ClinicalTrials.gov, Embase, and PubMed from 1 January 2010 to 1 January 2023. The search only included published RCTs on adult patients aged 18 and above, with heart failure with reduced ejection fraction (HFrEF). Data analysis was performed by using the software RevMan 5.4 . The included studies' bias risk was assessed using the Cochrane Collaboration's Risk of Bias tool. The quality of evidence for the primary outcome was done using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework.There exists a paucity of research data reported by analyses performed on randomized clinical trials (RCTs) that encompass quality of life (QOL) and the aftermath for patients suffering from heart failure with reduced ejection fraction (HFrEF). This systematic review and meta-analysis of randomized clinical trials (RCTs) have been done to evaluate the drug sacubitril/valsartan in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) with a clear focus on the effect it bestows on measures of physical exercise tolerance and quality of life. A thorough systematic search was done in databases including Cochrane Central Register of Controlled Trials (CENTRAL), 2 value is 61% , demonstrating a substantial heterogeneity within the studies. The left ventricular ejection fraction (LVEF) expressed in percentage was reported in the five studies, and thereby, a subgroup analysis that yielded a confidence interval (CI) of 95% had the standard mean difference of 0.02 . The trials had disparity between the reporting of effect on peak oxygen consumption (VO2), measured through cardiopulmonary exercise testing (CPET) methods, six-minute walking test (6MWT), overall physical activity, and exercise capacity. Sacubitril/valsartan did not exponentially improve peak VO2 or 6MWT in these trials; however, the patient-reported data suggested that the quality of life was modestly influenced by the drug. A subgroup analysis was performed using the pooled effect value by the random effects model. The findings showed that the sacubitril/valsartan group significantly was better than the control group in improving HFrEF-associated health-related quality of life (HRQoL).This systematic review and meta-analysis of RCTs yielded 458 studies, of which eight randomized clinical trials were included and analyzed. The meta-analysis of the included trials shows that the I2, or 6MWT with the use of sacubitril/valsartan; however, the reported exercise tolerance, including daytime physical activity, had a modest impact with the said drug. The pooled values demonstrated that the sacubitril/valsartan group significantly outperformed the control group in improving HFrEF HRQoL.This study is a systematic review and meta-analysis of randomized clinical trials that evaluated the drug sacubitril/valsartan in treating heart failure with reduced ejection fraction (HFrEF) and focused on its tangible effect on the measures of physical exercise tolerance and quality of life. It depicts that the statistical scrutiny due to the lack of significant data and parity across studies did not impart significant improvement of either LVEF, peak VO An operational or anatomical cardiac problem that impairs ventricular refilling or blood ejection to the systemic circulation causes heart failure (HF), a complicated medical condition. In essence, it is an inability to satisfy the underlying needs of circulation. Internationally, heart failure continues to be a condition with a significant death and disability rate . It is pHeart failure is classified according to its manifestations and determined left ventricular ejection fraction (LVEF). Heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with midrange ejection fraction (HFmrEF) are the three subtypes of heart failure caused by left ventricular dysfunction. The latter could include a variety of left ventricular dysfunction (a congruent effect of systolic and diastolic heart failure) .Etiology of heart failureHeart anatomical anomalies, cardiac functioning aberrations, and other initiating variables can contribute to congestive heart failure (CHF). In the past, myocardial infarction and coronary heart disease accounted for a vast majority of instances. The two strongest predictors for cardiovascular disease today are coronary artery disease and diabetes mellitus. Hypertension, valvular heart disease, uncontrolled arrhythmia, myocarditis, and congenital heart disease are other intrinsic causes of congestive heart failure (CHF). In addition to the obvious etiologies, restrictive cardiomyopathies and constrictive pericarditis can result in diastolic heart failure with poor ventricular filling .It is indeed critical to understand the causes of decompensated heart failure because they are mostly responsible for the incidence and death brought on by the condition. Reduced regular exercise, sodium limitation in the food, and incorrect medication therapy are the three main causes of decompensated congestive heart failure. The second most prevalent factor leading to decompensated heart failure is persistent hypertension . In indiElevated heart failure is characterized by a different spectrum of disorders connected to "congestive heart failure." By interpretation, this is not a myocardial function defect but rather the heart's inability to cope with the heightened systemic demands brought on by extracardiac illnesses. Severe anemia, thyrotoxicosis, obesity, nutritional deficiencies (such as thiamine deficiency), and pregnancy are common causes of this form of congestive heart failure .Epidemiology of heart failureHeart failure (HF) is a widespread healthcare concern that impacts roughly 2% of Westerners, with frequency rising significantly from 1% in those under the age of 40 to 10% in adults over the age of 75 .From 2013 to 2016, there were 6.2 million clinically evident cases of heart failure in the United States . AccordiSupported by small research studies from such countries, the most noticeable variation is a higher prevalence of isolated right heart failure. Theoretically, this is caused by the increased frequency of pulmonary, heart, and tuberculous diseases. Strong evidence is lacking to support such statements . The sciPathophysiology of heart failureDespite attempting to sustain acceptable cardiac efficiency, the adaptive mechanisms that may be sufficient to keep the heart's overall contractile function at a rough baseline state become problematic.Some compensatory mechanisms are used by cardiac physiology to modify during the early stages of congestive heart failure to sustain blood flow and satisfy systemic mandates. This encompasses cardiac hypertrophy, the Frank-Starling mechanics, modifications in myocyte renewal, and myocardial hypercontractility. The myocardium tries to make up for the incremental wall stress through eccentric remodeling, but this only worsens the loading circumstances and wall stress .The neuroendocrine system is stimulated by a decline in blood pressure, which results in the production of epinephrine, norepinephrine, endothelin-1 (ET-1), and vasopressin. Vascular constriction brought on by them increases afterload. Cyclic adenosine monophosphate (cAMP) levels rise, which in turn leads the myocytes' cytosolic calcium levels to rise. As a result, myocardial relaxation is further inhibited, and myocardial contractility is increased .Myocardial oxygen uptake rises as a result of an increment in afterload, cardiac contractility, and poorer myocardial relaxation. Myocardial cell loss and apoptosis ultimately occur from this contradictory requirement for higher cardiac output to meet myocardial needs. An ongoing loop of heightened neurohumoral excitement, decreased cardiac output, and unfavorable hemodynamic and myocardial responses results from the progression of apoptosis .Together with increasing salt and water accumulation and vasoconstriction, a decrease in cardiac output also stimulates the renin-angiotensin-aldosterone system (RAAS). This intensifies the heart's dysfunctional processes, which lead to progressive heart failure. The RAAS also secretes angiotensin II, which has been linked to an increase in interstitial fibrosis and cardiac cellular hypertrophy. This one has demonstrated that angiotensin II's detrimental effect causes myocardial remodeling to rise .History and physical criteria of heart failureHeart failure is typically diagnosed and categorized based on the presence/severity of symptoms and the results of a physical examination. To properly treat the patient, it is critical to gather a thorough history of symptoms, underlying medical issues, and functional capacity/exercise endurance. Breathlessness is the symptom that is most frequently mentioned .To clarify the potential causes of heart failure and choose the patient's treatment strategy, this complaint must be further qualified. It is necessary to categorize shortness of breath even further to ascertain whether it is transient or persistent and related to effort or postural changes (orthopnea) or both. Other manifestations of HF that are frequently mentioned include weariness, anorexia, tachycardia, and chest pain. Recumbent coughing, which some patients may present with, may be caused by orthopnea .Patients with heart failure require a thorough evaluation during the physical examination. Anxiety, diaphoresis, and poor nutritional status are among the general symptoms of individuals with severe, chronic heart failure or those with abruptly decompensated heart failure. The traditional diagnosis of pulmonary rales corresponds to moderate to severe heart failure .In cases of acute decompensated heart failure, wheezing may be evident. A mucus that is foamy and has a bloody tint may be seen as lung congestion becomes more severe. It is crucial to understand that respiratory congestion is not automatically ruled out by the lack of rales. A further common feature that all HF individuals must have evaluated is jugular venous distention . The KusDiagnostic criteria for heart failureAccording to the widely accepted Framingham Diagnostic Criteria for Heart Failure, the condition must meet either two main criteria or one major and two minor eligibility requirements to be diagnosed as having heart failure. Although this testing method has very low specificity, it is extremely sensitive for the diagnosis of heart failure .The major criteria include acute pulmonary edema, cardiomegaly, hepatojugular reflex, neck vein distention, paroxysmal nocturnal dyspnea or orthopnea, pulmonary rales, third heart sound (S3) gallop, weight loss of 4.5 kg or more in five days in response to treatment, central venous pressure greater than 16 cm of water, and radiographic cardiomegaly.The minor criteria include ankle edema, dyspnea on exertion, hepatomegaly, nocturnal cough, pleural effusion, tachycardia (heart rate greater than 120 beats per minute), and a decrease in vital capacity by one-third of the maximal value recorded.The New York Heart Association (NYHA) system does a poor performance of differentiating between HF patients with various levels of perceived disability. Studies done on trials discovered that the difference between NYHA classes II and III is a poor predictor of negative consequences in heart failure and fails to distinguish between patients across the breadth of functional disability and recognized that biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), the Kansas City Cardiomyopathy Questionnaire (KCCQ), and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and other markers of pathogenicity and patient-reported experiences may be more suitable for guiding recruitment methods and evaluating the effects of treatment approaches on clinical conditions . The claEvaluation of heart failureTo determine the source and/or degree of heart failure, a thorough scientific investigation is required, including testing for anemia, iron deficiency, renal dysfunction, and liver dysfunction. In individuals with persistent HF, serum osmolarity has a predictive value as a predictor of mortality . They asIn individuals with equivocal manifestations, serum levels of B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) can help distinguish between cardiac and noncardiac reasons for dyspnea. BNP is utilized to determine the rates of dying in individuals with heart failure since it is a significant determinant of elevated left ventricular end-diastolic pressure. BNP levels are used principally as a measure to evaluate treatment effectiveness and are correlated with New York Heart Association (NYHA) categorization ,22. NatrTransthoracic echocardiography (TTE) can identify the concentration of localized wall motion abnormalities or valvular pathology, evaluate for systolic and diastolic malfunction, and provide light on these conditions. However, it can be challenging to provide enough acoustic windows for people who have severe obesity, are pregnant, or use mechanical ventilation. These patients may benefit from other tests such as cardiac magnetic resonance imaging (MRI) or transesophageal echocardiography. The gold standard criterion for determining right ventricular (RV) function is cardiac MRI .Another method, despite the price, for assessing the functioning of the left and right ventricles is the radionuclide multiple-gated acquisition (MUGA) scan. When there has been a discrepancy in the ejection fraction (EF) readings from several investigations, patients will have a MUGA scan, which is the most reliable inspection to quantify ejection fraction (EF) . An addiScintigraph imaging with iobenguane I 123 injectable is known as iobenguane scanning. It has already been administered to individuals with an LVEF of around 35% and New York Heart Association (NYHA) classes II-III to determine their cardiac risk. Another homolog of norepinephrine is iobenguane I 123. The said examination can reveal how much norepinephrine is being taken up by the heart's sympathetic nerves. A better forecast is connected to norepinephrine reuptake that is strengthened . CardiovHeart failure with reduced ejection fractionHeart failure with reduced ejection fraction (HFrEF) is a form of heart failure that is characterized by a lower left ventricular ejection fraction and is one of the three types of heart failure ,27. It iStudies have shown that changes in left ventricular ejection fraction over time are associated with the risk of all-cause mortality or hospitalization for heart failure . HFrEF iAngiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, aldosterone antagonists, and device treatments have all been used in numerous major randomized controlled trials over the past few decades to show better survival in HF patients -32. TherHeart failure (HF) is a clinical illness that worsens with time and significantly lowers the quality of life (QOL). It is crucial to assist patients in maintaining their ideal QOL. Although definitions in the literature vary greatly and few consider the participant's perspective, QOL represents individuals' genuine impressions regarding the influence of a clinical experience of illness on ordinary living .Epidemiological data suggest that there is a huge burden of HF in the world . SurvivoOver the previous two decades, advances have been made in both the therapeutic and diagnostic aspects of HF treatment. Individuals with chronic HF and a low ejection fraction experienced a reduction in mortality rate when taking an angiotensin receptor-neprilysin inhibitor. The imbalance between the renin-angiotensin-aldosterone and natriuretic peptide systems is reduced by sacubitril/valsartan (LCZ696). The clinical effectiveness, practical experience, tolerability, validity of the etiology of cardiomyopathy, gender differences, and regulatory affairs of LCZ696 in the treatment of patients with HF with reduced ejection fraction have all been examined in previous studies . SacubitMethodologyLess attention has been paid to the overall aspect of health-related quality of life, which happens to be one of the main goals of HF treatment. In addition, earlier investigations provided different outcomes. It is currently unknown how sacubitril/valsartan affects the HRQoL. This study set out to undertake a thorough quantitative analysis of the data from recently published randomized clinical trials (RCTs) to determine how sacubitril/valsartan affected the quality of life in patients with HFrEF, which has previously been less explored. The methodology of this systematic review and meta-analysis is discussed in detail below.The Search Strategy Used in the StudyClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) to look for clinical trials relevant to the topic of interest. The search was a combination of Medical Subject Headings and keywords in the English language. The terms included were "heart failure," "HF," "heart decompensation," "heart insufficiency," "heart incompetence," "entresto," "sacubitril/valsartan," "valsartan/sacubitril," "sacubitril plus valsartan," "valsartan plus sacubitril," "sacubitril and valsartan sodium hydrate drug combination," "LCZ696," "angiotensin receptor/neprilysin inhibit," "ARNI," "neprilysin inhibit," "randomized controlled trial," "RCT," "controlled clinical trial," "random," "placebo," and "trial." To find relevant articles, these keywords were combined in varying combinations using the Booleans "and," "OR," and "not."A systematic search was made in the databases including PubMed, Embase, Timeline of the StudyThe literature search was carried out to identify studies conducted from 1 January 2010 to 1 January 2023.Study SelectionInclusion criteria: The inclusion criteria included the randomized controlled trials that included adult patients aged 18 and above with heart failure with reduced ejection fraction (HFrEF).Exclusion criteria: The exclusion criteria included duplicate reports, studies based on patients having HFpEF, studies that did not provide enough data to analyze the primary outcome, and studies in which the full text was not available.Data Extraction MethodThe data for this research project was extracted from each included study using a standardized data collection form that included the following: trial number/identifier, author, publication year, demographic characteristics, number of patients, intervention, control treatment, HRQoL outcome characteristics , and follow-up duration. The data analysis was performed by using the software RevMan 5.4  .The Statistical Method Used for the Analysis2 test was used to test heterogeneity. If there was no significant heterogeneity among the studies , the fixed-effects model was sought. If the heterogeneity among the studies was large , the random effects model sought and analyzed the causes of heterogeneity [Since different scales and questionnaires were used to assess the HRQoL, the continuous outcomes are presented as standardized mean difference (SMD) with 95% confidence intervals (CIs). For dichotomous outcomes, data were presented as risk ratio (RR) with 95% confidence intervals (CIs). The Z-test was used to calculate whether the pooled effect was statistically significant (p < 0.05). The χogeneity . In the Risk of Bias AssessmentThe risk of bias in the included studies was assessed using the Cochrane Collaboration Risk of Bias tool, and the assessment contents included (1) random sequence generation, (2) allocation concealment, (3) blinding of subjects and researchers, (4) blinding of outcome measurement, (5) incomplete outcome data, (6) selective outcome reporting, and (7) other biases .Quality of Evidence AssessmentThe quality of evidence for the primary outcome was done using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework , which cResultsStudy SelectionThe systemic search using the aforementioned parameters resulted in a total of 458 studies. Out of these 458 studies derived from the search, a total of eight studies -50 were The ACTIVITY-HF trial  investigIn the AWAKE-HF study , actigraThe Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction (EVALUATE-HF)  examinedThe OUTSTEP-HF trial  evaluateThe Prospective Comparison of ARNi With ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial  examinedThe Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure (PARALLEL-HF) trial  was carr2) was determined. A six-minute stroll trial was also conducted in this study.A study in Brazil comprised 52 patients with HFrEF and a left ventricular ejection fraction of less than 40% who were given enalapril or sacubitril/valsartan . ThroughThe LCZ696 In Hospitalized Advanced Heart Failure (LIFE-HF) study  dealt wiThe metadata obtained from the analysis of these selected eight studies is summarized in the tables below along with their detailed description of the analysis.Baseline Characteristics of the Included StudiesOver the course of a decade, the included trials evaluated the drug sacubitril/valsartan against a control drug to check for its efficacy, safety, and treatment modality to ensure HF patients achieve a stable quality of life. Table Comparison of the Age Groups Across the Included TrialsHF is a systemic disease rather than a singular phenomenon, and its symptoms might vary depending on factors such as age, gender, race, ethnicity, LVEF status, and the cause of the condition. Additionally, patients with HF and reduced LVEF exhibit different metabolic characteristics from those with HF, as well as intact LVEF, which recent investigations are starting to recognize deeper . The exiAccording to Saczynski et al., inhospital fatality rates rose from 3% for individuals under the age of 65 to 8.2% for some over the age of 75 . The cur2 value is 61% , which relays that there is substantial heterogeneity within the studies.The forest plot of the above comparison Figure  shows thComparison of the Drug Dosage Used Between TrialsWhen the doses of the drugs were looked at, sacubitril/valsartan had a standard of 200 mg twice daily (BD) dose. The control