Left ventricular myocardial constructive work predicts reduction of ejection fraction in patients with heart failure with preserved ejection fraction

doi:10.21203/rs.3.rs-5268112/v1

We aimed to found predictors of EF deterioration in HFpEF patients toprevent their further deterioration. Methods. We studied 215 patients(63% women) 73±8 years with HFpEF and with records of Charlson index(CI), glomerular filtration rate (GFR). Myocardial work (MW), globallongitudinal (LS), radial (RS), circumferential (SS) and area strain(AS).GW index , global constructive work (GCW), wasted work, GWefficiency were obtained by echocardiography. Patients followed up for 3years. Results. 5 patients developed myocardial infarction and wereexcluded from the study.Baseline EF was higher in women (61,2 ± 3,1 vs56,4 ± 2,7; P<0.002), in patients >70 years (62,4 ± 2,1 vs 57,1 ± 2,3;p<0.005), and with end-diastolic volume index <60 ml/m2 (56,1 ± 3,2vs 63,4 ± 2,3; p<0.001). EF decline compared to baseline was -7.3 ±1.6%, p<0.01. EF decline was significantly more in patients >70 years, inpatients with coronary artery disease and did not relate to sex, LV size,CI, and GFR. During follow up 58(27%) patients had EF<50%.,worsening in AS (-27.9±8.5% vs -24.7±5.3%, p<0.003), LS (-19.7±2.4% vs -17.1±1.6%, p<0.005), and GCW (2378±117 vs2102±10, p<0.002). Patients with EF <50% at the end of the study hadless AS and GCWbaseline values compared with patients with EF>50% (22.4±7.2% vs -27.6±8.1%,p<0.002; 2081±92 vs 2489±127, p<0.001). GCW was thepredictor of EF deterioration(area under curve 0,8853). Conclusion. GCW predicts EF decline in HFpEF patients which may help earlieridentify this subset of patients and prevent their furtherdeterioration.

Heart failure (HF) is a worldwide health problem with high morbidity and mortality. Its prevalence has been increased over time, mainly due to increase in share of heart failure with preserved ejection fraction (HFpEF) in overall HF syndrome, because of increased life expectancy and the emergence of age-related comorbidities which in turn predispose to HFpEF [1].

HFpEF remained an unresolved issue for years regarding its management. Proven therapies for heart failure with reduced EF (HFrEF) failed to show benefit in that category.

Recently SGLT2 inhibitors have been proven to reduce hospitalization in patients with HFpEF [2]. However, despite the advances in the treatment of HFpEF, its management remains challenging. SGLT2 inhibitors benefits across the full range of ejection fraction [3], and sacubitril/valsartan benefits up to the lower end of preserved EF <57% [4] imply that in some patients with HFpEF some pathophysiological mechanisms of HFrEF might co-exist, and some subset of HFpEF patients might benefit from proven therapies of HFrEF, particularly those with EF deterioration over time. EF changes are not infrequent in patients with HF and many patients move from one HF category to another [5].

We aimed to find out predictors of EF deterioration in HFpEF patients assuming that we might start treating these patients subset earlier with proven therapies of HFrEF, preventing further deterioration.

Study population

All patients with dyspnea admitted to our hospital between 2019 and 2020 were examined for HFpEF. Diagnosis of HFpEF was made based on the HFA-PEFF algorithm [6]. Exclusion criteria were poor acoustic window, age > 80 years old, acute coronary syndrome at the time of admission, significant valvular heart disease (moderate to severe regurgitations or stenosis), atrial fibrillation, constrictive pericarditis or hypertrophic cardiomyopathy. 215 patients (63% women) 71±8 years with HFpEF and excellent echo acoustic windows were enrolled. Patients were followed up for 3 years.

Patients baseline characteristics

Hyperlipidemia was defined by the patient’s serum lipid spectrum. Diabetes mellitus (DM) was defined by fasting blood glucose levels, A1C Hb or previous records. Chronic obstructive lung disease was identified from previous medical records. Hypertension was identified by the patient’s history or if office triple measurements of systolic blood pressure or diastolic blood pressure are >140 mm Hg and/or >90 mm Hg respectively. Coronary artery disease (CAD) was diagnosed from previous medical records as a history of myocardial infarction (MI), coronary intervention, or coronary artery bypass grafting. Anemia was diagnosed if hemoglobin <13.5 mg/dL in men and <12 mg/dL in women. Glomerular filtration rate was calculated from creatinine levels by the estimation fromula [7]. Patients’ height and weight were taken at the time of enrolment for body mass index calculation. The level of comorbidity was evaluated by Comorbidity Index [8]. The use of β blockers, angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) prior to the study enrollment was documented.

