To study the correlations of circulating miR-26b level with left ventricular hypertrophy (LVH) and cardiac function in elderly patients with hypertension.A total of 132 eligible patients were divided into low and high miR-26b level groups. Their baseline clinical data and biochemical indices were compared. The correlations between miR-26b level and echocardiographic parameters were studied by Pearson’s analysis. Factors affecting LVH were explored by multivariate logistic regression analysis. The role of miR-26b in diagnosing LVH was predicted by receiver operating characteristic curve.The relative expression level of miR-26b was 4.56-16.93, with a median of 7.62. The two groups had similar baseline clinical data and biochemical indices (P>0.05). Compared with high miR-26b level group, interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular mass index (LVMI) and number of LVH cases in low miR-26b level group significantly increased (P<0.05), and mitral ratio of peak early to late diastolic filling velocity (E/A) decreased (P<0.05). Circulating miR-26b level was negatively correlated with IVST, LVPWT and LVMI (P<0.0001), and positively correlated with E/A (P<0.0001). The proportion of cardiac hypofunction cases in low miR-26b level group significantly exceeded that of high miR-26b level group (P<0.05). Age and increased IVST, LVPWT and LVMI were independent risk factors for LVH (P<0.05), and elevated miR-26b level was a protective factor (P<0.05). AUC was 0.836, and the optimal cutoff value was 8.83, with high sensitivity and specificity.MiR-26b level is negatively correlated with LVH and positively correlated with left ventricular diastolic function in elderly hypertensive patients. It is a protective factor for LVH complicated with diastolic dysfunction and a potential biomarker for diagnosis. As a common chronic disease bringing a serious economic burden, hypertension is mainly typified by the continuous rise of arterial blood pressure, and its long course changes the cardiac structure and function. The early manifestations of hypertension include left ventricular hypertrophy (LVH) and diastolic dysfunction. As the disease progresses, ventricular systolic dysfunction and enlargement of the heart cavity occur, eventually triggering heart failure.A total of 132 elderly patients with hypertension treated in our hospital from January 2017 to October 2019 were selected. They were aged 62-85 years old, including 80 males and 52 females. Hypertension was diagnosed based on the 2018 Chinese Guidelines for Prevention and Treatment of Hypertension1) Patients aged over 60 years old; 2) patients who met the above diagnostic criteria for hypertension; 3) patients with primary hypertension; 4) patients who did not take antihypertensive drugs; 5) patients who signed the informed consent and actively cooperated in this study.th 2017.1) Patients with primary aldosteronism, pheochromocytoma, renal hypertension or other secondary hypertension; 2) patients with congenital cardiac malformation; 3) patients complicated with heart diseases such as hypertrophic cardiomyopathy, valvular heart disease and systolic heart failure; 4) patients with some diseases or those who had taken drugs affecting the heart rate; 5) patients with smoking, drinking or diabetes history; 6) patients complicated with severe liver, spleen, lung, kidney or other systemic diseases; 7) patients with metabolic diseases or tumors; 8) patients who received valve replacement, coronary artery bypass grafting, pacemaker implantation or surgery in the past year. This study was reviewed and approved by the Medical Ethics Committee of our hospital on January 6The baseline clinical data of patients were collected, including gender, age, height and weight, and the body mass index (BMI) was calculated according to the following formula: BMI = weight (kg)/ [height (cm)]-ΔCt.The venous blood was collected using a disposable vacuum blood collection tube containing anticoagulant ethylenediaminetetraacetic acid 12 hour after fasting in the morning of the next day after admission. Then the venous blood was let still for 1-2 hour at normal temperature and centrifuged at 4°C to obtain the plasma that was transferred into a sterilized RNase-free tube. Subsequently, total RNA was extracted from the plasma by the TRIzol method and quantified using a spectrophotometer. Next, the 3’ end of miRNAs was treated with poly(A), and reverse transcription was carried out. Using the synthesized cDNA as the template, RT-PCR was performed by the SYBR Green I method. Primers for miR-26b: F: 5’-ACACTCCAGCTGGGTTTGGTCCCCTTCAAC-3’, R: 5’-GGTGTCGTGGAGTCGGCAATTCAGTTGAG-3’. Primers for U6: F: 5’-CTCGCTTCGGCAGCACA-3’, R: 5’-AACGCTTCACGAATTTGCGT-3’. The relative expression of miR-26b was calculated according to 2The venous blood was collected using a heparin sodium anticoagulation tube 12 hour after fasting in the morning of the next day after admission. Following centrifugation, the levels of fasting plasma glucose (FPG), total glyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr), creatine kinase (CK), creatine kinase-muscle/brain (CK-MB), lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hs-CRP), blood urea nitrogen (BUN) and uric acid (UA) were measured with Olympus AU400 automatic biochemical analyzer (Japan).2  and >110 g/m2  indicated LVH.Echocardiography was performed by the same ultrasonographer. According to the criteria recommended by the American Society of EchocardiographyThe patients were classified as per the standard formulated by NYH2 test. The quantitative data were represented as mean ± standard deviation, and intergroup comparisons were conducted by the independent t test. The correlations between miR-26b level and various echocardiographic parameters were studied by the Pearson’s analysis. Multivariate logistic regression analysis was carried out to explore the factors affecting LVH. The role of circulating miR-26b in diagnosing LVH was predicted by plotting the receiver operating characteristic (ROC) curve. P<0.05 was considered statistically significant.All data were statistically analyzed by SPSS 22.0 software. The numerical data were expressed as percentage [n (%)] and subjected to the χThe relative expression level of miR-26b in 132 patients was 4.56-16.93, with a median of 7.62, so patients with miR-26b levels of <7.62 and ≥7.62 were included into low and high miR-26b level groups, respectively. The two groups had similar baseline clinical data including gender, age, BMI, DBP and SBP as well as biochemical indices such as FPG, TG, TC, LDL-C, HDL-C, HbA1c, ALT, AST, Scr, CK, CK-MB, LDH, hs-CRP, BUN and UA (P>0.05) .Compared with high miR-26b level group, IVST, LVPWT, LVMI and number of LVH cases in low miR-26b level group significantly increased (P<0.05), and the E/A ratio significantly decreased (P<0.05). The two groups had similar LVEDD and LVEF (P>0.05) .The circulating miR-26b level was significantly negatively correlated with IVST, LVPWT and LVMI , and positively correlated with E/A  .The proportion of cardiac hypofunction cases in low miR-26b level group  was significantly exceeded that of high miR-26b level group  (P<0.05) .Age and increased IVST, LVPWT and LVMI were independent risk factors for LVH in elderly patients with hypertension (P<0.05), and elevated miR-26b level was a protective factor (P<0.05) .The area under ROC curve was 0.836, with 95%CI of 0.757~0.916 (P<0.05). The optimal cutoff value was 8.83, the sensitivity was 81.4% and the specificity was 78.9%. Therefore, miR-26b level had high diagnostic value for LVH in elderly patients with hypertension .LVH is one of the common complications of hypertension. Long-term hypertension can increase the left ventricular afterload of the heart and thus leads to this chronic adaptive change, i.e. the occurrence of LVH.As endogenous non-coding small-molecule RNAs that are highly conserved during biological evolution, miRNAs can regulate gene expression at the post-transcriptional level.Compared with high miR-26b level group, IVST, LVPWT, LVMI and number of LVH cases in low miR-26b level group significantly increased (P<0.05). IVST and LVPWT determine LVMI, and the left ventricular weight index can be directly used as an important clinical index to measure LVH. A high LVMI means more serious LVH.Multivariate analysis showed that age and increased IVST, LVPWT and LVMI were independent risk factors for LVH in elderly patients with hypertension (P<0.05), and elevated miR-26b level was a protective factor (P<0.05). With increasing age, the volume of myocardial cells increases, the heart collagen component and heart weight increase, long-term overload pressure and left ventricular adaptive reaction failure may easily lead to LVH.In summary, the circulating miR-26b level is negatively correlated with LVH and positively correlated with left ventricular diastolic function in elderly patients with hypertension. It is a protective factor for LVH complicated with diastolic dysfunction and a potential biomarker for the diagnosis of LVH in these patients.JF & ZXP Designed this study and significantly revised this manuscript.FL Drafted this manuscript.FL & CW Collected and analyzed clinical data.All authors agree to the submission and publication of this manuscript.