drug was enalapril in most studies , with the dose being 10 mg BD; however, on the study done in Brazil, it was 20 mg BD . The LIFComparison of the NYHA Classification of the Study ParticipantsIn the PARADIGM-HF trial , all theWhen compared to the enalapril group, in the PARALLEL-HF study , the sacComparison of the Mean LVEF (Percentage) of the Study SamplesA good prognosis has indeed been factored into individuals with HF with low EF who recoup their LVEF in previous studies . But thiSubgroup Analysis of LVEFA subgroup analysis of comparable parameters was done wherever feasible. A heterogeneity test was performed using the random effects model. Left ventricular ejection fraction (LVEF) was reported in the five studies as depicted in Figure There were not enough data to clearly demarcate if LVEF changes were significantly noticeable at follow-up in the individual trials. It is an important factor to note that a previous statistically sound study  that triAnalysis of the Levels of NT-proBNP and HFrEFIn order to assess changes in left ventricular ejection fraction (LVEF) in patients with heart failure and lower LVEF managed with sacubitril/valsartan, a prospective, single-armed, observation cohort research was conducted in Taiwan . IndepenAccording to the LIFE-HF study findings, reducing NT-proBNP levels in patients with advanced heart failure did not differ between sacubitril/valsartan and valsartan. This result was true for the majority of the subgroups investigated. By week 24 of treatment, the geometric mean NT-proBNP level in both the sacubitril/valsartan and valsartan treatment groups had fallen below baseline levels . The geoIn the EVALUATE-HF trial, at 12 weeks, the levels of NT-proBNP decreased more in the sacubitril/valsartan group than in the enalapril group . The PARThe PARALLEL-HF trial done in the Japanese cohort demonstrated that patients in the sacubitril/valsartan and enalapril groups experienced reductions in plasma NT-proBNP levels of 21.3% and 22.9%, respectively, after receiving treatment with 50 mg of sacubitril/valsartan twice daily for two weeks during the run-in phase. After that, NT-proBNP levels were lowered by 27.1% from the run-in baseline after two weeks of treatment with sacubitril/valsartan 100 mg BD post randomization, compared to 1.9% with enalapril 5 mg BD  . SacubitThe study done in Brazil showed that BNP and NT-proBNP levels did not change substantially after 12 weeks  .Comparison of the Follow-Up Duration of the TrialsTable Comparison of the Tools Used for Health-Related Quality of Life (HRQoL) MeasurementsThe HRQoL scales are approved instruments for evaluating individuals' standard of health. It can be separated into universal scales and specialized dimensions based on various testing goals. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) are internationally acclaimed cardiovascular failure-specific HRQoL scales, whereas the Short Form 36 (SF-36) and Nottingham Health Profile (NHP) are universal scales .Since the same tool was not uniformly used in all the trials Table , a meta-According to the AWAKE-HF trial, in about week 8, there were almost no considerable variations in the geometric mean ratio of activity counts during the busiest 30 minutes of the day  or in the mean change from baseline in activity during sleep . Sacubitril/valsartan showed a sub-chronic change from baseline to week 8 on the KCCQ-23 .As per the EVALUATE-HF trial, in the sacubitril/valsartan pool, the KCCQ overall summary score (OSS) increased by 8.9 points, while in the enalapril group, it decreased by 4.3 points  . PremiseFrom the PARALLEL-HF study's randomization to the pre-specified time points of week 8  and month 6 , sacubitril/valsartan showed a trend to a lesser deterioration of KCCQ clinical summary score for HF symptoms and physical limitations . The KCCA subgroup analysis was performed using the pooled effect value by random effects model. The findings showed that the sacubitril/valsartan group significantly outperformed the control group in terms of improving HFrEF HRQoL  as shown in Figure 2, Physical Activity, and Exercise CapacityComparison of 6MWT, VO2, 6MWT, physical activity, and exercise capacity. Hence, a descriptive analysis was performed on those trials reporting these outcomes. In the ACTIVITY-HF trial, the peak VO2 was measured by cardiopulmonary exercise testing (CPET) using a cycle ergometer during screening throughout the week, and week 6 and week 12 visits in accordance with most materials have emerged [The trials had disparity between reporting of effect on VO emerged .2) slope. The Borg scale for dyspnea and exhaustion showed a similar change in the rate of perceived exertion during exercise in both treatment groups at baseline and at week 12, showing that the patients in both arms of the study similarly fatigued themselves during CPET [At week 6 and week 12, there were no discernible treatment variations for alterations in the ventilation/volume of exhaled carbon dioxide (VE/VCOing CPET .In patients with heart failure (HF) with a decreased ejection fraction, OUTSTEP-HF examined the impact of sacubitril/valsartan versus enalapril on a six-minute walk test (6MWT) distance, non-sedentary daytime physical activity, and HFrEF symptoms . Sacubit2) and the six-minute walk test (6MWT). This trial recruited 52 patients with HFrEF and a left ventricular ejection fraction of less than 40% who were randomly assigned to receive either enalapril or sacubitril/valsartan. Through the use of cardiopulmonary exercise training, peak VO2 was determined. A test of a six-minute walk has also been conducted. At 12 weeks, peak VO2 climbed by 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/minute) in the sacubitril/valsartan group (mean dose: 382.6 ± 57.6 mg daily) and by 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/minute ) in the enalapril cohort (mean dose 34.4 ± 9.2 mg daily). However, there was no distinction between the groups (p = 0.332 interaction). Peak VO2 rose in both sacubitril/valsartan (mean dose: 400 ± 0 mg daily) and enalapril (mean dose: 32.7 ± 11.0 mg daily) at 24 weeks by 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/minute) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/minute), correspondingly. Following 12 or 24 weeks, individuals with HFrEF showed no appreciable improvement in peak VO2 or 6MWT as contrasted to enalapril [The RCT done in Brazil  examinednalapril .DiscussionAccording to recent scientific literature, patients with heart failure statistically significantly worsen in all areas of quality of life, not only in physical functionality. Compared to other very common chronic illnesses, whether cardiac or affecting other systems, the physical (role and functioning) health burden was much greater. Patients with heart failure appear to perceive their quality of life as being better when their treatment is optimized to enhance their NYHA class. Given the sharp deterioration in the quality of life associated with heart failure, healthcare interventions should focus considerably more on this endpoint, especially those that use medications such as ACE inhibitors and beta-blockers, which have been demonstrated to enhance the quality of life .In the current systematic review, it is important to note that in the PARADIGM-HF clinical study, sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), demonstrated primacy over enalapril in lowering cardiac deaths and readmission .Only the NYHA functional class was consistently and closely related to all quality-of-life scores, according to a study's multiple regression analysis. Only one of the eight quality-of-life areas  was explained by the six-minute walk test and peak oxygen consumption records .Along with other clinical outcomes, sacubitril/valsartan is also known to enhance health-related quality of life (HRQoL) and symptom load . SacubitThrough week 12, sacubitril/valsartan treatment in ACTIVITY-HF increased the 6MWT by 29 m as opposed to 17 m with enalapril, but the exploratory endpoint showed no statistically significant changes between the treatment groups. These findings are consistent with the previously released OUTSTEP-HF trial, which randomly assigned stable symptomatic HFrEF patients (NYHA class II/III) to an equivalent regimen. Sacubitril/valsartan was found to slightly improve the 6MWT by 35.09 m in the OUTSTEP-HF trial, but the treatment difference was not statistically significant .2 values of 12.9 mL/minute/kg for the sacubitril/valsartan group and 13.7 mL/minute/kg for the enalapril group, making them possibly more resistant to intervention than patients with less symptoms [2 of 19 mL/minute/kg, the Brazilian investigation did not find any appreciable variations in peak VO2 between sacubitril/valsartan and enalapril [2 [The ACTIVITY-HF trial did not find any treatment differences between sacubitril/valsartan and enalapril, which could be attributed to a multitude of reasons. Individuals in this trial had very low baseline physical activity levels according to mean basal peak VOsymptoms . Even innalapril . Due to april [2 ,69.2 and QOL measurements generally showed a favorable connection, according to this comprehensive study. The ACTIVITY-HF trial, in contrast to PARADIGM-HF, demonstrated improvements in KCCQ scores in both treatment arms without a significant difference in the groups. This may be due to changes in the two trials' experimental designs; for example, one of PARADIGM-HF's objectives was the change in KCCQ scores from baseline to eight months [Heavy smokers made up a larger share of the patients in the sacubitril/valsartan group, which may have hampered their ability to exercise more effectively . Improvet months .LimitationsThis is the first quantitative analysis of sacubitril/valsartan's effects on HRQoL in HFrEF subjects from the standpoint of evidence-based medicine obtained from RCTs only. The Taiwanese researchers factored that heart failure has an irrevocable endpoint and that no therapy may be effective if cardiac fibrosis reaches its final level . As a reThe RCTs included in this systematic review and meta-analysis do not exactly pinpoint if the patient had fibrosis set in, as no detailed three-dimensional echocardiography or cardiac magnetic resonance imaging data could be compared, which if available would have fine-tuned the analysis further. In this study, it was not possible to compare whether myocarditis was ruled out as exact data to compare all these RCTs were not adequately available.The findings, as mentioned in the results above, demonstrate sacubitril/valsartan's positive impact on HRQoL in HFrEF, reinforce the lack of evidence about its influence on the treatment of HFrEF, and add more details for the clinical use of sacubitril/valsartan. However, the meta-analysis performed needs to consider a few possible drawbacks. First, there were some variations in the length of follow-up between studies, which may have had some