Prognostic Implications of Septal Hypertrophy in Patients with Heart Failure with Mildly Reduced Ejection Fraction

Cardiac remodeling is frequently observed in patients with heart failure (HF) and serves as an indicator of disease progression and severity. Septal hypertrophy represents an aspect of remodeling that can be easily assessed via an echocardiographic measurement of the interventricular septal end diastole (IVSd), but it has not been evaluated for its prognostic value, particularly in patients with heart failure with mildly reduced ejection fraction (HFmrEF). We retrospectively included 1881 consecutive patients hospitalized with HFmrEF (i.e., a left ventricular ejection fraction of 41–49% and signs and/or symptoms of HF) at one institution during a study period from 2016 to 2022. Septal hypertrophy, defined as an IVSd > 12 mm, was prevalent in 34% of the HFmrEF patients. Although septal hypertrophy was not associated with all-cause mortality at 30 months (median follow-up) (HR = 1.067; 95% CI: 0.898–1.267; p = 0.460), it was associated with an increased risk of hospitalization due to worsening HF at 30 months (HR = 1.303; 95% CI: 1.008–1.685; p = 0.044), which was confirmed even after multivariable adjustment (HR = 1.340; 95% CI: 1.002–1.792; p = 0.049) and propensity score matching (HR = 1.399; 95% CI: 1.002–1.951; p = 0.048). Although septal hypertrophy was not associated with the risk of all-cause mortality in patients with HFmrEF, it was identified as an independent predictor of long-term HF-related rehospitalization.


Introduction
Heart failure (HF) remains a profound challenge to global health, contributing to significant mortality rates and healthcare expenditures [1][2][3][4].As a complex clinical syndrome, HF arises from various etiologies and pathophysiological mechanisms, leading to impaired cardiac function and alterations in the pressures and dimensions of the heart walls and cavities [5,6].Structural cardiac remodeling, characterized by changes in the genome expression, neurohormonal activation, and ventricular structure, such as the wall thickness, is observed in many patients with congestive HF and serves as an indicator of disease progression [7][8][9][10][11].Here, the interventricular septum (IVS) is of vital importance due to its role in maintaining the ventricular integrity and coordinating efficient cardiac pumping [12][13][14].Previous studies have shown that septal hypertrophy affects the systolic and diastolic left ventricular and atrial functions [15].treatment of the underlying cardiovascular disease may prevent the progression of septal hypertrophy and improve long-term outcomes [16,17].Furthermore, septal hypertrophy has been shown to be a predictor of mortality even in patients with normal indexed left ventricular masses [18].
With the 2021 European Society of Cardiology (ESC) guidelines introducing HF with mildly reduced ejection fraction (HFmrEF), which is defined as a left ventricular ejection fraction (LVEF) of 41-49%, a new patient cohort has been formed [19].This group has typically been excluded from prior randomized controlled trials [20][21][22][23], resulting in limited data, which complicates risk stratification and clinical decision making for patients with HFmrEF.
Transthoracic echocardiography is a commonly used tool to assess patients with HF.Because of its broad accessibility, fast handling, and cost-effectiveness, it has become the standard in the diagnosis and management of HF patients [19].With advancing technology, such as tissue Doppler imaging or speckle tracking, it is possible to measure additional parameters and indices that can assist in the precise assessment of the heart function [24][25][26].In clinical practice, however, the interventricular septal end diastole (IVSd) remains a frequently measured parameter to determine the extent of the left ventricular hypertrophy and underlying heart conditions due to its simplicity.Although the IVSd is regularly used in conjunction with other parameters to estimate the severity of the underlying heart disease [27,28], its prognostic value in predicting clinical outcomes has yet to be evaluated, particularly in patients with HFmrEF.
This study seeks to fill this knowledge gap by investigating the long-term prognostic value of the IVSd for the all-cause mortality and HF-related rehospitalization of patients hospitalized with HFmrEF using a large retrospective dataset.