Analysis of subgroups defined by galectin-3 concentration and CRT response showed that patients with high baseline galectin-3 concentrations and a lack of response to CRT had a significantly lower probability of survival. In our patient cohort, the baseline galectin-3 concentration and RV function were independent predictors of long-term all-cause mortality in HFrEF patients following CRT implantation.Recently, associations between the biomarker galectin-3 and numerous pathological processes involved in heart failure (HF) and right ventricular (RV) function have been observed. We aimed to assess the long-term prognostic ability of galectin-3 and RV function parameters for all-cause mortality in HF patients treated with cardiac resynchronization therapy (CRT). We prospectively studied 63 symptomatic HF patients with a left ventricular (LV) ejection fraction (EF) ≤ 35%. The median serum galectin-3 concentration was 13.4 ng/mL . A detailed assessment of LV and RV geometry and function was performed with echocardiography. CRT defibrillator implantation was achieved in all patients without major complications. The follow-up lasted 5 years. In the multivariable Cox regression model, independent predictors for all-cause mortality were log baseline galectin-3 and baseline RV function expressed as tricuspid annular plane systolic excursion with HR 2.96 ( Therefore, there is a growing interest in biomarkers, both biochemical and imaging.Heart failure (HF) is a clinical syndrome with a high prevalence and remains one of the most challenging medical conditions. Moreover, HF is associated with high morbidity and mortality, reaching 50% at the 4-year follow-up, despite diagnostic and therapeutic efforts. Risk stratification remains difficult, even though numerous prognostic markers of death have been identified4. Galectin-3 is considered a “culprit” biomarker in HF, in contrast to “bystander” biomarkers such as N-terminal pro B-type natriuretic peptide (NT-pro BNP) or C reactive protein, as it stimulates pathological remodeling and the development of fibrosis, mainly by inducing fibroblast proliferation and collagen deposition5. Higher concentrations of Gal-3 have been found to be related to higher mortality in the general population and HF patients7.The biomarker galectin-3 , a lectin family member, is associated with numerous physiological and pathological processes in HF, including fibrogenesis, inflammation, and ventricular remodeling10. Excessive cardiac fibrosis and the presence of a myocardial scar were the likely causes of worse prognosis in patients with elevated Gal-3 concentrations. Right ventricular (RV) dysfunction, another potentially relevant mechanism, has been proven to be a prognostic factor among HF patients, including those treated with CRT12. Recently, some links between Gal-3 and RV function and pressure have been postulated. An association between Gal-3 and pulmonary artery hypertension was observed in experimental settings14. Furthermore, a few small studies have revealed the role of Gal-3 in RV remodeling and dysfunction induced by pulmonary arterial hypertension16. In our previous study in HFrEF patients, we found that Gal-3 was significantly negatively correlated with the echocardiographic parameter of long-axis RV function—tricuspid annular plane systolic excursion (TAPSE). Therefore, elevated Gal-3 concentrations in this population might indicate concomitant RV dysfunction17.Cardiac resynchronization therapy (CRT) has become a valuable, interventional therapeutic option for patients who, despite optimal medical therapy, have symptomatic HF with reduced ejection fraction (HFrEF). A few studies have shown data on the association between Gal-3 and adverse outcomes in CRT patientsIn the present study, we aimed to assess baseline Gal-3 and RV function parameters for the long-term prognosis of all-cause mortality in patients with HFrEF treated with a CRT defibrillator (CRT-D).Sixty-three symptomatic heart failure patients  in New York Heart Association (NYHA) class II or III, with a mean left ventricular (LV) EF of 25.6% (± 7.1%) and mean QRS duration of 156.8 ms (± 29.0 ms), were prospectively included. Seventy-three percent of them had ischemic cardiomyopathy. Five patients were upgraded from conventional RV apical pacing to biventricular pacing. The median serum Gal-3 concentration was 13.4 ng/mL (IQR 11.05–17.15 ng/mL).During the 5-year follow-up, 26 patients died. The median time from CRT-D implantation to death was 1.98 years . Four patients died within 6 months after CRT-D implantation. Table No significant differences were found in medical therapy, although nonsurvivors tended to be treated with oral anticoagulants more frequently than survivors.p-value of 0.022.Kaplan–Meier curves illustrate the cumulative survival of patients with low baseline concentrations of Gal-3 and those with high baseline concentrations of Gal-3 Fig. . Patientp = 0.007).In unadjusted Cox proportional hazards analysis, an increased hazard of death was found for the Gal-3 concentration .The association between baseline RV dysfunction, expressed by TAPSE under 17 mm, and long-term mortality was investigated. Kaplan–Meier curves illustrated the cumulative survival of patients with TAPSE under 17 mm and TAPSE equal to or over 17 mm Fig. . PatientSeparate analysis was performed to examine the association of Gal-3 with long-term mortality taking into account the response to CRT-D implantation. CRT response, defined as a decrease of more than 15% in baseline LV end-systolic volume (LVESV), was assessed for 59 patients 6 months after CRT-D implantation. In four patients, cardiovascular death occurred before this time. Thirty-two (51%) patients were considered responders. The rate of CRT-D responders was higher in the survivor group; the data are shown in Table p-value of 0.01, which means that at least one of the four groups had a significantly different mortality rate than the others. The most unfavorable outcome was shown for patients with high Gal-3 concentrations and a lack of response to CRT .The interaction between Gal-3 and the CRT response was tested in a Cox model with interaction. No significant interaction was found with an HR of 0.71 . RV function expressed as TAPSE was another independent predictor of long-term mortality, with an HR of 0.88 . In addition to log Gal-3 and TAPSE, the parameter of being a CRT responder was included in the model (model 1) of mortality prediction with an HR of 0.51 . After adjustment for age and sex (model 2), log Gal-3 and TAPSE remained significant independent predictors of all-cause mortality , an elevated Gal-3 concentration was a significant and independent predictor of nonfatal HF events or death8. However, in the CRT-D subgroup, an association of the Gal-3 concentration with outcome was absent8. Andre et al.10 confirmed the role of Gal-3 in predicting the response to CRT and long-term outcomes defined as death and hospitalization for a major adverse cardiovascular event (MACE) composite of hospitalization for HF, cardiogenic shock and sustained ventricular tachycardia. They also showed that Gal-3 serum concentrations equal to or greater than 22 ng/mL predicted survival after CRT implantation at the 48-month follow-up. However, they studied a particular patient population since only patients with typical left bundle branch block (LBBB) were included in the study. The response to CRT, defined as reversed remodeling expressed as a reduction in LV end-systolic volume, was found to be a strong predictor of reduced all-cause long-term mortality24. In our study group, the most unfavorable outcome was observed for CRT nonresponders with high Gal-3 concentrations. Interestingly, there was no significant difference between responders with low Gal-3 concentrations and nonresponders with low Gal-3 concentrations.Fibrosis and scar formation, which are maladaptive responses to injury or inflammation, are linked to disease progression and poor prognosis; therefore, they are relevant determinants of clinical outcome in HF26. This finding was also confirmed in some studies for HF patients treated with CRT12. Leong et al.11 found that baseline RV impairment, quantified by TAPSE as a highly feasible echocardiographic measure, was an independent predictor of all-cause mortality following CRT and conferred increased prognostic value over a broad range of clinical and echocardiographic parameters. In the cited study, RV dysfunction was observed in 34% of individuals. This is in concordance with our finding that TAPSE was an independent prognostic marker of long-term all-cause mortality. Echocardiographic diagnosis of RV function is complex and challenging. Therefore, various parameters have been used and examined for prognosis. Sade et al.12 demonstrated that preserved RV function—assessed by a novel echocardiographic application, speckle tracking strain—was an independent predictor of long-term event-free survival after CRT. In our study, RV dilatation, a decline in RV long-axis systolic function and RV strain impairment were observed in nonsurvivors at baseline echocardiographic examination. All the findings mentioned above are elements of a vicious circle in HFrEF when volume and pulmonary pressure overload lead to RV dysfunction development. Uncoupling of the right ventricle-pulmonary artery, expressed as significantly lower TAPSE/PASP ratios, was also found. Recently, the association between TAPSE/PASP and the established markers of prognosis NT-pro BNP and E/e´ ratio were found in patients undergoing CRT27.RV function was recognized as a significant prognostic marker in HFrEF patients in pathophysiological models of ischemia and dilated cardiomyopathy17.Thus, existing research has demonstrated the prognostic value of RV dysfunction for all-cause mortality. Importantly, it has yet to be demonstrated whether the prognostic ability of RV function assessment is confounded by other important determinants of outcome, such as a markers of fibrosis. In the present study, multivariate analysis revealed that the concentration of Gal-3 was an independent prognostic marker along with RV dysfunction expressed as TAPSE. In our previous study, we found that in symptomatic patients with chronic HFrEF, an elevated Gal-3 concentration was related to worsened RV function but not LV function. Significant, negative, moderate correlations between the Gal-3 concentration and RV long-axis function parameters (TAPSE and RVs’) as well as TAPSE/PASP were observed, and a moderate, significant, positive correlation between Gal-3 and PASP was found28. Furthermore, He et al.15, in a study on patients with pulmonary artery hypertension and in an animal model, found that Gal-3-mediated pulmonary artery hypertension through NADPH oxidase 4 and NADPH oxidase 4-derived oxidative stress led to RV remodeling. A facilitating role of Gal-3 in pulmonary artery remodeling and the progression of pulmonary artery hypertension were reported by Shen et al.14 in patients with congenital heart disease. In an animal model, Hao et al.13 showed that Gal-3 inhibition ameliorated hypoxia-induced pulmonary artery hypertension and reduced the inflammatory response. Although patients with primary pulmonary hypertension were not represented in our study group, we observed nonsignificantly higher PASP and right atrial pressure (RAP) and a significantly lower TAPSE/PASP ratio in the nonsurvivor group. Recently, the TAPSE/PASP ratio was found to be an important prognostic marker of mortality in HFrEF patients29.The development of RV dysfunction in HF patients may result from various pathological mechanisms, including RV injury, remodeling, fibrosis, and pulmonary hypertension. Recently, potential mechanisms underlying the relationship between Gal-3 and RV function have been investigated and reported. Established right ventricular fibrosis in patients with pulmonary hypertension and in experimental animal models was found to be characterized by marked expression of Gal-3 and enhanced numbers of proliferating RV fibroblasts30. However, we did not have access to 3D echocardiography at the time of the study.Certain limitations of this study should be considered. First, this is a single-center study with a