effect on the comparability. The aggregated effectiveness estimates, however, exhibited promising reliability. Furthermore, there were some restrictions on the consequences that were chosen, which were primarily affected by how the results were reported in research.Major changes in control medicines, average dose, the number of patients at various dose levels, and NYHA functional class between trials may have resulted in substantial heterogeneity between investigations on some endpoints. It was not possible to perform subgroup analysis due to a lack of sufficient data, even though some studies claimed that several demographic factors, such as age and etiology variations, could have had an influence on the treatment outcome with sacubitril/valsartan.The potential positive effects of both therapies  on aerobic fitness and its pathophysiological mechanisms should be examined in future trials comprising bigger sample sizes and longer follow-up periods with older adults and more severely impacted individuals with HFrEF.2 or 6MWT in these trials; however, the patient-reported data suggested that the quality of life was modestly influenced by the drug. The combined effects showed that the sacubitril/valsartan group improved the HRQoL score more than the control group in HFrEF. There were fewer clinical trials to evaluate the minimally significant improvement rate of HRQoL compared to the primary outcome, but the results from individual studies were consistent with the primary outcome's direction, further confirming sacubitril/valsartan's superior HRQoL improvement in HFrEF.This systematic review and meta-analysis study included eight randomized clinical trials. Sacubitril/valsartan did not exponentially improve peak VO


A newborn male child with prenatally identified aortic arch hypoplasia presented to our facility for cardiac management. He had been started on prostaglandins at the delivery facility and was subsequently placed on a high-flow nasal cannula due to associated apnea. On the day of life three, the patient underwent cardiac computed tomography scan for delineation of his anatomy. The patient remained intubated after his imaging study in anticipation of surgical intervention, which took place at the age of 5 days. The patient required a peritoneal dialysis catheter placement 2 days after his procedure due to oliguria. He progressed into renal failure requiring continuous renal replacement therapy.This patient was subsequently discussed at our departmental morbidity and mortality conference. The short time frame between contrast administration for the computed tomography and surgical intervention was thought to have contributed to his renal failure. We discussed the adequacy of transverse aortic arch imaging by echocardiogram and the utility of advanced imaging in the fragile neonatal period. This discussion resulted in our department asking, “Is transthoracic echocardiography accurate when diagnosing and characterizing aortic coarctation at our institution? Are advanced imaging studies necessary in instances of simple coarctation?” However, advanced cross-sectional imaging, including cardiac computed tomography (CT) and magnetic resonance imaging (CMR), has been increasingly used for surgical planning to provide conclusive anatomical details.3Coarctation of the aorta (CoA) is a frequently diagnosed congenital heart defect, and surgical repair is the second most common cardiac intervention performed in the neonatal period.Although these studies provide detailed anatomic information, advanced imaging exposes children to anesthesia, intubation, and radiation risks. TTE is known to be a safe, noninvasive imaging modality in children, but limited data are available correlating TTE findings related to CoA with advanced imaging in these patients.We investigated the current practice at our institute to evaluate and implement changes to reduce preoperative morbidity. The project aimed to determine our institution’s accuracy in the preoperative diagnosis and characterization of simple pediatric coarctation via the noninvasive modality of TTE in comparison to advanced imaging modalities. Given the morbidity associated with advanced imaging studies in the pediatric congenital heart disease population, we aimed to promote practice change that would limit the utilization of these imaging studies in routine cases.A single-center retrospective chart review from January 2015 to December 2020 identified patients diagnosed with simple CoA by TTE. Simple CoA was defined as coarctation of the aorta without other significant intracardiac abnormalities, except for minor lesions such as a bicuspid aortic valve or small ventricular or atrial septal defects. In contrast, we defined a complex CoA in the presence of other significant lesions, such as hypoplastic left heart, vascular ring, and interrupted aortic arch. These exclusions were performed to identify those patients who underwent advanced imaging strictly evaluating their CoA, as our underlying question pertained to the over-use of advanced imaging techniques in this population. Therefore, we included all simple CoA patients with preoperative TTE and advanced imaging in the study.t test. REDCap software was used for data management.We collected patient demographics and diagnostic data from all imaging modalities. The aorta was measured at specific anatomic locations for comparison: ascending aorta diameter via parasternal long axis views, proximal transverse arch diameter at the take-off of the brachiocephalic artery, distal transverse arch diameter before the left subclavian artery, and isthmus measurement in long segment CoA or narrowest diameter in discrete CoA. We obtained two sets of measurements and averaged from both studies to limit interoperative variability. We compared aortic arch findings and the accuracy of TTE with cardiac CT/CMR, using the Student paired Intervention: We presented the study results at a departmental research and quality improvement meeting attended by the medical and surgical staff. Recommendations were made regarding a change in practice. In addition, we discussed barriers to the changes. This educational intervention’s impact on changing our institute’s practice will be studied after 5 years.Baseline characteristics are presented in Table Table t test demonstrated a TTE mean measurement of 10.7 mm (SEM 0.8 mm) versus an advanced imaging measurement of 10.6 mm (SEM 0.7 mm) (P = 0.8). We noted that TTE measurements at the coarctation site tended to be smaller compared with cardiac CT/CMR, with measurements of 4.9 mm (SEM 0.3 mm) versus 5.8 mm (SEM 0.5 mm) (P = 0.02) in patients with discrete CoA. However, we did not consider this a clinically significant determinant for surgical planning.We obtained discrete measurements of the aortic arch by both TTE and cardiac CT/CMR. Although the exact measurements of the segments of aorta segments differed between two-dimensional TTE and cross-sectional imaging (cardiac CT/CMR), there was no significant difference in the transverse arch, typically used to determine the surgical approach for CoA repair. A paired 4TTE is the most frequently used imaging modality in pediatric cardiology, though using advanced imaging modalities has become more routine. Unfortunately, advanced imaging studies in this young patient population increases preoperative morbidity. Also, anesthesia and intubation, typically required for CMR in children, heighten the risk of associated adverse events. These risks are even more pronounced in the congenital heart disease population. Adverse events, ranging from bronchospasm and mild hypoxia to significant pulmonary edema and hypotension, may occur in as many as 10.4% of pediatric patients with congenital heart disease.5 One retrospective cohort study by Pearce et al demonstrated that cumulative radiation doses from CT scans in pediatric patients are associated with a heightened risk of leukemia and brain tumors.6 The utilization of cardiac CT/CMR exposes patients to increased risk compared with TTE but without a clear benefit in determining the surgical approach required in CoA repair.7The risks associated with anesthesia are not only applicable in CMR but also in the neonatal population requiring cardiac CT, as many of these patients will require sedation and intubation for image optimization given their young age. The National Cancer Institute also recognizes that no amount of radiation is safe. Pediatric patients are more sensitive to radiation than adults, and with a presumed longer lifespan, children have more opportunities to display the negative consequences of radiation.8Previous studies have attempted to determine the predictive value of aortic arch measurements in the preoperative diagnosis and management of obstructive aortic arch lesions. These studies have demonstrated a wide variability in the use of preoperative diameter definitions and indexed values for hypoplastic arches. The variability of measurement locations does not lend well to a normative predictive value.Our quality improvement analysis shows that TTE had a high degree of accuracy in ascertaining arch-sidedness, branching pattern, and coarctation type. As most indications for surgical intervention on the arch relate to clinical findings  and not discrete measurements by imaging studies, we can infer that arch characteristics and coarctation type are most helpful in determining the specific surgical approach. Therefore, limiting the use of advanced imaging studies that expose pediatric patients to increased risk should be emphasized.Limitations potentially influencing this study include the retrospective nature. When a TTE study had not appropriately evaluated a characteristic of the aortic arch, it was classified as inaccurate compared with advanced imaging, as all characteristics should be defined before surgical intervention in this population. In addition, we excluded patients with coarctation associated with other complex congenital heart disease  to limit sampling bias. These patients commonly undergo advanced imaging studies for reasons outside coarctation characterization and, therefore, would not be influenced by the outcomes/recommendations of our investigation. Our inclusion and exclusion criteria also helped make a more homogenous population. As in many pediatric studies, the population available for investigation remained quite limited, limiting our sample size for this study.Our study demonstrated that the noninvasive modality of TTE is highly accurate for the preoperative assessment of simple CoA and anatomic definitions in most pediatric patients. Therefore, with its associated risks, advanced imaging may be reserved for special circumstances. After 5 years, we will reassess our institutional practices relating to the utilization of advanced cross-sectional imaging in this population.The authors have no financial interest to declare in relation to the content of this article.