Study Patients, Design, and Data Collection
For the present study, all consecutive patients hospitalized with HFmrEF at one institution were included from January 2016 to December 2022 [29].Using the electronic hospital information system, all relevant clinical data related to the index event was documented, such as the baseline characteristics, vital signs upon admission, prior medical history, prior medical treatment, length of index hospital and intensive care unit (ICU) stay, laboratory values, and data derived from all non-invasive or invasive cardiac diagnostics and device therapies, such as echocardiographic data, coronary angiography data, and data derived from prior or newly implanted cardiac devices.Every revisit to the outpatient clinic, echocardiographic assessment, rehospitalization related to HF, and adverse cardiac event was documented until the end of the year 2022.The number of HF-related rehospitalizations during follow-up was additionally documented.
The present study was derived from the "Heart Failure With Mildly Reduced Ejection Fraction Registry" (HARMER), representing a retrospective, single-center, all-comers registry including consecutive patients with HFmrEF hospitalized at the University Medical Centre Mannheim, Germany (clinicaltrials.govidentifier: NCT05603390).The registry was carried out according to the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee II of the Medical Faculty Mannheim, University of Heidelberg, Germany (ethical approval code: 2022-818).

Inclusion and Exclusion Criteria
All consecutive patients ≥ 18 years of age hospitalized with HFmrEF at one institution were included.All included patients underwent at least one standardized transthoracic echocardiography at index hospitalization in the cardiology department, where the diagnosis of HFmrEF was assessed.The diagnosis of HFmrEF was determined retrospectively according to the "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure" [19].Accordingly, all patients with LVEFs of 41-49% and symptoms and/or signs of HF were included.The presence of elevated amino-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels and other evidence of structural heart disease were considered to make the diagnosis more likely but were not mandatory for the diagnosis of HFmrEF.The presence of right ventricular dysfunction was defined as a tricuspid annular plane systolic excursion (TAPSE) < 18 mm.A standardized transthoracic echocardiography was performed by cardiologists during routine clinical care in accordance with the current European guidelines [30,31].The echocardiographic operators were blinded to the final study analyses.For the present study, patients with insufficient data quality of the index echocardiography to measure the IVSd were excluded.No further exclusion criteria were applied.All echocardiographic examinations and reports were reassessed post hoc by two independent cardiologists blinded to the final data analysis to determine the interrater reliability.In cases of ambiguous findings or documentation, the echocardiographic source data were reassessed in individual cases based on the available Digital Imaging and Communications in Medicine (DICOM) files.

Risk Stratification
For the present study, risk stratification was performed according to the presence or absence of septal hypertrophy.Septal hypertrophy was defined as an IVSd > 12 mm as assessed via transthoracic echocardiography during index hospitalization.The IVSd was measured in the parasternal long-axis view in accordance with current international guidelines [32].Further risk stratification was performed according to the severity of the left ventricular hypertrophy, and patients with IVSds ≤ 10 mm, 10-12 mm, >12-14 mm, and >14 mm were compared.

Study Endpoints
The primary endpoint was long-term all-cause mortality.Long-term was defined as the median time of the clinical follow-up in months.The secondary endpoints comprised rehospitalization for worsening HF, the in-hospital all-cause mortality, the all-cause mortality at 12 months, cardiac rehospitalization, acute myocardial infarction (AMI), stroke, coronary revascularization, and major adverse cardiac and cerebrovascular events (MACCEs) during long-term follow-up.The all-cause mortality was documented using the electronic hospital information system and by directly contacting state resident registration offices ('Bureau of Mortality Statistics').Identification of patients was verified by place of name, surname, date of birth, and registered living address.HF-related hospitalization was defined as a rehospitalization due to worsening HF requiring intravenous diuretic therapy.HF-related rehospitalizations comprised patients with hospitalizations due to worsening HF as the primary cause or as a result of another cause but associated with worsening HF at the time of admission, or as a result of another cause but complicated by worsening HF during its cause.Cardiac rehospitalization was defined as rehospitalization due to a primary cardiac condition, including worsening HF, AMI, coronary revascularization, and symptomatic atrial or ventricular arrhythmias.MACCEs were defined as the composite of all-cause mortality, coronary revascularization, non-fatal AMI, and non-fatal stroke.

