; peak early diastole and end of early diastole; onset, peak, and end of atrial filling; onset of the second QRS wave; and aortic valve opening of the second heart cycle –23.The time between mitral valve closure and aortic valve opening was considered the isovolumic contraction. The time from aortic valve opening to aortic valve closure was considered the ejection period. The time between aortic valve closure and mitral valve opening was defined as isovolumic relaxation. The time from mitral valve opening to mitral valve closure was the diastole period.P-value was less than 0.05. To determine normality, the distribution of the peak longitudinal systolic strain of the subendocardial, midmyocardial, and subepicardial layers in all subjects was assessed using the Kolmogorov-Smirnov’s test. If the data distribution was normal, differences between the HCM patients and normal subjects were compared with an independent Student’s t-test. For variables with a non-normal distribution, the nonparametric Mann-Whitney test was used. The correlation between the IVSD and the peak longitudinal systolic strain of the subendocardial, midmyocardial, and subepicardial layers was determined by Pearson’s correlation if the data distribution was normal. For variables with a non-normal distribution, Spearman’s correlation was chosen. We defined the peak longitudinal systolic strain values of different layers in control subjects as the normal state, and considered the values of HCM patients as abnormal. The values for measuring the peak longitudinal systolic strain of subendocardial, midmyocardial and subepicardial in HCM patients were determined from receiver operating characteristic (ROC) curve analysis. Yoden’s index was selected for the cut-off point which can give the best composite of specificity and sensitivity.All of the analysis was performed using SPSS 17.0 software . Data are presented as the mean ± standard deviation. Any difference was considered statistically significant in all tests when the P < 0.01; Table P > 0.05).There were significant differences in left atrial diameter, IVSD, LVPWD P < 0.0; Table 1The trend of the peak systolic longitudinal strain of the subendocardial, midmyocardial, and subepicardial layers in all the subjects was: subendocardial > midmyocardial > subepicardial Table , Fig. 1.The lateral wall rotated counter-clockwise, whereas the septum wall rotated clockwise in the normal subjects, the rotational degree was similar, whereas the direction was opposite Table , Fig. 2.The longitudinal rotation degrees in normal subjects was <3°, around the zero baseline for a small angle movement. In HCM patients, the clockwise longitudinal rotation was found Table , Fig. 3.r = 0.353, P = 0.035; midmyocardial, r = 0.407, P = 0.014; subepicardial, r = 0.444, P = 0.007;  than for the subendocardial and subepicardial layers (94.4% and 91.7%). Specificity was higher for peak longitudinal systolic strain of subepicardial layer (88.9%) than for the subendocardial and midmyocardial layers (80.6% and 83.3%). The cut-off values of the subendocardial, midmyocaidial and subepicardial were −19.43%, −16.33% and −15.33%.  than for the subendocardial and subepicardial layers (94.4% and 91.7%). Specificity was higher for the peak longitudinal systolic strain of the subepicardial layer (88.9%) than for the subendocardial and midmyocardial layers (80.6% and 83.3%). Cut-off values for the subendocardial, midmyocardial and subepicardial layers were −19.43%, −16.33% and −15.33%.HCM is a very common and important cardiac disease. LV hypertrophy, myocardial fibrosis, and fiber disarray in the LV myocardium has been reported as the major structural myocardial abnormalities in HCM patients , and sysSystolic function by conventional measurements, such as LVEF, cannot detect cardiac myocardium impairment; microscopic abnormalities result in intrinsic functional abnormalities . CardiacIn the present study, the peak systolic longitudinal strain of the subendocardial, midmyocardial, and subepicardial layers in both HCM and healthy individuals was: subendocardial > middle myocardial > subepicardial. A normal myocardium consists of the subendocardium, middle, and subepicardium fibers. Longitudinally oriented fibers of the subendocardium and subepicardium lead to longitudinal contraction, and middle wall fibers that are circumferentially oriented lead to circumferential shortening. Differences in contraction of the subepicardial and subendocardial layers lead to high subendocardial strain. The subendocardial region is responsible for most of the longitudinal deformation.The present result was consistent with previous studies , 21. By The different orientation of the ventricular muscle fibers led to the different motion of the heart. In the short-axis view, when viewed from the apex, the LV apex rotates counterclockwise, whereas the base rotates clockwise in systole period. However, when a normal heart is viewed from the long-axis view, the motion can be described as shortening of its long axis and thickening of its walls , 32.Longitudinal rotation, first discussed by Popovic et al. , refers In the HCM patients of the present study, the rotational motion of the septum, apex, and the lateral wall of LV also differed from that of the controls. Differences in the segmental and global longitudinal rotation were associated with the unique distribution of myocardium disarray in the HCM patients. The myocardial hypertrophy and fibrosis of these patients was probably responsible for the global and regional abnormalities of the LV myocardial mechanics. When the heart contracted, the abnormal balance of the various myocardial layers resulted in aberrant differences in rotational degrees and the direction of global longitudinal rotation. We also considered that neural and humoral regulation mechanisms may underlie the orientation of the longitudinal rotation. Further researches are necessary to confirm this hypothesis.In the present study, the IVSD of the HCM patients was found to correlate positively with the peak longitudinal systolic strain of the subendocardial, midmyocardial, and subepicardial layers; thickening of the IVSD in HCM patients was consistent with its systolic function. We therefore conclude that obvious thickening of the IVSD reflects impaired longitudinal systolic function.The ROC analysis for detecting the accuracy of the peak longitudinal systolic strain showed that the area under ROC curve values for subendocardial, midmyocardial and subepicardial layers were 0.923, 0.938, 0.948. The sensitivity was higher for peak longitudinal systolic strain of midmyocardial layer (97.2%) than for the subendocardial and subepicardial layers (94.4% and 91.7%). Specificity was higher for peak longitudinal systolic strain of subepicardial layer (88.9%) than for the subendocardial and midmyocardial layers (80.6% and 83.3%). From ROC analysis, we knew that using 2D–STE for detecting the peak longitudinal systolic strain of HCM is accurately. The results also showed that the LV function was impaired in HCM patients.Longitudinal function in HCM is damaged, despite normal LVEF. The changes of peak systolic longitudinal strain of the subendocardial, midmyocardial, and subepicardial layers, and the longitudinal rotation detected by 2D–STE can reflect the LV systolic dysfunction in HCM patients. In clinician, early detection of LV dysfunction in HCM patients can make us to understand the pathophysiology of HCM better, and it also can help the physician to have an earlier symptomatic treatment and then compare the efficacy of the different drugs. The peak longitudinal systolic strain of the subendocardial, midmyocardial, and subepicardial layers and the longitudinal rotation (detected by 2D–STE) are very sensitive determinants of systolic function in patients with HCM.The high standard deviations are indicative of the high variability with this technique - when narrow ROI is chosen to try and assess myocardial layers, higher strain values (more deformation) are recorded and more noise is introduced.