relatively small number of patients. Second, advanced HFrEF is an extremely complex syndrome with multiorgan involvement and requires multiparameter assessment. We were able to analyze a limited number of parameters, but not all potentially relevant parameters, in multivariate analyses. Third, hospitalization for HF was not defined as an outcome in our study. We chose all-cause mortality as the only hard endpoint, and therefore, we avoided the risk of error in the adjudication of events. We are aware that Gal-3 is a potent marker of fibrosis found in a wide range of species and tissues. In addition, it plays a regulatory role in inflammation and cancer. Gal-3 might have an impact on all-cause mortality regardless of advanced heart failure. To our knowledge, three patients died due to lung cancer. However, we did not include patients with chronic inflammatory diseases. Although we used multiple echocardiographic techniques to asses RV parameters, including advanced speckle tracking analyzes, it may be not as accurate as 3D echocardiography, which allows better RV volumes and function characterizationThis study indicates that elevated Gal-3 concentrations and RV dysfunction quantified by TAPSE are independent predictors of long-term all-cause mortality in HFrEF patients after CRT implantation. An association between the baseline Gal-3 concentration and outcome was found regardless of CRT response, which requires further research.31. A total of 67 consecutive patients referred to our Cardiology Department for implantation of a CRT defibrillator (CRT-D) were included between January, 7 2013 and November, 28 2015 and prospectively assessed. The inclusion criteria were as follows: symptomatic heart failure in NYHA classes II–III despite optimal medical therapy, severe LV systolic dysfunction—EF ≤ 35%, and QRS duration ≥ 120 ms. Patients were qualified for CRT-D implantation by the attending cardiologist according to current ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure32. Patients with hemodynamic instability, severe organic valvular disease, chronic lung disease, end-stage liver or kidney disease, or chronic inflammatory disease were excluded. The ischemic etiology of heart failure was proven by coronary angiography or by a documented history of myocardial infarction. At the time of qualification for CRT-D, none of the patients required surgical or interventional revascularization for coronary symptoms. Of these patients, 63 underwent CRT-D implantation and were able to participate in the follow-up.The design of this study and the initial results were previously described and publishedThe study was approved by the Bioethical Committee of the Centre of Postgraduate Medical Education and was performed following the requirements of the Declaration of Helsinki. All the participants signed informed consent before inclusion in the study.Clinical evaluation with NYHA functional status assessment, ECG and transthoracic echocardiography (TTE) was performed within 48 h before CRT implantation. Blood samples were obtained from each patient, and routine laboratory tests, including measurements of serum NT-pro BNP concentrations, were performed immediately. The remaining serum was frozen for further Gal-3 concentration measurements. Even though patients with end-stage liver disease were not enrolled, to have a broader description of patient characteristics, we calculated indexes of cirrhosis and liver fibrosis using well-defined formulas of the following scores:Model for End-Stage Liver Disease eXcluding INR (MELD-XI) = 5.11 ×  + 11.76 × ln of creatinine in mg/mL) + 9.44;9/L] × alanine aminotransferase1/2 [U/L]34.Fibrosis-4 (FIB-4) = (age [years] x aspartate aminotransferase [U/L])/ by experienced cardiologists, according to the recommendations of esteemed echocardiographic societies The evaluation of the LV comprised assessment of geometry, systolic function expressed as EF , dP/dt, LV peak systolic myocardial velocity (sʹ) and global longitudinal strain (GLS), diastolic function expressed as LV diastolic dysfunction grade, E/eʹ ratio, left atrial maximum volume index (LAVi), and mitral regurgitation grade.Right ventricular evaluation comprised detailed geometric calculations and functional assessment: TAPSE, fractional area change (FAC), RV peak systolic myocardial velocity (sʹ), peak early (eʹ) diastolic velocity, RV 2D systolic speckle tracking-derived longitudinal strain, and free wall 2D strain. Based on tricuspid regurgitation, peak velocity and respiratory variation in inferior vena cava diameter, PASP and RAP were estimated. A TAPSE/PASP ratio was used to noninvasively assess RV-to-pulmonary circulation coupling.bioMerieux SA, France)38. Previously collected clinical samples were thawed at room temperature just before the measurement of the Gal-3 concentration. An enzyme-linked fluorescence assay (ELFA) was used to measure the serum Gal-3 concentration. This method is a combination of an immunoassay with a final fluorescence measurement. The functional measuring range of ELFA is between 3.3 and 100 ng/mL, and the assay has high repeatability (CV approximately 1%) and reproducibility (CV approximately 5%). The intra-assay variances for Gal-3 were 1.25%, and the interassay variances for Gal-3 were 5.5%.The concentration of serum Gal-3 was quantified using VIDAS  and interventricular delays optimized using Doppler echocardiography.All the patients were under the care of the outpatient CRT clinic during the follow-up period. Follow-up started on the date of CRT-D implantation and ended after 5 years or at the time of death. All-cause mortality was the endpoint of the study. Data on long-term all-cause mortality were collected, and complete data for each patient were obtained from the hospital database, outpatient clinic records and interviews with patients’ relatives.39.The patients were classified as CRT-D responders if they showed a decrease equal to or greater than 15% in LV end-systolic volume at the 6-month follow-up TTEContinuous variables are presented as the mean ± standard deviation (SD) or as the median and interquartile range (IQR) when appropriate. Categorical variables are presented as numbers and percentages.p-value < 0.05 was considered statistically significant.The normality of continuous parameters was tested using the Shapiro Wilk test. Then, two-sample t-tests and the Kruskal–Wallis test were used to test whether samples originated from the same distribution. A p-value < 0.1. Then, using the backward elimination method, we obtained the final model (model 1), which was then adjusted for demographic variables (model 2). Model assumptions were tested on the basis of Schoenfeld residuals40. The natural logarithm of Gal-3 and the natural logarithm of NT-pro BNP were used in the Cox model to improve the linearity assumption. We used Harrell’s C-index (concordance index) to assess the models’ goodness of fit41. Statistical analysis was performed using R software, version 4.1.0, https://www.R-project.org/.Survival curves were calculated using the Kaplan–Meier method, and a log-rank test, or score test and log-rank test with Bonferroni adjustment respectively, were used for assessment overall differences between groups. The Cox proportional hazards model was used to identify independent predictors of long-term all-cause mortality and to assess the influence of potential confounding variables. After assessing the importance of the variables using a univariate Cox proportional hazards model, we selected further modeling variables with a


This review provides background on prior infarct size reduction efforts. The authors describe the preclinical data that shows the effectiveness of SSO2 in reducing MI size, improving regional myocardial blood flow and cardiac function, and reducing adverse left ventricular remodeling—presumably by reducing patchy areas of residual ischemia within the reperfused risk zone. Potential mechanisms by which SSO2 is beneficial are described, including the delivery of high levels of dissolved oxygen through plasma to ischemic, but viable, vascular and myocardial cells, thus allowing their survival and function. The authors then describe the SSO2 clinical trials, demonstrating that in patients with anterior ST-segment elevation MI, SSO2 therapy safely and effectively reduces infarct size, improves cardiac function, and reduces adverse left ventricular remodeling.Despite the fact that door-to-balloon times have been greatly reduced, the rates of death and the incidence of heart failure in patients with ST-segment elevation myocardial infarction (MI) have plateaued. There is still an unmet need to further reduce MI size in the reperfusion era. Most adjunctive therapies to enhance myocardial salvage have failed, but some have shown promise. Currently, the only adjunctive therapy in a pivotal trial that has demonstrated reductions in infarct size is localized delivery of supersaturated oxygen (SSO  Our review includes analysis of preclinical studies as well as completed clinical trials with SSO2  undergoing mechanical reperfusion therapy, numerous adjunctive approaches have been developed to further reduce the extent of myonecrosis ,2. The pith SSO2 .Central In 1971, Peter Maroko and Eugene Braunwald published a seminal paper establishing various factors that could influence myocardial infarction (MI) size . In 197Experimental studies confirmed that early reperfusion reduced infarct size , and cliHowever, there is still an unmet need to further reduce the MI size using agents and therapies that directly protect the myocardium while opening the infarcted artery and keeping it patent. Despite reducing mean door-to-balloon times to <90 minutes  and the routine use of optimal pharmacology, 20%-30% of acute MI (AMI) patients still develop heart failure (HF) within 1 year . UnfortuSalvaging an additional 5% of the LV myocardium can have major beneficial effects on clinical outcomes, including reducing mortality and new-onset HF . TherapiMany therapies that worked in experimental models failed when tested clinically (often referred to as the “graveyard” of therapies) , 15, 16.One major mechanism of infarct size reduction targeted by many of these therapies is the prevention of reperfusion injury . Whereas some investigators claim that about one-half of all cell death during an infarct is caused by reperfusion, others are less convinced of the existence of reperfusion injury in humans or its substantial role in myonecrosis , 18, 19.Despite a host of negative studies, there are still a few approaches that have shown promise for further reducing MI size beyond epicardial reperfusion alone . Some reSystemic hypothermia has been demonstrated in preclinical models to reduce infarct size . The pivLV unloading before reperfusion may reduce infarct size by decreasing oxygen demand, increasing oxygen supply, and activating cardioprotective mechanisms , which iStudies on post-conditioning—a series of brief ischemia–reperfusion cycles induced after achieving patency of the infarct-related coronary artery—have been mixed, with early studies of mechanical or pharmacologic post-conditioning  showing enhanced myocardial salvage ,30, but 2 therapy has shown promise as an adjunct to primary PCI. In the AMIHOT  I and II trials, patients with anterior wall STEMI who were reperfused within 6 hours had smaller LV infarcts with SSO2 therapy compared with controls  (2 therapy was Food and Drug Administration (FDA)-approved  “indicated for non-shock left anterior descending coronary artery (LAD) STEMI treated successfully with PCI within 6 hours of symptom onset.”Hyperoxemic infusion of SSOLV mass) . Followi2 therapy to regions of microvascular ischemia to help counter the problem of ongoing cardiac cell death. He developed a catheter-based approach of delivering hyperbaric levels of oxygen to the ischemic myocardium without bubbles and was able to increase the PO2 (Pao2) of coronary blood perfusate to ∼900 mm Hg  in patients. Spears et al  followed by reperfusion . Intracoronary SSO2 therapy was started after 30 minutes of normoxemic autoreperfusion and was then continued for 90 minutes. Control groups received normoxemic reperfusion by either passive reperfusion or active