Statistical Methods
Quantitative data is presented as means ± standard errors of the means (SEM), median and interquartile ranges (IQRs), and ranges depending on the distribution of the data.They were compared using the Student's t-test for normally distributed data or the Mann-Whitney U test for nonparametric data.Deviations from a Gaussian distribution were tested using the Kolmogorov-Smirnov test.Qualitative data is presented as absolute and relative frequencies and were compared using the chi-square test or the Fisher's exact test, as appropriate.The association between the IVSd and the other laboratory and echocardiographic parameters was measured with Spearman's correlation.Interrater realiability was tested using kappa statistics.Kaplan-Meier analyses were performed, stratified by the IVSd, and univariable hazard ratios (HRs) were obtained together with 95% confidence intervals (CIs).The prognostic impact of septal hypertrophy was thereafter investigated within multivariable Cox regression models using the "forward selection" option.
Due to the heterogeneous distribution of the baseline characteristics and comorbidities present within the all-comers registry, propensity score matching was performed to create more balanced subgroups and thereafter re-evaluate the prognostic impact of septal hypertrophy.Propensity score matching was applied for the comparison of patients with IVSds > 12 mm vs. ≤12 mm, including the entire study cohort, and a nonparsimonious multivariable logistic regression model was applied.Propensity scores were created according to the presence of the following independent variables: age; sex; body mass index (BMI); prior congestive HF; prior decompensation; prior myocardial infarction; prior percutaneous coronary intervention; chronic obstructive pulmonary disease; arterial hypertension; diabetes mellitus; hemoglobin; NYHA functional class; ischemic cardiomyopathy; AMI; diastolic dysfunction; the left ventricular end-diastolic diameter; beta blockers; SGLT-2 inhibitors; and ACE inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors at discharge.Based on the propensity score values counted via logistic regression, for each patient, one patient in the control group with a similar propensity score value was found (accepted difference in propensity score values: <5%).Within the propensity-score-matched subgroup, the Kaplan-Meier method was applied, and univariable HRs were obtained together with 95% CIs.
Results of all statistical tests were considered significant for p ≤ 0.05.SPSS (Version 28, IBM, Armonk, New York, NY, USA) was used for statistics.

Study Population
From 2016 to 2022, a total of 2228 consecutive patients with HFmrEF were hospitalized at our institution.Totals of 1.97% (n = 44) with incomplete follow-up data and 13.6% (n = 303) with insufficient data quality to measure the IVSd were excluded (Appendix A Figure A1).The final study cohort comprised 1881 patients hospitalized with HFmrEF with a median IVSd of 12.0 mm (mean: 12.4 mm; IQR: 9.9-14.8mm).Septal hypertrophy, defined by an IVSd > 12 mm, was present in 34% (n = 647) of all patients.The interrater agreement of the IVSd was high (κ = 0.890).

Discussion
The present study investigates the prevalence and prognostic value of septal hypertrophy on long-term prognosis in consecutive patients hospitalized with HFmrEF using a large retrospective registry-based dataset from 2016 to 2022.Septal hypertrophy, defined by an IVSd > 12 mm, was prevalent in 34% of all patients hospitalized with HFmrEF.Patients with septal hypertrophy were more commonly males and presented with higher rates of arterial hypertension, diabetes, chronic kidney disease, and valvular heart diseases.Although the presence of septal hypertrophy was not associated with the primary endpoint, all-cause mortality at 30 months, septal hypertrophy was associated with an increased risk of HF-related rehospitalization at 30 months, which was demonstrated using multivariable Cox regression analyses and propensity score matching.Specifically, patients with higher IVSds (i.e., >14 mm) were associated with the highest risk of HFrelated rehospitalization.
Various pathologies, like chronic volume and pressure overload due to arterial hypertension or aortic stenosis, ischemic diseases, storage diseases, and hypertrophic or dilated cardiomyopathies, are considered to cause myocardial hypertrophy [33,34].While the etiology may vary, the resulting hypertrophy can temporarily compensate for the underling alterations in some cases.In the long term, however, it may lead to cardiac remodeling, perfusion abnormalities, and diastolic dysfunction, further deteriorating the ventricular function [35].
While it remains unclear whether septal hypertrophy itself can cause HF, our observation of an increased risk of HF-related rehospitalization in HFmrEF patients with septal hypertrophy corresponds to the established concept of cardiac remodeling to impair the systolic function and increase the susceptibility to acute decompensation [36][37][38].Supporting evidence that shows that septal hypertrophy is not only a bystander of HF but also a contributor to it is provided in a study by Gardin et al. in which the IVSd was an independent predictor of the incident HF (HR = 1.87; 95% CI: 1.13-3.11;p < 0.001) in a population aged ≥65 years [39].While the prognostic value of the IVSd has not been evaluated in detail so far, various methods to measure LV hypertrophy have been used to