Echocardiography

Echocardiography (EchoCG) was performed by two experienced echocardiographers using GE vivid 7 ultrasound system. All linear, volumetric measurements and assessment of left ventricular filling pressures were done according to joint ASE and EACVI recommendations [9,10]. 3D images were obtained by full volume acquisition from four cycles with the patient holding breath at the best visualization. All images were stored and analyzed offline using software EchoPac v.203. Speckle tracking were performed offline using Q analysis by manually tracing endocardium in 3 apical and 3 parasternal short axis views, after which the program automatically delineated left ventricular walls, manual correction were performed if needed, and then the program automatically obtained longitudinal (LS), circumferential (CS), radial strain (RS), area strain (AS) and LV twist values. Global work index (GWI) was obtained from pressure-strain loops derived from 2D speckle tracking analysis multiplied by brachial blood pressure measured right before the echocardiography exam with patient in the left lateral decubitus position. Global constructive work (GCW) as the sum of positive work due to myocardial shortening during systole and negative work due to lengthening during isovolumic relaxation, global wasted work (GWW) as energy loss by myocardial lengthening in systole and shortening in isovolumic relaxation, and global work efficiency (GWE) as the percentage ratio of constructive work to the sum of constructive work and wasted work were obtained. Ejection fraction and area strain (AS) were calculated in 3D using LVQ analysis on EchoPac.

Statistical analysis

Statistical analysis was conducted using SAS Version 9.2.1 with a significance level set at P < 0.05. Baseline clinical variables were summarized as means with standard deviations, medians with interquartile ranges for variables with skewed distributions, or as frequencies. Differences between groups were analyzed using t-tests for continuous variables and chi-square tests for categorical variables. To evaluate the longitudinal change in ejection fraction (EF), linear mixed effects regression models were employed, allowing for the fitting of a linear regression line for everyone. The cohort results were aggregated to assess overtime changes in EF. Only age and left ventricular end-diastolic diameter (LVEDD) were analyzed as continuous variables within the model, the other results were expressed categorically for simplicity in interpretation. In order to assess the prognostic importance of EF changes, EF was considered a time-varying variable in the Cox proportional hazards regression models.

Patients with HFpEF have high prevalence of hypertension, CAD and DM, anemia, the prevalence of smokers was relatively low (table 1).

Table 1. Baseline patient characteristics

Age, y	71±8
Gender (Women), n (%)	144 (67.0)
Current smoking n (%)	39 (18.1)
Diabetes mellitus n (%)	69 (32.0)
Hyperlipidemia n (%)	90 (41.9)
CAD n (%)	82 (38.1)
Anemia n (%)	71 (33.0)
COPD n (%)	60 (27.9)
Cerebrovascular disease n (%)	88 (40.9)
EDVi (ml/m²)	60.0 ± 12
eGFR, ml/min	56.9 ± 21.7
Charlson index ≥3	81 (37.7)
ACE/ARB n (%)	161 (75)
n (%)	137 (64)
MRA n (%)	146 (68)

The mean baseline value of EF was 58.7%. Baseline EF was higher in women, in patients >70 years, with anemia, and with end-diastolic volume index <60 ml/m². Overall reduction in EF was 7.3% over 3 years and was statistically significant and more prominent in patients >70 years, and in patients with CAD and did not relate to sex, LV size, CI, and GFR (table 2). 5 patients who developed myocardial infarction were excluded from the study.