reperfusion using a roller pump. Mean arterial Pao2 was 108 mm Hg in the normoxemic reperfusion groups and 530 mm Hg in the SSO2 group. Coronary artery balloon occlusion was associated with a mean acute decline in LVEF of 18%. In this study, a significant increase in LVEF (mean +17%) was observed in the SSO2 group at 90 minutes of reperfusion compared with normoxemic autoreperfusion (P < 0.05). In addition, SSO2 was associated with an improvement in LV regional wall motion abnormalities compared with normoxemic autoreperfusion. SSO2 improved ST-segment deviation and reduced the number of premature ventricular beats. At 120 minutes of reperfusion, regional myocardial blood flow, measured with radioactive microspheres, was 0.92 ml/g per minute in the previously ischemic zone of the SSO2-treated animals versus 0.43 ml/g per minute in the normoxemic autoreperfusion control group (P < 0.01)   44). Th. Th2 (pro2 of 834 mm Hg) versus several control groups, including continuous normoxemic autoperfusion and normoxemic reperfusion (using an active perfusion system similar to that used with SSO2 but without the SSO2). Reperfusion was continued for a total of 195 minutes. Serial LV angiograms were performed to assess LV function in this porcine model. Area at risk was determined by reoccluding the coronary artery and injecting blue dye into the left atrium. Following euthanasia, the hearts were sliced from apex to base and the transverse slices were incubated in triphenyl-tetrazolium chloride, which stains viable cells red, whereas infarcted myocardium appears unstained (white/yellow). Hyperoxemic reperfusion was associated with a higher LVEF (mean 62%) after 90 minutes of treatment compared with values during the 15-minute normoxemic autoreperfusion period in the same animals (mean 51%). Hyperoxemic reperfusion was associated with a higher LVEF (62% at 105 minutes and 60% at 165 minutes) than in the normoxemic groups at 105 minutes  and 165 minutes . Myocardial infarct size, expressed as percent area of necrosis divided by area at risk, was smaller in the hyperoxemic perfusion group (<20% of the LV) compared to the other control groups (between ∼70%-80% of the LV)  . Hemorrh the LV)  were als2 treatment also prevented myocardial apoptosis  versus normoxemic autoperfusion. Echocardiographic assessment showed better LV function in the hyperoxemic group at 1 and 2 hours after randomization. There was a reduction in infarct size as assessed by triphenyl-tetrazolium chloride staining in pigs with an LVEF of <50% before randomization, suggesting that hyperoxemic therapy was effective in pigs with larger risk zones.Kantor et al  reported2 was evaluated for deleterious effects after primary PCI with stent implantation, Kaluza et al  did not cause coronary thrombi or affect pathology of the coronary artery at the site of stent implantation compared with normoxemic (sham) controls. Histologic analysis of the infarcted ventricles revealed that there was a nonsignificant trend toward less myocardial scarring at 30 days in the SSO2 group versus normoxemic controls. Echocardiography showed LV function improvement in the SSO2 group. The investigators concluded that SSO2 infusion did not cause coronary artery thrombus or toxicity to the coronary arteries or myocardium after coronary stenting in the AMI setting.Finally, in a porcine model of 60-minute coronary artery occlusion followed by reperfusion in which SSOza et al  demonstr2, and a series of clinical studies subsequently commenced. These included a phase 1/1A feasibility study, the AMIHOT I and II studies, the Optimized SSO2 Pilot, and the IC-HOT (Intracoronary Hyperoxemic Oxygen Therapy) study.Preclinical studies established the safety and effectiveness of SSOo2 of 600-800 mm Hg) was infused for 60 to 90 minutes after establishing proximal patency (2 therapy was safe and well-tolerated.The feasibility study was a multicenter study of 29 patients with acute STEMI reperfused with primary PCI in which hyperoxemic blood (Pa patency . Hyperox2 therapy or normoxemic autoperfusion (2 group (P = 0.30). However, in subgroup analysis, patients <59.5 years of age, those having reperfusion time of <6 hours, and those having initial TIMI flow grade 2 demonstrated smaller infarct size with SSO2(P = 0.02 to 0.06). In patients with anterior MIs treated within 6 hours, LV infarct size in the control group was 23% versus 9% in the hyperoxemic group (P = 0.04). Although change in regional wall motion score index did not differ between groups in all patients, in the subgroup of patients with anterior infarcts treated within 6 hours, the improvement in regional wall motion score was better in the SSO2 group versus the normoxemic group . The area under the ST-segment deviation time curve over 3 hours did not differ among patient groups. In the subgroup of patients with anterior wall infarcts and reperfusion within 6 hours, SSO2 demonstrated superior reperfusion stability as assessed by serial ST segment measurements.The AMIHOT I study was a prospective, multicenter study of 269 acute STEMI patients with either anterior or large inferior infarctions who were randomized after successful primary PCI to either 90 minutes of intracoronary hyperoxemic reperfusion using SSOerfusion . This st(P = 0.62).Although not powered for clinical events, the primary composite safety endpoint of death, reinfarction, target vessel revascularization (TVR), or stroke occurred in 5.2% of the control normoxemia group and 6.7% of the hyperoxemia group P < 0.05), whereas in the SSO2 group, there was no increase from 24 hours (120 mL) to 1 month (117 mL). LV end-systolic volumes also increased significantly in the control group, but not the SSO2 group. Furthermore, LVEF increased in the SSO2 group from 24 hours to 1 month , whereas LVEF did not change in the control group from 24 hours (51%) to 1 month (50%). The investigators concluded that SSO2 in the AMIHOT I trial prevented adverse LV remodeling (LV dilatation) and improved LV ejection fraction. These findings are notable because adverse post-infarction LV remodeling is associated with worse early and late clinical outcomes . The primary efficiency endpoint was MI size measured by nuclear scanning (Tc-99m-sestamibi SPECT) at 14 days, powered for superiority, with a safety endpoint consisting of the composite of major adverse cardiovascular events  at 30 days, powered for noninferiority. A Bayesian hierarchical modeling technique was used to allow conditional borrowing of evidence from the AMIHOT I trial  , meeting the prespecified superiority criteria for an absolute reduction in infarct size of 5%  . The pooze of 5%   groups (posterior probability of noninferiority = 99.5% with a prospective noninferiority margin = 6%). The investigators thus concluded that in patients with anterior STEMI having successful PCI within 6 hours of symptom onset, a post-PCI 90-minute infusion of SSO2 therapy safely reduced infarct size. However, some adverse safety signals were evident. There was an increase in access site-related events, mainly hematomas in the SSO2 group (6% vs 3%). This was attributed to use of a larger infusion catheter and dual femoral access during the early phase of the study, but during the later phase of the study, hematomas were reduced by introduction of a lower profile infusion catheter and single femoral access. Stent thrombosis within 30 days occurred in 2.5% of control patients and 4.1% of SSO2 patients (P = 0.73), and incidence of mortality was 0% versus 1.8% of patients respectively (P = 0.58). Although the rates of stent thrombosis were not significantly different between the groups, concerns were raised that the intracoronary positioning of a catheter for SSO2 delivery for 90 minutes may have contributed to the observed numerical increase in thrombotic events. Specifically, contact of the distal catheter tip with the coronary luminal surface and/or flow stasis proximal to the point of infusion may have predisposed to thrombus formation, particularly if the anticoagulation regimen was subtherapeutic.As regards safety, there was no difference in 30-day major adverse cardiovascular events between the control (5.2%) and the SSO2 therapy, an “optimized” method was developed whereby hyperoxemic blood was infused through a standard diagnostic catheter in the left main coronary artery (LM) rather than through an infusion catheter in the LAD. A 7-F femoral sheath was used for the draw line and coaxial insertion of the delivery catheter, the SSO2 therapy was infused through a 5-F coronary diagnostic catheter into the ostium of the LM, and the infusion time was reduced from 90 to 60 minutes by increasing the flow rate from 75 mL/min to 100 mL/min to ensure the same dose of SSO2 solution. Of note, a simple LM stem SSO2 infusion approach for 60 minutes only was used in the first 9 patients in the TherOx Phase I trial . SSO2 therapy was associated with both a lower rate of cardiovascular mortality  and new-onset HF or HF hospitalizations . There were no differences between groups in rates of reinfarction or TVR. Stent thrombosis within 1 year occurred in only 1 patient after SSO2 versus 4 control patients . Subanalysis of the IC-HOT trial also showed similar reductions in LV volumes measured over 30 days as in the 2005 AMIHOT I substudy by Warda et al (2 therapy reduces adverse LV dilatation (remodeling) during the healing phase of infarction (2 therapy following primary PCI in patients with anterior STEMI is safe and may improve 1-year clinical outcomes (The 1-year clinical outcomes from IC-HOT were compared with a propensity-matched control group of similar patients from the INFUSE-AMI study  Table 2Table 2. da et al , confirmfarction . These doutcomes , althoug2 delivery and other practical issues are contained in the Details on how to perform SSO2 therapy is a safe and efficacious adjunctive agent to use with reperfusion to reduce infarct size, preserve cardiac function, reduce adverse LV remodeling, and potentially improve clinical outcomes in patients with acute anterior STEMI reperfused within 6 hours of symptoms. A major advantage of this treatment compared with many other investigative therapies to reduce infarct size is that reperfusion is not delayed. Future studies will examine the real-world outcomes of SSO2 therapy in STEMI and further explore its effect on clinical outcomes following STEMI.The clinical studies completed to date have demonstrated that SSO2. Dr Spears was involved with preclinical studies with SSO2.Drs Kloner and Burkhoff have been consultants for ZOLL TherOx. Dr Creech is an employee of ZOLL TherOx. Drs. Stone and O’Neill have been consultants for ZOLL TherOx; and were involved in previous clinical trials with SSO