Discussion
The present study investigates the prevalence and prognostic value of septal hypertrophy on long-term prognosis in consecutive patients hospitalized with HFmrEF using a large retrospective registry-based dataset from 2016 to 2022.Septal hypertrophy, defined by an IVSd > 12 mm, was prevalent in 34% of all patients hospitalized with HFmrEF.Patients with septal hypertrophy were more commonly males and presented with higher rates of arterial hypertension, diabetes, chronic kidney disease, and valvular heart diseases.Although the presence of septal hypertrophy was not associated with the primary endpoint, all-cause mortality at 30 months, septal hypertrophy was associated with an increased risk of HF-related rehospitalization at 30 months, which was demonstrated using multivariable Cox regression analyses and propensity score matching.Specifically, patients with higher IVSds (i.e., >14 mm) were associated with the highest risk of HF-related rehospitalization.
Various pathologies, like chronic volume and pressure overload due to arterial hypertension or aortic stenosis, ischemic diseases, storage diseases, and hypertrophic or dilated cardiomyopathies, are considered to cause myocardial hypertrophy [33,34].While the etiology may vary, the resulting hypertrophy can temporarily compensate for the underling alterations in some cases.In the long term, however, it may lead to cardiac remodeling, perfusion abnormalities, and diastolic dysfunction, further deteriorating the ventricular function [35].
While it remains unclear whether septal hypertrophy itself can cause HF, our observation of an increased risk of HF-related rehospitalization in HFmrEF patients with septal hypertrophy corresponds to the established concept of cardiac remodeling to impair the systolic function and increase the susceptibility to acute decompensation [36][37][38].Supporting evidence that shows that septal hypertrophy is not only a bystander of HF but also a contributor to it is provided in a study by Gardin et al. in which the IVSd was an independent predictor of the incident HF (HR = 1.87; 95% CI: 1.13-3.11;p < 0.001) in a population aged ≥65 years [39].While the prognostic value of the IVSd has not been evaluated in detail so far, various methods to measure LV hypertrophy have been used to assess the prognosis of LV remodeling.An analysis of the studies of the left ventricular dysfunction (SOLVD) registry and trials by Quinones et al. used the cube formula applied to the IVSd and posterior wall thickness to estimate the LV mass in patients with LV dysfunction.In contrast to our findings, the LV mass was associated with both all-cause mortality (HR = 1.62; 95% CI: 1.62-4.66;p = 0.0002) and cardiovascular hospitalization (HR = 1.81; 95% CI: 1.39-2.36;p = 0.0001) [40].A different approach was used in a post hoc analysis of the CHARM trials, where Hawkins et al. assessed the LV hypertrophy via a 12-lead electrocardiogram (ECG).Using this method, the LV hypertrophy was an independent predictor of cardiovascular death in both patients with HF and LVEFs > 40% (HR = 1.58; 95% CI: 1.05-2.37;p = 0.029) and patients with LVEFs ≤ 40% (HR = 1.68; 95% CI: 1.09-2.58;p = 0.019), but not for hospitalization related to HF (HR = 1.03, 95% CI: 0.73-1.44,p = 0.884 and HR = 1.35, 95% CI: 0.94-1.95,p = 0.105, respectively) [41].Interestingly, the baseline characteristics differed between both groups.Arterial hypertension (81.1% vs. 61.6%)and atrial fibrillation (AF) (32.2% vs. 24.1%)were more common, and myocardial infarction (37.4% vs. 44.0%)and mitral regurgitation (18.9% vs. 25.7%) were less common in the group with LVEFs > 40%.These differences may account for the different clinical characteristics of the HF phenotypes and imply distinct etiologies of septal hypertrophy according to the LVEF, although the outcomes appear to be comparable between the two groups.
In line with this, a subsequent analysis of the PARAGON-HF trial reported comparable echocardiographic characteristics in patients with HF and LVEFs ≥ 45%.High proportions of the patients had comorbid arterial hypertension (94%) and AF (35%), but only 21% had a prior myocardial infarction [42].In line with the findings of the present study, Shah et al. demonstrated an increased risk of HF hospitalization (HR = 1.35; 95% CI: 1.01-1.81;p = 0.04) in patients with increased mean wall thicknesses, while no association with cardiovascular death (HR = 1.48; 95% CI: 0.91-2.40;p = 0.11) was found.
In contrast, a post hoc analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial suggested that the IVSd was able to independently predict both the all-cause mortality (HR = 1.46; 95% CI: 1.14-1.86;p = 0.003) and the risk of stroke (HR = 1.89; 95% CI: 1.17-3.08;p = 0.010) in patients with atrial fibrillation [43].It is worth mentioning that the AFFIRM trial only included patients with at least a moderate risk of stroke or death according to age and clinical risk factors, possibly limiting the comparability to unselected cohorts.
While our study defines the previously unclear prognostic value of septal hypertrophy in HFmrEF patients, further evidence that septal hypertrophy not only increases the susceptibility to HF hospitalization but also increases the mortality in selected patients is provided by a study conducted by Huang et al. [18].In a prospective cohort of coronary artery disease (CAD) patients, septal hypertrophy was associated with a higher risk of all-cause mortality (HR = 1.49, 95% CI: 1.00-2.23,p = 0.05 for mildly abnormal IVS thickness, and HR = 2.13, 95% CI: 1.29-3.54,p = 0.003 for moderately to severely abnormal IVS thickness, compared to patients with normal IVS thickness) [18].While the increased mortality contrasts with the present study, CAD patients may be more vulnerable to the deleterious effects of septal hypertrophy due to the additive burden of CAD and its associated complications.This underscores the complex interplay between comorbidities, cardiac structural changes, and clinical outcomes, emphasizing the need for tailored management strategies in different patient populations.