Table 2. Ejection fraction values at baseline relative to patients’ characteristics

Baseline parameters	EF values	P value
EF mean (%)	58.7 ± 3.1
Women, n=144	61,2 ± 3,1	<0.002
Men, n=71	56,4 ± 2,7	<0.002
>70 years, n=112	62,4 ± 2,1	<0.005
<70 years, n=103	56,7 ± 2,3	<0.005
CAD yes, n=82	58,9 ± 2,9	0.12
CAD no, n=133	57,6 ± 3,3	0.12
EDVi (ml/m²) <median (60), n=87	63.4 ± 2.3	<0.001
EDVi (ml/m²) ≥median, n=128	56.1 ± 3.2	<0.001
Comorbidity Index ≥3, n=90	59.2 ± 3.8	0.23
Comorbidity Index ≤3, n=125	58.1 ± 3.5	0.23
eGFR (ml/min) <median (56.9), n=76	58.2 ± 3.1	0.28
eGFR <median, n=139	57.8 ± 3.5	0.28
Anemia yes, n=71	62.1 ± 3.8	< 0.002
Anemia no, n=144	56.9 ± 3.1	< 0.002

There was an overall decrease in EF by -7.3 ± 1.6% irrespective of baseline EF values. Reduction in EF was more prominent in patients >70 years, and in patients with CAD and did not relate to sex, LV size, CI, and GFR. (table 3).

Table 3. Changes in EF for 3 years follow up

Parameters	Change in EF over 3 years FU	P value
Overall change in EF (%)	-7.3 ± 1.6	<0.002
Women, n=142	-7.0 ± 1.9	0.34
Men, n=68	-7.4 ± 2.1	0.34
>70 years, n=109	-7.9 ± 1.8	<0.01
<70 years, n=101	-5.7 ± 1.7	<0.01
CAD yes, n=80	-7,8 ± 1,9	<0.001
CAD no, n=130	-5,3 ± 1,6	<0.001
EDVi (ml/m²) <median (60), n=85	-6.8 ± 1.5	0.53
EDVi (ml/m²) ≥median, n=125	-7.1 ± 1.8	0.53
Comorbidity Index ≥3, n=87	-7.2 ± 1.9	0.76
Comorbidity Index ≤3, n=123	-7.1 ± 1.7	0.76
eGFR (ml/min) <median (56.9), n=73	-6.9 ± 1.4	0.47
eGFR <median, n=137	-7.2 ± 2.1	0.47
Anemia yes, n=68	-7.3 ± 1.4	0.72
Anemia no, n=142	-7.2 ± 1.5	0.72

We observed significant reduction in AS, LS, GCW. (table 4)

Table 4. Changes in global strain values and myocardial work

Parameters	Baseline	3 years FU	P value
Longitudinal strain	-19.7±2.4%	-17.1±1.6%	<0.005
Circumferential strain (%)	14.3±3.5%	13.9±3.1%	0.18
Radial strain (%)	31.7±10.8%	29.8±10.1%	0.06
LV twist (%)	1.9±0.8	1.8±0.9	0.150
Area strain (%)	-27.9±8.5%	-24.7±5.3%	<0.003
GWI (mg%)	2470±161	2210±147	<0.005
GCW (mg%)	2378±117	2102±101	<0.002
GWW (mg%)	112±9	116±7	0.07
GWE (%)	95±2	94±3	0.21

There was a correlation of EF with LS, AS, GWI, and GCW (table 5)

Table 5. Correlation of deformation and myocardial work parameter with EF

	LS	AS	GWI	GCW
EF	0.43	0.52	0.51	0.59
P value	0.01	0.001	0.003	<0.001

58(27%) patients had EF<50%. Patients with EF <50% at the end of the study had significantly less AS and GCW baseline values compared with patients with EF>50%. (table 6).

Table 6. Baseline parameters of patients who consequently had EF <50% or >50% at the end of the study

Parameters	EF <50%	EF >50%	P value
Longitudinal strain (%)	-18.1 ± 2.2	20.2 ± 2.4	<0.01
Circumferential strain (%)	-13.4 ± 3.8	-14.5 ± 4.1	<0.04
Radial strain (%)	31.4 ± 11.2	31.8 ± 10.6	0.12
LV twist (%)	1.9 ± 0.9	1.9 ± 1.2	0.17
Area strain (%)	23.9±7.2	-28.8±8.1	<0.002
GWI (mmHg%)	2451±142	2493±158	0.06
GCW (mmHg%)	2081±92	2489±127	<0.001
GWW (mmHg%)	118±9	111±8	0.06
GWE (%)	94.6 ± 2.1	95.7 ± 1,8	0.05

GCW was the only predictor of EF deterioration (area under curve 0.8853) Fig. 1, Table 7