To explore the effect of initial surgery for type I and II pulmonary atresia with intact ventricular septum (PA/IVS).50 children with type I PA/IVS and 50 with type II PA/IVS who had undergone initial surgery were enrolled. Children with Type I were divided into groups A (n = 25) and B (n = 25). Group A had received BT shunt combined with PDA ligation and balloon dilatation of pulmonary valve, whereas group B had undergone BT shunt combined with PDA ligation and pulmonary valve incision. Children with type II were divided into groups C (n = 25) and D (n = 25). Group C had received BT shunt combined with PDA ligation, right ventricular outflow tract (RVOT) incision and transannular patch. Group D had undergone BT shunt combined with PDA ligation, RVOT incision, transannular patch and artificial pulmonary valve implantation. The differences in mechanical ventilation time, length of ICU stay, mortality rate, tricuspid Z value, tricuspid regurgitation, oxygen saturation, pulmonary regurgitation, McGoon ratio, pulmonary artery transvalvular pressure, survival rate were compared between groups A and B, between groups C and D respectively.P = 0.045; 222.00 ± 11.72 h vs. 162.48 ± 7.91 h, P = 0.048). The pulmonary artery transvalvular pressure was significantly higher in group A than in group B at 3, 6, 12, 24 and 36 months after surgery . Furthermore, the tricuspid Z value was significantly greater in group B than in group A at 3 and 24 months after surgery (− (1.37 ± 0.04) vs. − (1.43 ± 0.06), P = 0.03; − (0.41 ± 0.06) vs. − (0.51 ± 0.11), P = 0.02).The ventilator assistance time and length of ICU stay were greater in group C than in group D (80.96 ± 8.42 h vs. 65.16 ± 4.85 h, The effect of BT shunt combined with PDA ligation and pulmonary valve incision is superior to BT shunt combined with PDA ligation and balloon dilatation of pulmonary valve, and the effect of BT shunt combined with PDA ligation, RVOT incision, transannular patch and artificial pulmonary valve implantation is superior to BT shunt combined with PDA ligation, RVOT incision and transannular patch. Pulmonary atresia with intact ventricular septum (PA/IVS) is a type of complex cyanotic congenital heart disease with a low incidence, accounting for only 1% to 3% of congenital heart disease (CHD) [Given a large anatomical variation of PA/IVS, and diverse surgical treatments in each center, there is still no unified standard , 3. NeveThis retrospective study aimed to investigate the effect of different initial surgical procedures on the prognosis of type I and type II PA/IVS, and to evaluate the therapeutic effect, thereby providing reliable clinical data for optimizing the selection of initial procedures for PA/IVS.Using random number table method, we selected 25 cases of children with type I PA/IVS who had been treated by BT shunt combined with PDA ligation and balloon dilatation of pulmonary valve in our hospital from January 2010 to December 2019, and included them in group A; another 25 cases, who had been initially performed with BT shunt combined with PDA ligation and pulmonary valve incision, were enrolled in group B. Meanwhile, 25 cases of children with type II PA/IVS in group C had initially undergone BT shunt combined with PDA ligation, right ventricular outflow tract (RVOT) incision and transannular patch, and another 25 cases were enrolled in group D, in which BT shunt combined with PDA ligation, RVOT incision, transannular patch and artificial pulmonary valve implantation had been perfomed initially. Type I PA/IVS refers to mild dysplasia of the right ventricle; the tricuspid valve and right ventricular cavity reach 2/3 above normal, and the right ventricular outflow tract is well developed. Type II PA/IVS refers to moderate dysplasia of the right ventricle; the tricuspid valve and right ventricular cavity reach normal 1/3–2/3, and the right ventricular outflow tract is well developed. All patients had patent ductus arteriosus (PDA), atrial septal defect (ASD)/patent foramen ovale (PFO) and extensive tricuspid regurgitation (TR)  indicated mild right ventricular dysplasia, and the one (− 4–2) indicated moderate right ventricular dysplasia. In addition, the ratio of tricuspid valve diameter to mitral valve diameter measured by echocardiography can provide some evidence of right ventricular development as a reference index. The diameter ratio of tricuspid valve to mitral valve in neonates was less than 0.7, suggesting right ventricular dysplasia. All patients were diagnosed as type I PA/IVS or type II PA/IVS without RVDCC. There were no significant differences between groups A and B, and between groups C and D with respect to gender, age, weight, tricuspid Z value, degree of TR, McGoon ratio, oxygen saturation (SpO2), inner diameter of PDA, size of ASD or PFO  incision and transannular patch, and group D had undergone BT shunt combined with PDA ligation, RVOT incision, transannular patch and artificial pulmonary valve implantation Fig. . BT shunFour groups of patients underwent the initial surgery according to the corresponding surgical methods. The mechanical ventilation time, length of ICU stay and perioperative mortality rate were recorded and statistically analyzed. The tricuspid Z value, McGoon ratio, and TR in each group were recorded before surgery, and at 1 month, 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months and 72 months after surgery, and statistical analysis was performed. Pulmonary regurgitation (PR) and pulmonary artery transvalvular pressure were recorded and statistically analyzed before discharge, and at 1 month, 3 months, 6 months 12 months, 24 months, 36 months, 48 months, 60 months and 72 months after surgery. During the follow-up period, the data of patients who had undergone surgical intervention or radical surgery were excluded at the corresponding time points. The survival rate from the day of surgery to 72 months after initial surgery were recorded and statistically analyzed.P < 0.05 indicated that the difference was statistically significant, and P < 0.01 indicated that the difference was highly significant.IBM SPSS Statistics22 statistical software was used for statistical analysis. One-sample Kolmogorov–Smirnov Test was used to determine normality of data. Measurement data are expressed as mean ± standard deviation (One case died of hypoxemia after the initial surgery in group A Fig. ; at 3 moP > 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.01; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P > 0.05; Fig. P < 0.05; Table P < 0.01; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table P < 0.01; Table P < 0.05; Table P > 0.05; Fig. There were no statistically significant differences in the mechanical ventilation time, length of ICU stay, and perioperative mortality rate after surgery between group A and group B (all The purpose of this study was to investigate the effects of two different kinds of initial surgical strategies on type I and II PA/IVS respectively, which has a low incidence but a high mortality rate and great anatomical variation. Surgical programs are also diverse in each center, therefore, there is still no unified standard. Individualized surgical treatment is favourable, and the key step is to improve the early survival rate. According to our experience, few patients have one-stage radical operation; instead, most need staging surgery. Moreover, it is important to pay attention to the anatomy of the coronary arteries. The ratio of right ventricular-coronary artery fistula is higher if echocardiography shows severe right ventricular dysplasia and narrow tricuspid valve opening, usually in which there is coronary artery intimal fibrous hyperplasia, resulting in coronary artery stenosis or even complete occlusion. RVDCC could be caused if obstruction occurs at the proximal end of the coronary artery. Such children have a high risk of myocardial ischemia, that is, hypoxic blood is perfused from the right ventricle to a considerable range of myocardium, even worse when the diastolic aortic pressure falls after BT shunt is established. It is hard for such children to tolerate the drop in right ventricular pressure if right ventricular outflow tract patch and pulmonary valve incision are performed to implement right ventricular decompression, and acute myocardial infarction will occur. In this study, the children’s right ventricle and tricuspid valve development are mild to moderate dysplasia, and even some children had undergone cardiac catheterization before surgery, which can rule out coronary artery malformations. For patients with mild and moderate right ventricular dysplasia and without RVDCC, right ventricular decompression should be performed as early as possible through initial surgery, thereby promoting the development of the right ventricle, providing a precise pulmonary blood supply to improve the systemic arterial blood oxygen saturation, and improving the opportunity of biventricular repair in children , 6, and Although much more surgical methods of right ventricular decompression are available for PA/IVS , 8–12, sBT shunt can be established to correct hypoxemia. Nonetheless, it is still controversial whether decompression surgery is routinely combined with BT shunt, and some studies have reported that BT shunt may lead to volume overload and left heart failure . HoweverP > 0.05; Table In recent years, balloon dilatation of pulmonary valve has become a new approach for right ventricular decompression in the early stage of PA/IVS , which aHowever, the balloon dilatation of pulmonary valve has several shortcomings, in which the puncture needle may be deviated from the center of the pulmonary valve, and the pulmonary valve is unevenly dilated, which finally reduces the function of the pulmonary valve and causes severe PR. Moreover, due to tissue growth, adhesion, scar and other reasons after balloon dilatation, pulmonary valve will be reduced to varying degrees, hindering the growth of the right ventricle.P < 0.05; Table P < 0.05; Table P < 0.01; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table The corresponding data showed that the PR was greater in group A than in group B at 1 and 3 months after surgery (P < 0.05; Table P < 0.01; Table P < 0.05; Table P < 0.05; Table P < 0.05; Table Compared with group C, group D added an artificial pulmonary valve made of Gore-tex membrane, which could reduce pulmonary valve regurgitation, protect right ventricular function, shorten mechanical ventilation time and length of ICU stay, promote right ventricular development, and improve the survival rate of initial surgery to a certain extent. The corresponding data showed that the PR was higher in group C than in group D at discharge (P < 0.05; Table P < 0.01; Table P < 0.05; Table Since each surgical method has its advantages and disadvantages, and different surgeons have different understandings and preferences for the same surgical method. Meanwhile, the selection of surgical methods also should be combined with the overall state of children for comprehensive evaluation. For example, if children with type I PA/IVS would performed with pulmonary valve incision, superior vena cava, inferior vena cava and distal main pulmonary artery need to be temporarily occluded. If the vital signs are not stable and children can not tolerate this operation, only pulmonary balloon dilatation can be selected. For children with type II PA/IVS, especially with membranous atresia, artificial pulmonary valve was probably unnecessary if the remaining pulmonary valve membrane was in good condition,. If there were calcification and stiffness in the pulmonary valve, artificial pulmonary valve could be made to reduce pulmonary blood reflux. However, due to the presence of calcified contracture and lack of growth in the artificial pulmonary valve, complications such as pulmonary artery stenosis and obstruction can be caused in the postoperative period. The corresponding data showed that the pulmonary artery transvalvular pressure was greater in group D than in group C at 6 month (In addition, this study has several limitations. First, we failed to detect the real differences between groups due to insufficient sample size and low incidence. Second, the follow-up period after initial surgery was insufficient to reflect the trend of the observation indexes, which may have introduced a certain bias on the statistical analysis results. Furthermore, several patients with radical conditions did not receive timely surgery, and some patients who needed early reintervention fail to undergo timely surgery for various reasons, including large pulmonary transvalvular pressure or severe PR. It was related to the economic conditions and ideas of the guardians of the patients. Some parents could not afford medical treatment, and some parents believed that their children were in good living conditions and did not need reoperation. Moreover, it is also associated with the conception of several surgeons that the older the child is, the higher the success rate of reoperation is.Early active surgical treatment of PA/IVS is the key to improving the survival rate, and staged decompression is relatively stable, even if this may increase the rate of postoperative reintervention. The reasonable choice of the initial surgical strategy is an important factor affecting the prognosis. Taken together, BT shunt combined with PDA ligation and pulmonary valve incision is superior to BT shunt combined with PDA ligation and balloon dilatation of pulmonary valve, and BT shunt combined with PDA ligation, RVOT incision, transannular patch and artificial pulmonary valve implantation is superior to BT shunt combined with PDA ligation, RVOT incision and transannular patch.