Cardiac involvement constitutes the primary cause of mortality in patients with Danon disease (DD). This study aimed to explore the cardiac magnetic resonance (CMR) features and progressions of DD cardiomyopathies in a family with long-term follow-up.Seven patients , belonging to the same family and afflicted with DD, were enrolled in this study between 2017 and 2022. The cardiac structure, function, strain, tissue characteristics on CMR and their evolutions during follow-up were analyzed.s r= −0.586), circumferential strain (r = 0.589), and longitudinal strain (r = 0.514) were all moderately correlated with the LGE proportions of corresponding segments (P < 0.001). T2 hyperintense and perfusion defect foci were identified, overlapping with the LGE areas. During follow-up, both the young male patients exhibited notable deterioration of their cardiac symptoms and CMR. The LVEF and strain decreased, and the extent of LGE increased year by year. One patient underwent T1 mapping examination. The native T1 value was sensitively elevated even in regions without LGE.Three young female patients  exhibited normal cardiac morphology. Four patients  displayed left ventricle hypertrophy (LVH), and mostly with septal thickening . A single male case  showed decreased LV ejection fraction (LVEF). Nonetheless, the global LV strain of the four adult patients decreased in different degree. The global strain of adolescent male patients was decreased compared to the age-appropriate female patients. Five patients  exhibited late gadolinium enhancement (LGE), with proportion ranging from 31.6% to 59.7% . The most common LGE location was the LV free wall , followed by right ventricle insertion points  and intraventricular septum . Segmental radial strain (Left ventricular hypertrophy, LGE with sparing or relatively less involved IVS, and LV dysfunction are prominent CMR features of Danon cardiomyopathy. Strain and T1 mapping may have advantages in detecting early-stage dysfunction and myocardial abnormalities in DD patients, respectively. Multi-parametric CMR can serve as an optimal instrument for detecting DD cardiomyopathies. Danon disease (DD) OMIM#300257) is a rare X-linked dominant lysosomal glycogen storage disorder induced by lysosome-associated membrane protein-2 (LAMP-2) deficiency . Dozens 57 is a rin vivo  is well-established for accurately evaluating cardiac structure, function, and tissue characteristics in various types of cardiomyopathies . Most noin vivo , 8. The in vivo –12. A hiThe proband experienced palpitations following conscious activity since age 13. He was initially admitted to our hospital at 14 years old due to palpitations accompanied by transient loss of consciousness. Echocardiography showed that the thickness of left ventricular (LV) posterior wall and interventricular septum (IVS) were 15 mm and 14 mm, respectively. LVEF remained within the normal range (65%). Additionally, electrocardiogram (ECG) demonstrated WPW syndrome. Subsequently, Danon disease was diagnosed at Beijing Union Hospital through electron microscopic examinations and genetic testing  with eight-channel or thirty-two-channel coil using retrospective ECG gating.Cine cardiac images were performed by breath-hold steady-state free precession (SSFP) in short-axis (from base to apex), four-chamber, two-chamber, and left ventricle outflow tract (LVOT) views. T2-weighted short-tau inversion recovery (T2w-STIR) images were obtained in multiple short-axis views with an 8 mm slice thickness, encompassing the entire LV and four-chamber views. First-pass perfusion imaging was acquired along with the administration of a bolus intravenous injection of 0.05 mmol/kg gadolinium-DTPA  at 4 ml/s through an arm vein. LGE images were obtained 10–15 min after intravenous administration of another 0.15 mmol/kg gadolinium-DTPA in multiple short-axis (from base to apex), two- and four-chamber views with phase-sensitive inversion recovery sequence. Native and post-contrast T1 mapping were obtained before and 15 min after the administration of gadolinium-DTPA, respectively, by a modified Look-Locker inversion recovery (MOLLI) method .CMR data were analyzed on an offline workstation using commercially available software . All the images were measured and assessed through consensus by two cardio-radiologist experts who were blinded to the clinical data. Any inconsistency was resolved by a senior supervisor.Segmental end-diastolic LV wall thickness (LVWT) was measured using short-axis cine images in a 16-segment American Heart Association (AHA) model. Moreover, the right ventricular (RV) wall thickness, end-diastolic dimension of LV (LVEDd) and RV (RVEDd) were measured. LV phenotype, asymmetric hypertrophy, and symmetric hypertrophy were defined according to the previous literature , 16. RV δR1myocardium/δR1blood), where R1 = 1/T1, and hematocrit level was determined from a venous blood sample prior to the CMR examination within 24 h. Then we obtained the maximal and minimal ECV by drawing areas of interest in regions with and without LGE, respectively.To avoid any influence on the judgment, T2-weighted images and perfusion images were assessed prior to LGE images. Hyperintense T2-weighted signal would be recognized if the ratio of myocardial signal intensity to skeletal muscle was greater than 1.9 . PerfusiP-values less than 0.05 were considered statistically significant.Data analysis was performed by SPSS software . Normality was determined using the Shapiro–Wilk statistical test. Continuous variables were presented as median and ranges. Categorical variables were presented as frequency and proportion. The correlation between segmental LVWT, LV strain and LGE proportions were assessed using Pearson's correlation coefficient  and Spearman's correlation coefficient . All tests were two-sided, and By summarizing the genetic analysis and medical history, the pedigree of the family was obtained . Among tCMR examination of Ⅳ-1, an asymptomatic 8-year-old boy, was failed due to lack of cooperation and subsequently excluded from the study. Therefore, seven patients  performed CMR examinations were eventually enrolled, including five females  and two males (14 and 20 years old). Their demographic features, clinical manifestations, ECG and laboratory results are summarized in Both IV-1 and IV-6 experienced cardiomyopathy with earlier onset during their second decade of life. Ⅱ-2, Ⅱ-3, and Ⅲ-2 manifest cardiomyopathy during adulthood. Four patients presented with palpitation , three with dyspnea , three with fatigue , and one with syncope (Ⅲ-1). Moreover, Ⅲ-1 exhibited attention deficit and learning difficulty, and Ⅲ-6 displayed learning difficulty. During the 12-lead ECG examination, Ⅲ-2, Ⅲ-1 and Ⅲ-6 were accompanied by WPW syndrome. Additionally, ECG of Ⅱ-2, Ⅱ-3, Ⅲ-4, and Ⅲ-5 showed inverted T waves.Serum enzyme analyses, including aspartate aminotransferase (AST), creatine kinase (CK), creatine kinase isoenzyme-MB (CK-MB), α-hydroxybutyrate dehydrogenase (HBDH) and lactate dehydrogenase (LDH) were performed. In Ⅲ-1 and Ⅲ-6, the levels of all aforementioned markers were significantly elevated. In the five female patients, only HBDH and LDH levels were slightly elevated.The cardiac structural features of DD are summarized in Except for one case with decreased LVEF , LVEF in the remaining six cases was normal . Global The cardiac tissue characteristics of DD are summarized in Mild to moderate hyperintensity on T2w-STIR were revealed in all five patients with LGE and all emerged in the LGE areas. Likewise, among the five patients with LGE, perfusion defect foci were demonstrated in some areas with LGE . Regardir = 0.238, P = 0.058). However, segmental radial strain (Spearman's r = −0.586), circumferential strain (Pearson's r = 0.589), and longitudinal strain (Pearson's r = 0.514) were all moderately correlated with the LGE proportions of corresponding segments (P < 0.001)  .Follow-up for all the seven patients lasted from 2017 to May 2022. Three patients  underwent follow-up CMR and summarized in Patient Ⅲ-6, a male adolescent, experienced multiple hospitalizations due to acute heart failure exacerbation. Cardioverter defibrillator implantation was indicated, but refused by the patient and his parents. Follow-up CMR were performed in 2019, 2021 and 2022 . The LVERegarding patient Ⅲ-1, a young male, the most prominent CMR change was the decrease of LVEF and strain values in 2019 compared to 2017 . The LV None of the five female patients  exhibited substantial symptom deterioration. With regard to Ⅱ-2, the extent and proportion of LGE markedly increased, the LV wall slightly thickened, and the LVEF mildly decreased in 2019 .This study presents the clinical and CMR features of seven DD patients followed up since 2017. To the best of our knowledge, this is the first study to assess the comprehensive CMR characteristics and evolutions of DD in a large family with long term follow-up. In our cohort, young male patients suffer from DD with severe presentation and aggressive progression vs. female patients. Furthermore, cardiac involvements are the most prominent clinical feature, such as arrhythmias and heart failure. The typically CMR features of DD were LVH, LGE of the LV, diminished strain , and preserved or reduced LVEF. Moreover, both T2 hyperintensity and resting perfusion defect were also frequently observed. Consistent with the clinical characteristics, these CMR changes in male patients appeared earlier and more significant, and progressed faster than female patients. As males have one X chromosome, while females have two. The haploinsufficiency of the X-linked LAMP2 gene in male patients, and the degree of skewed X inactivation in females lead to the sex-specific differences in clinical and CMR characteristics .Three young female patients showed normal cardiac morphology. This in part may reflect the late-onset of CMR change in female patients for both of the young males of similar ages presented with profound LVH. In our cohort, LVH in female patients tended to be asymmetric phenotype with predominantly thickened IVS, echoing the previous studies , 21. AccThe global longitudinal, radial, and circumferential peak strain of LV in the adult patients were all decreased to varying degrees. However, LVEF was reduced in only one young male patient. Additionally, the global strain of the