Table 7. Predictive values of deformation and myocardial work parameters for EF

Parameters	AUC
Longitudinal strain	0.6348
Circumferential strain(%)	0.5839
Radial strain (%)	0.6184
LV twist (%)	0.5841
Area strain (%)	0.6972
GWI (mg%)	0.6483
GCW (mg%)	0.8853
GWW (mg%)	0.6235
GWE (%)	0.6872

We conducted this study to assess the dynamics of systolic function in patients with HFpEF. We observed significant reduction in systolic function parameters, with average EF reduction of 7.3% over 3 years follow up. About a third of our patients with HFpEF had EF < 50% during follow up of which 12% had EF < 40% at the end of the study. Though HFpEF is considered as predominantly diastolic deterioration entity there are many pathophysiologic factors that determine concomitant systolic dysfunction [11]. Though some mechanisms of systolic disfunction has been proposed, including development of myocardial infarction, neurohormonal activation, infiltrative and inflammatory processes, the mechanism remains unclear. We excluded patients with new MI from the study, so it cannot explain EF decline in our study. Also, the Dunlay et al showed that neurohormonal modulator medication did not change the course of EF decline in patients with HFpEF [12].

In our study changes in EF were not affected by baseline LV dimensions, baseline EF and comorbidity index which suggests that other mechanisms than initial systolic functional status, neurohormonal activation and inflammation might be involved in the development of systolic dysfunction.

We observed a decline in longitudinal, circumferential and area strain in patients with EF reduction. These parameters positively correlated with EF, but GCW was the only predictor of EF decline. The results of the study allow to predict patients with later decline in EF so start treating them more aggressively. Though Dunlay et al study did not show benefit of ACE/ARB and \(\:\beta\:\:\)blockers [12] it is unclear how these patients would respond to the newer heart failure medications such as sacubitril/valsartan and probably gain more benefits from SGLT2 inhibitors when they are still in the normal EF range compared with their counterparts with lower risk of EF deterioration. We speculate that the patients with HFpEF with increased risk of systolic function deterioration might get more benefits from HFrEF evidence-based treatment, and it can be started before EF goes down. Though data from PARAGON-HF showed that ARNI are effective in patients with HFpEF with EF up to 57% [4], in our study EF decline did not relate to baseline EF values, and patients even with higher EF and lower GCW are at risk of EF decline and probably they might benefit from ARNI. Further studies are needed to answer this question.

HF	Heart Failure
HFpEF	Heart failure with preserves ejection fraction
HFrEF	Heart failure with reduced ejection fraction
EF	Ejection fraction
DM	Diabetes Mellitus
MI	Myocardial infarction
CAD	Coronary artery disease
EchoCG	Echocardiography
ASE	American Society of Echocardiography
EACVI	European Association of Cardiovascular Imaging
LS	Longitudinal strain
CS	Circumferential strain
RS	Radial strain
AS	Area strain
GWI	Global work index
GCW	Global constructive work
GWE	Global work efficiency
LVEDD	Left ventricular end-diastolic diameter
COPD	Chronic obstructive lung disease
EDVi	End-diastolic volume index
eGFR	Estimated glomerular filtration rate

Ethics approval and consent to participate

Study conduction has been approved by Yerevan MC Ethical Committee. All participants signed the consent.

Consent for publication

All participants signed the consent for publication at the time of signing the consent to participate

Competing interest

Authors have nothing to declare as a conflict of interests

Funding

The study was funded by The RA Ministry of Education, Science, Culture and Sports Higher Education and Science Committee

Authors contributions

Aram Chilingaryan Contribute to collecting patient's data, making and interpreting exams, writing papers.

Hovik Balyan Contribute to writing papers.

Milena Arzumanyan Contribute to collecting patient's data, making and interpreting exams, writing papers.

Tsiala Ustyan and Anush Barkhudaryan Contribute to making exams.

Nadezhda Iskandaryan-Contribute to collecting patient's data.

Armenuhi Asatryan Contribute to interpreting exams.

Harutyun Ghrmajyan Contribute to collecting patient's data.

Lusine Tunyan Contribute to collecting patient's data, making and interpreting exams, writing papers.

Acknowledgements

Aslanyan Levon for co-participating and providing programs for statistical analysis

Arzumanyan Ashot for revising the document

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No competing interests reported.

Left ventricular myocardial constructive work predicts reduction of ejection fraction in patients with heart failure with preserved ejection fraction

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Abstract

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Introduction

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Discussion

Abbreviations

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