Bortezomib (BTZ) is a proteasome inhibitor (PI) used for the treatment of several hematologic malignancies, including multiple myeloma (MM), and various lymphomas including mantle cell lymphoma (MCL). It acts via disruption of the ubiquitin-proteasome pathway which plays a major role in regulating cell cycle and inhibiting synthesis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB). The ubiquitin-proteasome pathway is also important in maintaining the integral signaling in cardiac myocytes. By inhibiting this system, BTZ induces cellular apoptosis in cancer cells, and possibly the cardiomyocytes. BTZ-induced cardiotoxicity in monotherapy and combination treatments is not well described in the literature.We observed a series of three patients who developed cardiotoxicity after treatment with BTZ. All patients had echocardiograms every 3 months until recovery to assess ejection fraction (EF) and global longitudinal strain (GLS). Two of the patients had a cardiac MRI (CMR) conducted during follow-up to assess for late gadolinium enhancement (LGE). The median age of our patients was 55 years (range 37-74). Two of them had MM, while one patient had MCL. Table This case series demonstrates that BTZ-induced cardiomyopathy is potentially reversible with discontinuation of the drug and early initiation of GDMT. Further studies are needed to determine the ideal surveillance strategy for BTZ-induced cardiomyopathy.  Multiple myeloma (MM) is a widely prevalent hematological malignancy that affects thousands of people worldwide, with a median age of 65-74 years at diagnosis , 2. The Proteasome inhibitors (PIs) are a recent addition to the armamentarium of cancer chemotherapeutics. They are widely used for several malignancies, including MM and lymphoma. The first PI approved for the treatment of MM was BTZ in 2003. Subsequently, there have been few other PIs that have been approved for the treatment of refractory hematological malignancies .PIs are known culprits of cardiovascular toxicity, carfilzomib more often than bortezomib (BTZ) (7% versus 2-5% respectively) . CarfilzAccording to data from the phase II SUMMIT trial , the FooHere, we describe a case series of 3 patients who had BTZ-induced left ventricular dysfunction that recovered with standard guideline-directed medical therapy (GDMT) for heart failure and discontinuation of BTZ, as well as provides a review of the current literature on the topic of BTZ-related cardiotoxicity.Patient 12 on days 1, 4, 8, and 11 for 4 months (cumulative dose of 20.2mg/m2). During follow-up, the patient was experiencing shortness of breath with exertion concerning for worsening CHF. Thereafter, a transthoracic echocardiogram was performed, which showed a new reduction in LVEF (30-35%). Cardiac MRI showed an LVEF of 34% with no late gadolinium enhancement (LGE). Subsequently, BTZ was stopped, and he was started on metoprolol succinate and lisinopril with improvement in LVEF. Following melphalan dose-reduced autologous hematopoietic stem cell transplant (AHSCT), his subsequent therapy included a switch to an alternative PI, ixazomib, for the remainder of consolidative combination therapy for his ultra-high-risk MM.A 55-year-old man with known non-compaction cardiomyopathy with a baseline left ventricular ejection fraction (LVEF) of 45-50% developed revised international staging system stage II, ultra-high-risk t and 1q21.3 MM. He was treated with subcutaneous BTZ, lenalidomide, and dexamethasone in 21-day cycles. BTZ was delivered at 1.3 mg/mPatient 22). Subsequently, he developed decompensated CHF (LVEF of 40%) requiring hospital admission for intravenous diuresis. He had no previous history of CHF or coronary artery disease, and his prior baseline LVEF was normal. Subsequent CMRI showed an LVEF of 45% with no LGE and BTZ was stopped. Metoprolol succinate and lisinopril were initiated and LVEF improved to 65% over the next 13 months with no further CHF hospitalizations. He achieved a complete response to MCL treatment, but was later diagnosed with MM as a second malignancy for which he was treated with an alternative PI-based (ixazomib) therapy to avoid further BTZ-suspected cardiotoxicity.A 74-year-old man with a history of hypertension developed stage IIB mantle cell lymphoma (MCL). He was started on subcutaneous BTZ, lenalidomide, and dexamethasone in 28-day cycles, with BTZ given weekly. He received 10 months of combination therapy  on routine echocardiogram performed as part of stem cell transplant evaluation. She had no symptoms of heart failure. By that point, she had received a cumulative BTZ dose of 135 mg/m2. Subsequently, BTZ was stopped and metoprolol succinate and lisinopril were initiated. Her LVEF recovered to normal after 3 months of GDMT with no admissions for decompensated CHF. For salvage therapy, she was started on a regimen that was non-PI-containing. However, with disease progression, she was subsequently treated with another PI (carfilzomib)-containing regimen on which she did not experience further reductions in LVEF. A 37-year-old woman with a history of revised international staging system stage II, high-risk MM with extramedullary splenic involvement, received subcutaneous BTZ, lenalidomide, and dexamethasone in 21-day cycles. BTZ was delivered at 1.3 mg/mTable PIs work by interrupting the Ubiquitin-Proteasome System (UPS),  which plThe Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial  was one A single-center retrospective analysis by Gurram et al.  in 2017 The ENDEAVOR trial  evaluateA meta-analysis by Xiao et al.  in 2014 There have been several other case reports describing BTZ-induced congestive heart failure -24. The Aside from these, there are isolated case reports of BTZ-induced complete heart block with myocardial scar on CMRI -29 requiThe use of GDMT  for leftPatterns of LV dysfunction with BTZ have not been well described since most of these case reports did not have data from CMRI. Foley et al.  describeOur patients (2 out 3 had CMRI) did not have any evidence of scar or LGE on CMRI, which supports the hypothesis of myocardial recovery with appropriate GDMT. Furthermore, the third patient was successfully and safely treated for relapsed malignant disease with another PI, which signifies the feasibility of utilizing further non-BTZ PI-based therapy in patients adequately supported with GDMT.To our knowledge, this is the first series of patients who had recovery of BTZ-induced left ventricular systolic function with appropriate GDMT and subsequent discontinuation of BTZ.Our group did attempt to titrate GDMT to target doses to maximize the chance of LVEF recovery, however, this was limited by orthostatic hypotension from BTZ induced autonomic neuropathy. This needs special attention as neuropathy is a common side effect with BTZ and other PIs. We did make sure that GDMT was continued even after the recovery of LV function.Currently, no specific recommendations exist for monitoring for BTZ-related cardiotoxicity with imaging or cardiac biomarkers like cardiac troponin and brain natriuretic peptide. It is unclear if the timing of initiation of GDMT impacts the likelihood of reversibility of BTZ-related cardiomyopathy/ However, we do know that early detection of subclinical cardiotoxicity impacts recovery of LV function in other forms of chemotherapy-induced cardiac dysfunction . Future This case series highlights the potential reversibility of BTZ-related cardiomyopathy with the initiation of GDMT, even in patients with a significant underlying cardiac structural abnormality like non-compaction cardiomyopathy. Future studies should help delineate specific monitoring for cardiotoxicity with BTZ, be it overt or subclinical, as well the outcomes of patients who have recovery in LV function and are re-challenged with BTZ after initial cessation.This case series highlights the potential reversibility of BTZ-related cardiomyopathy with the initiation of GDMT, even in patients with a significant underlying cardiac structural abnormality like non-compaction cardiomyopathy. Future studies should help delineate specific monitoring for cardiotoxicity with BTZ, be it overt or subclinical, as well the outcomes of patients who have recovery in LV function and are re-challenged with BTZ after initial cessation.


Diabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA). Remodeling of the LAA, which predisposes to thrombi formation, has been previously described in diabetic patients with atrial fibrillation, but whether remodeling of the LAA occurs in diabetics also in the absence of atrial fibrillation is unknown. To investigate the contribution of diabetes, as opposed to atrial fibrillation, to remodeling of the LAA, we went from humans to the animal model.We studied by echocardiography the structure and function of the heart over multiple time points during the evolution of diabetes in the Cohen diabetic sensitive rat (CDs/y) provided diabetogenic diet over a period of 4 months; CDs/y provided regular diet and the Cohen diabetic resistant (CDr/y), which do not develop diabetes, served as controls. All animals were in sinus rhythm throughout the study period.Compared to controls, CDs/y developed during the evolution of diabetes a greater heart mass, larger left atrial diameter, wider LAA orifice, increased LAA depth, greater end-diastolic and end-systolic diameter, and lower E/A ratio—all indicative of remodeling of the LAA and left atrium (LA), as well as the development of left ventricular diastolic dysfunction. To investigate the pathophysiology involved, we studied the histology of the hearts at the end of the study. We found in diabetic CDs/y, but not in any of the other groups, abundance of glycogen granules in the atrial appendages , atria  and ventricles, which may be of significance as glycogen granules have previously been associated with cell and organ dysfunction in the diabetic heart.We conclude that our rodent model of diabetes, which was in sinus rhythm, reproduced structural and functional alterations previously observed in hearts of human diabetics with atrial fibrillation. Remodeling of the LAA and of the LA in our model was unrelated to atrial fibrillation and associated with accumulation of glycogen granules. We suggest that myocardial accumulation of glycogen granules is related to the development of diabetes and may play a pathophysiological role in remodeling of the LAA and LA, which predisposes to atrial fibrillation, thromboembolic events and left ventricular diastolic dysfunction in the diabetic heart. Diabetic patients have a high prevalence of heart disease , 2 and aThe LAA, an anatomical structure pouching out of the LA of the heart, is distinct embryonically and anatomically from the atrium . It actsIn the diabetic patients, what is the contribution of the LAA to the predisposition to thromboembolic events? The high incidence of atrial fibrillation in diabetics appears to be a major inciting factor, and yet additional factors may be involved. Yosefy et al.  recentlyTo determine the contribution of diabetes to LAA remodeling, an important predisposing factor to clot formation and thromboembolism, we studied the heart structure and function in an animal model in sinus rhythm during the evolution of diabetes. We reasoned that if we were to detect LAA remodeling in the animal model during the course of the development of diabetes, such finding would support a causal relationship between remodeling of the appendage and diabetes, dissociate remodeling from atrial fibrillation and establish an experimental platform for investigating the mechanisms involved as well as for testing novel preventive and/or therapeutic measures for the diabetic heart in humans.Our study hypothesis was that in the diabetic animal with a normal sinus rhythm, structural changes in the LAA occur during the development of diabetes, and that they are causally associated with diabetes and not necessarily related to atrial fibrillation.We used the inbred Cohen Diabetic rat, an experimental model of diet-induced type 2 diabetes mellitus, which consists of the sensitive CDs/y and resistant CDr/y strains . When feWe procured the animals from the Israeli Rat Genome Center at the Barzilai University Medical Center in Ashkelon, Israel. Animals were housed up to six in a cage. We maintained 12-h diurnal light-darkness cycles and room temperature at 22–25 °C. We used male animals only. We weaned the animals at age 1 month and provided them with RD and tap water ad libitum.The use of animals and the experimental protocol were approved by our Institutional Committee for Animal experimentation. The animal procedures were performed in accordance with the NIH guidelines for the care and use of laboratory animals.At baseline, we studied animals fed RD at ~ 6–7 weeks. We then divided the animals into two groups—providing DD or RD. Four groups were thus studied in a 2 × 2 design: The experimental CDs/y-DD group , the diet control CDs/y-RD , CDr/y-DD groups , and the strain CDr/y-RD control group . We used a larger number of animals in the experimental diabetic group in view of anticipated mortality in this group (based on experience from previous studies) and the need to ensure that sufficient animals survive the entire study period.We studied the animals at four time points: At “baseline” at age 6–7 weeks; after 1 month of DD or RD, by which time the diabetic phenotype was already fully expressed in CDs/y-DD but not in any other group; after 2.5 months; and after 4 months of DD or RD, to allow the diabetes-related phenotype to evolve in full in the experimental group. We studied both experimental and control strain/diet groups at all time-points, so as to allow us to differentiate between changes attributable to diet, strain or diabetes.We studied the heart structures by echocardiography  at baselThe echocardiographic measurements were performed with a conventional GE Vivid 7 echocardiographic machine , with a linear epi-aortic transducer . The acquisition included still images and loops in parasternal (long axis and short axis views), apical  and suprasternal views. An electrocardiogram was recorded to identify end-systole and end-diastole. Imaging parameters were standardized at a frequency 5–10 MHz, depth 2.5 cm, frame rate of at least 125 fps, Doppler sample volume of 1.0 mm and color Doppler aliasing velocity of 40 cm/s. Loops were recorded with at least three heart beats.i (corrected per 100 g body mass), LVESD and LVESDi (corrected per 100 g body mass) and LVPWT and LVPWTi (corrected per 100 g body mass); septum—thickness and thickness index; aorta—root diameter and diameter of ascending aorta; and Doppler mitral valve inflow—E and A waves.We measured or derived the following variables: LA diameter; LAA—orifice length and depth; LVEDD and LVEDDWe sacrificed the animals after 2.5 and 4 months of DD or RD (n = 8 in each group). Euthanasia was by exsanguinating the animals from the bifurcation of the aorta under xylazine/ketamine anesthesia, as described above. After exsanguination, we surgically excised the heart, weighed it, fixed it in formaldehyde and embedded it into paraffin blocks. We prepared 4–6 micron sections of the heart, including the ventricles, septum, atria and atrial appendages, and stained the slides with hematoxylin–eosin or PAS without and with diastase. We examined the slides under light microscopy.We analyzed the data using the Statistica software . Results are provided as mean ± standard error. Between-group analysis was by one-way ANOVA with the LSD test as the post-hoc analysis measure. We set the significance level at p < 0.05. To test for correlation between variables, we used linear regression analysis.In the experimental CDs/y group provided diabetogenic diet, one animal failed to thrive as it was developing diabetes, as evidenced by failure to increase in weight beyond the lag generally observed in this strain; this animal died between 2.5 and 4 months. Two more CDs/y provided diabetogenic diet and two CDs/y provided regular diet (control group) died during the anesthesia that was necessary for the echocardiographic study. We had previously observed increased sensitivity of the CDs/y strain to anesthesia. As preventive measures, we used as a rule a 10–20% lower dose of anesthetics in this strain and monitored these animals more closely while they were under anesthesia. All CDr/y animals survived the full length of the study.Body mass increased in all groups during the 4 months of the study, but CDs/y-DD lagged behind the other groups Fig. A. As resThe mass of the heart rose significantly and to a similar extent in all groups during the 3 months of the study Fig. B. The inWe tested by linear regression if heart mass within each group correlated with body mass, as indication of growth in parallel of heart and body mass Fig. D–G. The All animals were in sinus rhythm at baseline and at 1, 2.5 and 4 months of the study, as demonstrated by echocardiography electrocardiogram (one-lead) and by the presence of E and A waves by doppler echocardiography.At baseline and after 1 and 2.5 months of DD or RD, LA diameter was not different among the four study groups  of the pulse wave across the mitral valve (early LV diastolic filling) Fig. A was notAs of 1 month after initiation of DD, the “A” wave (late LV diastolic filling) Fig. B tended E/A ratio As of 1 month after initiation of DD, the E/A ratio (diastolic function of the left ventricle)  Fig. C was sigWe examined histological sections of the heart, including the ventricles, septum, atria and atrial appendages, under light microscopy (×100 and ×400) in the four groups after 2.5 and 4 months of feeding with DD or RD. H&E staining did not reveal differences in the histological appearance of the four groups at both time points. PAS staining revealed at 4 months, but not at 2.5 months, pink-staining granules within the cardiomyocytes in the atria, atrial appendages and ventricles Fig. A–C of diTo provide a quantitative estimate of the granule content at 4 months, PAS stained slides were blindly examined under light microscopy (×200–400) by two investigators (CY and IN), who estimated independently the percent area covered by glycogen granules in the atria, atrial appendages and ventricles of the four groups. There was a significantly greater amount of glycogen granules in all three heart structures (with no discernable difference between right and left chambers—data not shown) in CDs/y-DD than in all the other groups. Percent surface covered by glycogen granules was 63% in the atrial appendages, 51% in the atria and 45% in the ventricles  of DD stood out as a major pathological finding and may be of pathophysiological significance in relation to cardiac remodeling, as excess glycogen accumulation appears to be detrimental and can lead to cell and organ dysfunction . Our finExtrapolating our findings to human subjects and returning from the animal model to humans, our starting point in this study, we hypothesize that glycogen accumulation may also occur in the human diabetic heart, accounting at least in part for the development of diabetic cardiomyopathy, with remodeling of the atrial appendages first and subsequently of the atria. The latter would render the diabetic patient susceptible to develop atrial fibrillation and the former to develop thromboembolic complications during atrial fibrillation. Ventricular diastolic dysfunction would be a late sequela. It remains incumbent on us to pursue this hypothesis and demonstrate increased glycogen content in the diabetic heart in humans, a technology that may soon become available , and corWe conclude that our rodent model of diabetes reproduced structural and functional alterations previously observed in hearts of human diabetics with atrial fibrillation. Remodeling of the LAA and of the LA in our murine model was unrelated to atrial fibrillation, as our animals were consistently in sinus rhythm throughout the entire study period, and was associated with accumulation of glycogen granules. Our findings carry an important implication on our understanding of the pathogenesis of the diabetic heart and its complications and suggest that myocardial accumulation of glycogen granules, which is directly related to the development of diabetes, is likely to play a pathophysiological role in remodeling of the LAA and LA, which predispose to atrial fibrillation, thromboembolic events and to left ventricular dysfunction in the diabetic heart. These findings establish our rodent model as an experimental platform for investigating further the mechanisms involved in diabetes-related remodeling of the heart, for continuing research in the prevention of thromboembolic events of cardiac origin in diabetic patients, and for testing of novel preventive and/or therapeutic approaches to the diabetic heart in humans.