adolescent male patient (Ⅲ-6) was decreased compared to the age-appropriate female patients. The high incidence and premature onset of global strain diminution indicate that DD may impact the ventricular contraction and relaxation resulting in a heart failure with preserved ejection fraction in initial stage. This advantage of global strain over LVEF has also been confirmed in previous studies on other heart disease , 23. DurLGE is nearly always seen in affected patients. A controlled CMR and histopathological study revealed that LGE regions corresponded closely to the distribution and extent of fibrosis and scarring in Danon cardiomyopathy . In our Native T1 and ECV are predominant quantitative parameters for CMR myocardial tissue characteristics, serving as optimal instruments for detecting diffuse and early-stage myocardial abnormalities. To our knowledge, there are only two previous literatures involving native T1 and ECV alterations in DD , 31. In sr = 0.238, P = 0.058). However, in a previous study concerning typical HCM, the regional LGE proportion moderately correlated with the corresponding LVWT  (sr = −0.586), circumferential strain (r = 0.589), and longitudinal strain (r = 0.514) were all moderately correlated with the LGE proportions of corresponding segments (P < 0.001). These findings suggest that the segmental radial strain value, as well as the absolute values of circumferential and longitudinal strains are negatively correlated with the extent of segmental LGE. Moreover, the global strain is diminished in the stage of heart failure with preserved ejection fraction in DD as revealed in this study. Therefore, it can be speculated that fibrosis and scarring in Danon cardiomyopathy may directly affect the regional LV strain, then the global strain, and eventually the LVEF.Our study further investigated the correlation between the segmental LVWT, LV strain and LGE proportions. The results suggest the correlation between the segmental LVWT and the corresponding segmental LGE proportions was not significant (< 0.001) . One pos< 0.001) . RegardiT2w-STIR imaging is one of the best approaches for oedema-weighted CMR, as it suppresses the signal of fat and flowing blood, and enhances sensitivity to myocardial free water content , 34. TheThere are several limitations to the present study. Firstly, a mere seven cases were incorporated. However, this in part reflects the relatively low prevalence of DD in the general population. It is exceedingly rare for all the seven patients come from the same family. Secondly, follow-up CMR were not conducted for all participants. The CMR follow-up of female patients needs to be further supplemented in. Thirdly, only a single patient underwent quantitative CMR, including T1 mapping and ECV.Left ventricular hypertrophy, LGE with sparing involved IVS, and LV dysfunction are common CMR features of Danon cardiomyopathy. LGE of IVS and RV free wall may emerge with the disease progression. Both abnormal T2 signal and perfusion defect foci are not rare, and may be employed to reflect the severity of the lesion. LV strain and T1 mapping may have advantages in detecting early-stage dysfunction and myocardial abnormalities, respectively, in DD patients. Therefore, further investigation is warranted to explore the applications of quantitative CMR techniques in DD.


The objective of this study was to investigate cardiac abnormalities in intensive care unit (ICU) survivors of critical illness and to determine whether temporary acute kidney injury (AKI) is associated with more pronounced findings on cardiovascular magnetic resonance.t test, Mann‐Whitney U test, and χ2 tests were used. There were 48 ICU survivors  and 20 healthy controls who were included. ICU survivors had elevated markers of myocardial fibrosis , more frequent focal late gadolinium enhancement lesions , and an impaired left ventricular function  compared with healthy controls. ICU survivors with AKI had higher myocardial T1  and extracellular volume fraction values  compared with participants without AKI.There were 2175 patients treated in the ICU (from 2015 until 2021) due to critical illness who were screened for study eligibility. Post‐ICU patients without known cardiac disease were prospectively recruited from March 2021 to May 2022. Participants underwent cardiovascular magnetic resonance including assessment of cardiac function, myocardial edema, late gadolinium enhancement, and mapping including extracellular volume fraction. Student ICU survivors of critical illness without previously diagnosed cardiac disease had distinct abnormalities on cardiovascular magnetic resonance including signs of myocardial fibrosis and systolic dysfunction. Findings were more abnormal in participants who experienced AKI with necessity of continuous kidney replacement therapy during their ICU stay.https://www.clinicaltrials.gov; Unique identifier: NCT 05034588.URL:  AKIacute kidney injuryCKRTcontinuous kidney replacement therapyCRScardiorenal syndromeECVextracellular volume fractionGLSglobal longitudinal strainLGElate gadolinium enhancementP=0.03; T1 relaxation time: 995±31 ms versus 957±21 ms, P<0.001; extracellular volume fraction: 24.9±2.5% versus 22.8±1.2%, P<0.001) compared with healthy controls.Survivors of critical illness without prior known cardiac disease showed mildly impaired parameter of left ventricular function and elevated markers of myocardial fibrosis in the absence of myocardial edema .Myocardial markers were more abnormal in participants after transient acute kidney injury .In the present era, it is important to highlight that such cardiac abnormalities may generally occur in intensive care unit survivors, regardless of COVID‐19 disease.Critical illness syndromes are characterized by different acutely life‐threatening clinical conditions that usually require intensive care unit (ICU) treatment and, if survived, can lead to physical, cognitive, and psychological impairment.Severe sepsis is often accompanied by acute kidney injury (AKI), a condition that is one of the most common complications of critical illness.In this cross‐sectional study, CMR was performed in ICU survivors of critical illness without previously known cardiac disease to investigate the extent of subclinical myocardial abnormalities such as fibrosis, inflammation, or ventricular dysfunction. Based on the latest evidence of type 3 CRS,clinicaltrials.gov (identifier: NCT 05034588).The data that support the findings of this study are available from the corresponding author upon reasonable request. This cross‐sectional study was approved by the institutional ethics committee . All participants gave written informed consent before CMR. The study is registered at Survivors of critical illness with past treatment in the ICU were screened for study eligibility. Patients with ICU treatment of >3 days at the Department of Anesthesiology and Intensive Care Medicine  between January 2015 and December 2021 due to critical illness 2 in the absence of CKRT.2 at the time of MRI were included. Intensive care scores  were derived from medical records. The control group consisted of healthy subjects without previous ICU stay and no cardiac disease history who underwent CMR for study control reasons. Controls had normal CMR results without structural abnormalities.Post‐ICU participants were subdivided into (1) participants who had recovered from AKI with necessity of CKRT during critical illness (AKI group), and (2) participants without acute or chronic kidney injury during critical illness (non‐AKI group). Only participants with history of AKI including temporary CKRT  with subsequent recovery of kidney function after ICU treatment were included. Convalescence was defined according to the Kidney Disease: Improving Global Outcomes guidelines as glomerular filtration rate ≥60 mL/min per 1.73 mAll CMR examinations were performed using a clinical 1.5T whole‐body system . ECG‐gated steady state free‐precession cine sequences, T2‐weighted short‐τ inversion‐recovery sequences, and late gadolinium enhancement (LGE) based on segmented inversion recovery gradient echo sequences were acquired in standard orientations. Myocardial T1 and T2 mapping was obtained in apical, midventricular, and basal end‐diastolic short‐axis view using the modified look‐locker inversion recovery scheme and the gradient and spin‐echo sequence sequence.Two experienced cardiovascular radiologists  performed image analysis in consensus agreement blinded to the clinical data using appropriate software . Functional analysis including the assessment of ventricular volumes, function, mass, and feature‐tracking strain  were analyzed as previously described.t test  or the Mann‐Whitney U test . Independence between dichotomous variables was tested using the χ2 test (when cell count >5) and Fisher exact test (when cell count ≤5). One‐way analysis of variance with subsequent Tukey multiple comparison tests was performed to compare CMR characteristics between the ICU subgroups and healthy controls. Continuous nonparametric variables between the 2 ICU subgroups were compared using the Kruskal‐Wallis test. Correlations between continuous variables were tested using Pearson correlation coefficients. The level of statistical significance was set at P<0.05.Statistical analysis was performed using SPSS Statistics  and Prism . Participant characteristics are reported as mean±standard deviation, median and interquartile range (IQR), or as percentages and absolute frequencies. Normal distribution was assessed visually using normal distribution plots and supplemented by the Shapiro‐Wilk test. Continuous variables were compared using the independent 2‐sample Student A total of 2175 patients with past ICU treatment due to critical illness was retrospectively screened for study eligibility . AKI and non‐AKI participants did not differ in terms of length of ICU stay, duration of mechanical ventilation, or intensive care scoring; however, the AKI group had higher absolute scores in all these categories (Table P=0.40). Troponin peak values showed no significant difference between the AKI and non‐AKI group (Table The AKI group consisted of 29 of 48 (60%) participants, and the non‐AKI group consisted of 19 of 48 (40%) participants. The AKI group received temporary CKRT over a median duration of 12 days . Over the clinical course, return of