Study Limitations
This study has several limitations.Due to the retrospective and single-center study design, the results may have been influenced by measured and unmeasured confounding.In the absence of clear guideline recommendations for the treatment of patients with HFmrEF, cardiac magnet resonance imaging was performed on a minor part of the study population only and was not taken into account in the present study.Related to the overall low rates of patients with primary non-ischemic cardiomyopathy and hypertrophic cardiomyopathy, no further sub-analyses could be performed according to the prognostic impact of the IVSd in this specific population.HF-related and cardiac rehospitalizations were assessed at our institution only.In relation to the inclusion period until 2022, not all patients could have been followed for 30 months.Therefore, the primary endpoints were assessed in accordance with the median follow-up time of the study population.Finally, causes of death beyond index hospitalization were not available for the present study.

Conclusions
In summary, septal hypertrophy (i.e., an IVSd > 12 mm) was present in one out of three patients with HFmrEF.While the presence and absence of septal hypertrophy showed comparable risks of long-term all-cause mortality, septal hypertrophy was associated with a higher risk of HF-related rehospitalization at 30 months.

Figure 1 .
Figure 1.Kaplan-Meier analysis comparing the prognostic impact of septal hypertrophy versus that of no septal hypertrophy on the risk of all-cause mortality (left panel) and hospitalization for worsening HF (right panel) in patients with HFmrEF.

Figure 1 .
Figure 1.Kaplan-Meier analysis comparing the prognostic impact of septal hypertrophy versus that of no septal hypertrophy on the risk of all-cause mortality (left panel) and hospitalization for worsening HF (right panel) in patients with HFmrEF.

Figure 3 .
Figure 3. Kaplan-Meier analysis comparing the prognostic impact of septal hypertrophy versus that of no septal hypertrophy on the risk of all-cause mortality (left panel) and hospitalization for worsening HF (right panel) in patients with HFmrEF after propensity score matching.

Figure 3 .
Figure 3. Kaplan-Meier analysis comparing the prognostic impact of septal hypertrophy versus that of no septal hypertrophy on the risk of all-cause mortality (left panel) and hospitalization for worsening HF (right panel) in patients with HFmrEF after propensity score matching.

Table 2 .
Heart-failure-related and procedural data.

Table 3 .
Correlations of IVSd with laboratory, echocardiographic, and clinical parameters.

Table A1 .
Follow-up data and primary and secondary endpoints.HR, hazard ratio; ICU, intensive care unit; IVSd, interventricular septal end diastole; MACCEs, major adverse cardiac and cerebrovascular events.Level of significance, p ≤ 0.05.Bold type indicates statistical significance.