Hypertension is a well-recognized risk factor for the development of cardiovascular disease, and the early detection of cardiac changes from hypertension can allow reversing these. Hypertensive heart diseases (HHD) refer to the complex and diverse change of the cardiac structure and function secondary to hypertension. Although conventional echocardiography is the most common imaging modality in detecting HHD, it cannot detect subtle changes of cardiac structure in subclinical states. Because strain echocardiography is another echocardiographic modality can detect subclinical myocardial dysfunction by measuring intrinsic myocardial deformation, it became more and more popular in clinical and research fields. In this review article, we described the basic concept of strain echocardiography and summarized several clinical studies showing its clinical utilities in the detection of HHD. Hypertension is the most important cardiovascular risk factor with an increased risk of heart failure (HF), myocardial infarction, stroke, and cardiovascular death –4. HyperTraditionally, conventional echocardiography is the most common imaging modality in detecting HHD by providing useful structural and hemodynamic findings. The presence of abnormal conventional echocardiographic findings, including abnormal LV geometry and LVH, dilatation of left atrium (LA), and LV systolic and diastolic dysfunction, is associated with poor prognosis associated with hypertension. Speckle-tracking echocardiography (STE) is a non-invasive echocardiographic modality providing myocardial deformation, which helps detect early ischemic changes and myocardial dysfunction, even before symptom onset, undetected by the conventional echocardiographic examination.In this review article, we described the basic concept of STE and summarized the clinical utility of STE in the evaluation of patients with hypertension.Because the target organ damage like HHD from arterial hypertension can be associated with a poor prognosis, identification of these HHD can improve clinical outcomes of these patients. In terms of biochemical alterations, myocardial fibrosis is one of the factors responsible for deterioration of myocardial function in hypertension , 9. MyocLVH and abnormal LV geometry are common forms of HHD and important independent predictors of adverse long-term prognosis in many cardiovascular diseases. Chronic systolic and diastolic arterial hypertension can cause myocyte hypertrophy. And, hypertension can produce perivascular and myocardial fibrosis, and medial thickening of the intramyocardial coronary arteries . ConsequLA structural and functional changes can be observed in HHD . AlthougWithout prompt antihypertensive treatment, HF and arrhythmias can occur in patients with LVH and abnormal LV geometry. HF with reduced ejection fraction and HF with preserved ejection fraction can be observed in patients with HHD. Ischemic events, including myocardial ischemia and stroke, can also accompany.Myocardial fibers are a 3-dimensional structure including circumferential fibers in the mid-wall layer and longitudinal fibers in the endocardial and epicardial layers. Myofiber can stretch, shorten and thicken, and these movements in different myocardial layers change myofiber orientation continuously from right-handed helix in subendocardium to left-handed helix in subepicardium . Thus, mLeft ventricular ejection fraction (LVEF) as conventional echocardiographic index does not represent intrinsic myocardial property. However, strain echocardiography, a newer echocardiographic modality, can measure myocardial deformation representing the intrinsic myocardial property.Myocardial strain is a dimensionless index that can represent myocardial performance. It can be calculated as the change from the original muscle length to the final muscle length after myocardial contraction and presented as a percentage Fig. . During − 1 and has the same direction as the strain value, negative value during shortening and positive value during elongation of the myocardium  include hemodynamic factors, chamber geometry, myocardial tissue characteristics, and synchrony of myocardial contraction.The increase in LV afterload or increasing heart rate can lead decrease in LVLS . Also, tSTE can measure LA strain Fig. A and RV Although echocardiographic strain assessment has relatively high inter-observer and intra-observer variability, as well as inter-vendor variability , it shouThere are several clinical utilities of STE in patients with arterial hypertension Fig. .Table 1P = 0.02). In contrast, Doppler tissue imaging (DTI) was able to detect an LV systolic dysfunction only in the patients with LVH (P < 0.001) [P < 0.001) and RS , higher CS , and twist  than controls. Although basal LS by DTI was not evaluated, velocity measures were normal in hypertensive patients without LVH. This finding demonstrates the advantages of 2-dimensional strain over DTI in the early detection of LV systolic dysfunction. Early impairment of myocardial contractility may be secondary to hemodynamic or biochemical changes. The increased end-systolic wall stress plays a crucial role in leading to longitudinal dysfunction in HHD. Chronic increase in end-systolic wall stress promotes the subendocardial synthesis of collagen, reducing longitudinal deformation.It is well known that a preclinical LV systolic dysfunction occurs in hypertensive patients with LVH . Even be< 0.001) . MoreoveKang et al.  revealedLVH is a common response to chronically elevated afterload, enabling normalization of LV wall stress and preservation of LV mechanical function . LVH is A previous study indicated that longitudinal LV contractility was decreased in healthy elderly people, and in patients with hypertension, diabetes, hypertrophic cardiomyopathy, or diastolic HF –64. The Age-related changes in LV relaxation have recently facilitated the detection of impaired LV diastolic function as reflected by E/A < 1 and a prolonged deceleration time of early diastolic transmitral flow with the widespread use of pulsed Doppler echocardiography. Several studies reported that diastolic LV dysfunction precedes systolic LV dysfunction especially in patients with cardiovascular risk factors such as hyperlipidemia, diabetes, hypertension, obesity, and smoking habits –72. LV m2 vs. 24 ± 4.9 mL/m2); strain of pump (− 5.7% ± 2.4% vs. − 17% ± 3.5%) and reservoir phases (34% ± 9% vs. 48% ± 10%) were worst. The minimum LA volume was higher (26 ± 10 mL vs. 15 ± 8 mL) and LA independent strain was lower in hypertensive patients . The LA independent strain quantifies LA reservoir phase deformation during isovolumetric relaxation. These findings suggest that in the early stages of HHD, the LA experiences a remodeling with dilation and reduction of LS in the pump and reservoir phase while sustains normal LVEF and global LS. LA strain represents a new tool in the evaluation of atrial function. STE is more sensitive method to initial changes in myocardial function and independent of the insonation angle, but since the absolute value is affected by the hemodynamic loading condition, the evaluation of LA strain during isovolumic relaxation may reflects a condition independent of the hemodynamic loading and traction by the atrioventricular plain [Previous study demonstrated that hypertension is directly associated with LA volume change, and it has been demonstrated that despite normal LA volume, there is abnormal LALS in hypertension . This shar plain . In addiArterial hypertension can impact pulmonary circulation and change pulmonary arterial structure. Sequentially, these can provoke RV remodeling. Common pathophysiologic mechanisms include common pathways of arterial hypertension and impaired LV diastolic function as results of increased LV afterload. Overstimulation of the sympathetic system and the renin—angiotensin—aldosterone system can alter pulmonary vascular structure and increase pulmonary vascular resistance. Increased pulmonary vascular resistance impairs RV function and causes RV hypertrophy, subsequently . ArteriaConventional echocardiographic study is insufficient in the demonstration of RV dysfunction in patients with arterial hypertension in several studies , 77–79. Hypertension is a well-recognized risk factor for the development of cardiovascular disease. Preclinical LV systolic dysfunction occurs in hypertensive patients and LVH, but even before LVH occurs, hypertension causes early changes in LV dynamics. Therefore, the accurate assessment of their influence on LV systolic and diastolic function in a subclinical state is clinically important for preventing the development of overt cardiovascular diseases. STE can detect subtle changes in myocardial dysfunction that cannot be detected with conventional echocardiography before the overt manifestation of LVH appear.Both longitudinal LV diastolic and systolic function can be impaired early even in asymptomatic patients with cardiovascular risk factors and preserved LV systolic function. In systolic phase, longitudinal shortening decreases and radial thickening was preserved, but the circumferential shortening increases to maintain the LVEF. In the diastolic phase, the early diastolic strain rate decreased, especially in the longitudinal direction, even if the LV filling pressure did not increase significantly. In this regard, strain appears to be more sensitive than both conventional echocardiography and DTI in identifying a decrease of intrinsic myocardial contractility in hypertensive patients even long before LVH occurs. Thus, the assessment of myocardial contractility by the STE will be useful in the early detection of subclinical systolic dysfunction and change of LV mechanics. Echocardiographic strain provides more insight into subtle changes in LV function in terms of identifying patients at higher risk for HF and clarifying its clinical impact on the prognosis of HHD.