normal kidney function was observed in all AKI participants, as defined by the Kidney Disease: Improving Global Outcomes guidelines ; 8 of 48 ICU survivors (17%) demonstrated a left ventricular ejection fraction of <50%. Also, ICU survivors of critical illness had impaired GLS  and global circumferential strain  compared with healthy controls (Table P=0.008) but not in non‐AKI participants  but not between non‐AKI participants and healthy controls .Left ventricular ejection fraction was reduced in ICU survivors compared with healthy controls . A small pericardial effusion (≤10 mm) was detected in 10 of 48 ICU survivors (21%) but in none of the healthy control participants .Neither the post‐ICU group nor the control group had focal myocardial edema, and there were no group differences in global myocardial T2 relaxation times  and ECV values  were significantly higher in ICU survivors compared with controls. The AKI group had higher T1 relaxation times (1002±33 ms) compared with both the non‐AKI group  and the healthy control group   and the healthy control group . LGE was present in 10 of 48 ICU survivors (21%) and not detectable in healthy controls (P=0.03). From the participants with visible LGE, 5 of 10 (50%) had an ischemic pattern, 4 of 10 (40%) had a nonischemic pattern, and 1 of 10 (10%) showed pericardial enhancement  and the non‐AKI group . Participants with AKI had a higher LGE extent compared with healthy controls  . There were no significant correlations found between myocardial T1 relaxation times and the length of ICU stay , the duration of mechanical ventilation , or the duration of CKRT during ICU stay . Intensive care scoring Simplified Acute Physiology Score II and Therapeutic Intervention Scoring System‐10 correlated significantly with quantitative LGE values (%) . No significant differences were found between participants with and without previous extracorporeal membrane oxygenation treatment in functional  or structural parameters . There was no significant difference in the presence of LGE  or quantitative parameters  among ICU survivors with and without COVID‐19 during ICU treatment.In ICU survivors of critical illness, peak troponin T values correlated with myocardial T1 relaxation times  that survivors of critical illness without prior known cardiac disease had signs of myocardial fibrosis and systolic cardiac dysfunction, and (2) that these abnormalities were more pronounced after transient severe AKI. Our findings suggest that survival of acute critical illness requiring intensive care can be associated with clinically unrecognized cardiac sequelae, and those cardiac abnormalities appear to be exacerbated by severe AKI.Critical illness causes an acute state of stress that affects the body and heart in several ways, including dysregulated proinflammatory and immunosuppressive mechanisms as well as neurohormonal and electrolyte disturbances associated with fibrotic cardiac remodeling.Compared with healthy controls, we found elevated myocardial T1 and ECV values in combination with normal myocardial T2 values in ICU survivors of critical illness, which may indicate the presence of diffuse myocardial fibrosis. Post‐ICU participants who recovered from AKI had the highest levels of myocardial T1 and ECV values, suggesting an association between AKI and the development of diffuse myocardial fibrosis. Profibrotic potential has been found to be associated with both chronic and acute kidney disease, with prolonged activation of the renin‐angiotensin‐aldosterone system appearing to promote cardiac fibrosis.In line with previous literature describing sepsis as a common cause of AKI,Two previous echocardiography studies found left ventricular dysfunction to be common during critical illness.Some limitations have to be mentioned because of the observational form of this study. The sample size was moderate, and statistical tests may be underpowered. However, recruiting survivors of critical illness who are still eligible for CMR examination is challenging. Some differences in clinical diagnoses and treatment remained that might be confounding factors on cardiac involvement in this study. Although patients with systemic diseases with potential cardiac involvement were excluded, cardiac abnormalities might also have been present as unrecognized/subclinical conditions before the ICU stay. Also, time between ICU treatment and CMR varied. Participants in the AKI group were more frequently diagnosed with sepsis, which could be a confounding factor, because sepsis has been shown to cause myocardial injury.In conclusion, we showed that survivors of critical illness have unrecognized cardiac abnormalities suggestive of myocardial fibrosis and systolic dysfunction. These findings were observed in participants without known cardiac disease, indicating effects of critical illness and AKI on cardiovascular health. Transient AKI requiring CKRT was associated with more pronounced signs of myocardial fibrosis and systolic dysfunction. Because these cardiac findings may be associated with poor long‐term outcomes, survivors of critical illness could benefit from close cardiovascular monitoring. Unrecognized fibrotic and functional myocardial abnormalities in ICU survivors of critical illness may also be associated with physical impairment in postintensive care syndrome. In the present era, it is important to highlight that such cardiac abnormalities may generally occur in ICU survivors, regardless of COVID‐19 disease. Future studies should further investigate the prognostic value of such cardiac abnormalities detectable by CMR in patients after critical illness as well as in patients after AKI.A.I. was funded by the BONFOR Research Commission of the Medical Faculty Bonn (BONFOR‐Forschungskommission der Medizinischen Fakultät Bonn) and by the German Research Foundation  under Germany's Excellence Strategy EXC2151–390873048. The funders had no influence on study conceptualization and design, collection and analysis of the data, article preparation, as well as the decision to publish.The authors declare relationships with the following companies: C.C.P., speakers bureau: Guerbet, Philips Healthcare and Bayer Vital; grant support: Guerbet, Medserena AG. U.A., speakers bureau: Siemens Healthcare. J.‐C.S., grant support: Maquet Getinge. J.A.L., speakers bureau: Philips Healthcare; research consultant: Bayer AG. The authors declare that this research article was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study aimed to evaluate the early morphology and function of the left heart in hypertrophic obstructive cardiomyopathy (HOCM) after transapical beating-heart septal myectomy (TA-BSM) using cardiovascular magnetic resonance (CMR).Between April 2022 and January 2023, HOCM patients who underwent CMR before and 3 months after TA-BSM were prospectively and consecutively enrolled in the study. Preoperative and postoperative cardiac morphological and functional parameters, including those for the left atrium (LA) and left ventricle (LV), were compared. The left ventricular remodeling index (LVRI) was defined as the ratio between left ventricular mass (LVM) and left ventricular end-diastolic volume (LVEDV). Healthy participants with a similar age and sex distribution were enrolled for comparison. Pearson or Spearman correlation analysis was used to investigate the relationships between the parameters and LVRI. Last, univariate and multivariate linear regression identified variables associated with the LVM index (LVMI) and LVRI.Forty-one patients  and 41 healthy control participants were evaluated. Eighteen (44%) HOCM patients were classified as having a sigmoid septum, and 23 patients had a reverse septal curvature. LA volume, diameter and function were significantly improved postoperatively, but still worse than healthy controls . Compared to before the operation, left ventricular wall thickness, left ventricular ejection fraction (LVEF), LVMI, and LVRI decreased after TA-BSM . The left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-diastolic diameter (LVEDD) decreased in patients with a sigmoid septum. However, LVEDVI and LVEDD increased in those with a reverse septal curvature (both p < 0.001). In addition, both preoperative and postoperative LVRI was positively correlated with LVMI  and maximum wall thickness , respectively. In the multivariable analysis, the weight of the resected myocardium  and △mitral regurgitation degree  were associated with △LVRI. Last, the △LVOTG  and baseline LVMI  were independently associated with greater left ventricular mass regression after TA-BSM.CMR confirmed early reverse remodeling of left heart morphology and function in HOCM patients following TA-BSM. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiomyopathy with an incidence of 0.2–0.5% and is characterized by asymmetric myocardial hypertrophy . Left veThe most effective treatment to relieve LVOT obstruction in HOCM and significantly reduce the risk of SCD is surgery , 5. TranSurgery relieves the mechanical stress overload of the left ventricle (LV) and greatly improves the LV hyperdynamic state. It is essential to evaluate left heart morphology and function accurately after surgery. Cardiovascular magnetic resonance imaging (CMR) has been widely used for the non-invasive evaluation of cardiac morphology and function, particularly considering that it is the gold standard for cardiac function. Previous studies have shown that transthoracic myectomy effectively improves patients' clinical symptoms and cardiac function –9. HowevWe experimentally performed 10 cases of TA-BSM approved by the Tongji Hospital ethics committee and collected clinical data from the initial 10 HOCM patients as a pre-test result. The sample size was calculated according to the formula of the paired experimental design, taking into account the actual clinical surgical volume of this procedure (Standard transthoracic echocardiography (TTE) was performed to evaluate LVOT stenosis within one week before TA-BSM and to assess the surgical outcome three months after the operation. Conventional cardiac parameters were measured by two experienced echocardiographers. The peak LVOT velocity was acquired by continuous-wave Doppler echocardiography in the apical long-axis or five-chamber view in the resting and provoked states, respectively. The LVOT peak gradient was calculated using the simplified Bernoulli equation. Assessments of LV diastolic function performed were the ratio between early mitral inflow velocity and early diastolic mitral annular velocity (E/e') and mitral inflow early-to-late filling velocity ratio (E/A). Mitral regurgitation was graded as 0 (none), 1 + (mild), 2 + (moderate), 3 + (moderate to severe), 4 + (severe) . Systoli2, matrix size = 189 × 154, flip angle = 46°, temporal resolution 32 ms, and calculated phases 25.All patients underwent a standard CMR examination on a 3T system . Cine images  were acquired with ECG-gated and breath-holding using a segmented, balanced, steady-state free-precession sequence. Short-axial cine covered the LV from the apex to the mitral valval ring. The typical parameters were: section thickness = 8 mm, section gap = 2 mm, echo time = 1.39 ms, repetition time = 3.2 ms, field of view = 360 × 360 mmAll CMR function analyses were performed using commercial cardiac software . Epicardial and endocardial LV contours from the base to the apex were automatically delineated on short-axial cines. The maximum wall thickness of surgical and non-surgical segments was measured manually according to the sixteen American Heart Association (AHA) segments. Left ventricular end-diastolic diameter (LVEDD) was measured from anteroseptal wall to inferolateral wall in the middle short-axial slice at the end-diastolic phase. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV), cardiac output (CO), left ventricular ejection fraction (LVEF), and left ventricular mass (LVM) were obtained through end-diastolic and end-diastolic delineation. In addition, LVEDV, LVESV, CO, and LVM were indexed to the body surface area. The left ventricular remodeling index (LVRI) was calculated as the ratio between LVM and LVEDV (LVRI = LVM/LVEDV) , 13 whicmax) and minimum LA volume (LAVmin) were acquired with a combination of two- and four-chamber cine images at the end of ventricular systole and diastole. The left atrial ejection fraction (LAEF) was calculated as follows:The left atrial (LA) anteroposterior and LA left–right diameters were obtained on four- and three-chamber cine images, respectively. The maximum LA volume . Continuous and normally distributed data were expressed as means ± standard deviations (SD), while medians [interquartile range ] were used for variables with non-normal distributions. Categorical variables were presented as percentage frequencies and compared using the chi-squared test. Parameters at baseline and follow-up CMR were compared using the paired t-test if the differences conformed to a normal distribution. Otherwise, non-normally distributed variables were compared using paired Wilcoxon signed-ranks test. In addition, comparisons of normally distributed continuous variables between HOCM patients and the general population were performed using the independent sample t-test. Mann–Whitney U test were used for comparation of non-normally distributed continuous variables. Statistical significance was indicated by p < 0.05.s) were used to investigate the relationships between the parameters. Predictors of the left ventricular mass index (LVMI) reduction and LVRI were calculated using a stepwise multiple linear regression model entered as covariate factors. Last, variables with p < 0.05 were entered into the multivariable analysis.The change in each variable was denoted by △, equal to the preoperative value minus the postoperative value. The Pearson correlation coefficient (r) and Spearman correlation coefficients (rTwenty patients were random selected from HOCM patients and controls respectively for the intra- and interobserver reproducibility assessment of CMR parameters by the intraclass correlation coefficient (ICC). All measurements were performed by two observers who were unaware of the values obtained during the selection process. The intra-observer measurements were repeated after 2 weeks by observers unawarded of the previous data.Forty-one HOCM patients were enrolled in this study, with a mean age of 45.9 ± 2.4 years. A total of 65.9% were male. The baseline characteristics of the 41 HOCM patients are listed in Table All patients underwent TA-BSM performed by the same cardiac surgeon with 25 years of experience. Minimally invasive myocardial resection without extracorporeal circulation was performed to remove abnormal hypertrophic myocardium. The mean myocardial resection mass was 5.6  g. Almost all patients experienced an improvement in symptoms after TA-BSM, and intraoperative catheter manometry showed a decrease in LVOTG to normal levels (< 30 mmHg). A total of 92.7% of postoperative patients were classified as NYHA I or II compared to 41.5% before myectomy . LAEF increased postoperatively and was slightly lower than that of the healthy controls .As shown in Table The LV morphological and functional parameters of the study groups are displayed in Table 2 vs. 71  g/m2, 26 ± 1.1 mm vs. 19 ± 1.0 mm, both p < 0.001), but their LVEDD was smaller  mm, p = 0.001). In addition, SV, CI, LVEF, LVMI, LVRI, maximum wall thickness, and maximum wall thickness in the non-surgical segments were significantly reduced postoperatively in both subgroups . However, the left ventricular end-diastolic volume index (LVEDVI) and LVEDD decreased in patients with a sigmoid septum postoperatively  mm vs. post-TA-BSM, 47  mm, both p < 0.001) but increased in patients with reverse septal curvature  . After TA-BSM, both remained significantly associated with LVRI. The correlation between LVMI and LVRI was enhanced , but the correlation between maximal wall thickness and LVRI did not change significantly .The correlations between LVRI and conventional parameters are shown in Fig. Clinical variables, including patient demographics, echocardiographic parameters, and CMR measurement parameters, were analyzed to identify the predictors of reverse remodeling. In the univariate analysis, the weight of the resected myocardium, maximum wall thickness, △SAM, △LVOTG, baseline LVEDVI, and baseline LVMI appeared to predict a reduction in LVMI . However, in the multivariate analysis, only △LVOTG  and baseline LVMI  were independent predictors of LV mass regression .In this study, we performed a pre- and postoperative structural and functional analysis of the left heart during the TA-BSM procedure. Our study demonstrated the following three findings: (1) left heart morphology and function partially recovered after relieving the LVOT obstruction; (2) morphological remodeling after TA-BSM differs between the various types of hypertrophy; (3) baseline LVMI and maximum wall thickness were significantly correlated with LVRI both preoperatively and postoperatively; and (4) the weight of the resected myocardium and △mitral regurgitation degree might be associated with remodeling after TA-BSM. In addition, △LVOTG and baseline LVMI might be potential independent predictors of LV mass regression.There are two primary mechanisms of myocardial hypertrophy. The first is when genetic factors lead to cardiomyocyte hypertrophy and extracellular matrix fibrosis; the other is secondary hypertrophy caused by increased afterload . Genes aInitially, myocardial remodeling was used to describe changes in ventricular expansion and cardiomyocytes after myocardial infarction . VentricPrevious clinical studies have shown that drug and cardiac resynchronization therapy can somewhat improve cardiac size and function . CurrentThe phenotypic variation in HOCM patients results from a combination of many factors, including afterload, wall stress, and microvascular dysfunction . FinallySimilar to our results, a study of 44 patients with obstructive HCM reported a significant degree of regional LV thickness regression in all segments . AnotherDuring short-term follow-up, we found that the left ventricular myocardial mass was much greater than that resected during TA-BSM, strongly confirming left ventricular reverse remodeling. Previous studies have shown that abnormal gene expression persists despite ventricular function and structure improvements after reduced mechanical stress , 30. ThiThe primary pathophysiology in patients with sigmoid septum is LVOT obstruction. This process results in blood stagnation and increased pressure in the left ventricular chamber. The LV is progressively enlarged due to prolonged hyper-stress and is spherically dilated in most patients. In addition, patients in the reverse septal curvature group also experience diffuse hypertrophy of most segments, mainly manifesting as diastolic dysfunction. Systolic ventricular occlusion is common due to the space occupied by the over-thickened myocardium. Previously, there were fewer studies on HCM subtypes. Individualized treatment for different hypertrophic forms is critical.We also found that preoperative LVMI and ΔLVOTG correlated with LVMI reduction. Left ventricular hypertrophy, myocardial fibrosis, and the HF development are well-recognized . Left veA study of 71 patients with ventricular septal myectomy showed that sufficient relief of obstruction and lower resected thickness lead to more favorable remodeling . In addiThis study has several limitations. First, this was a single-center study with a small sample size because the clinical application time of this minimally invasive technique was brief. Therefore, the study results might not be generalizable. Second, we excluded patients who failed to undergo a complete CMR before and after surgery, possibly leading to selection bias. Third, we did not perform a predictive analysis because there were few clinically malignant events, and this study was only a short-term follow-up study. Last, we did not study the characteristics of late gadolinium enhancement in the myocardium because some patients did not complete perfusion or enhancement examinations for various reasons, such as mild renal impairment.Our study summarizes the CMR findings indicative of left heart remodeling after TA-BSM. Following partial ventricular septal resection, LVOT obstruction was entirely relieved. The degree of left ventricular myocardial hypertrophy was reduced, including in the non-surgical segments. In addition, the structure and function of LA and LV were recovered to some extent. Future studies are needed to verify the long-term structural and functional changes of the left ventricular myocardium in patients after TA-BSM.