Fluctuation of Dynamic Diastolic Function Relative to Static Cardiac Structure　― New Insights Into the Underlying Mechanism of Heart Failure With Preserved Ejection Fraction in Elderly Patients ―

Abstract

Background: The mechanisms of heart failure with preserved ejection fraction (HFpEF) need to be clarified immediately.

Methods and Results: We examined diastolic function relative to arterial elasticity among hypertensive patients with preserved EF. Diastolic elastance (EdI)/effective arterial elastance (EaI), EdI/EaI=E/e’/(0.9×systolic blood pressure [SBP]) was significantly more impaired in women than in men among patients ≥75 years. The higher EdI/EaI value in elderly women implies they are intermittently exposed to higher left ventricular filling pressure relative to SBP during daily life.

Conclusions: Highly fluctuating impairment of diastolic function relative to arterial elasticity may predispose elderly women to pulmonary edema.

Arterial Elasticity-Related Diastolic Function Relative to Cardiac Structure

Heart failure with preserved ejection fraction (HFpEF) is an important clinical condition that mainly occurs in elderly women.¹ Two major hypotheses may explain the pathophysiology of HFpEF: increased arterial stiffness^2,3 and left ventricular (LV) passive stiffness.^4–6 The pathophysiological base of HFpEF may be an extreme form of age-related deterioration with ventricular-arterial interrelation, possibly related to the prevalence of noncardiac comorbidities.⁷ Regression modeling has identified that changes in cardiac structure, such as greater LV hypertrophy (LVH) and atrial dilation, best distinguish HFpEF from hypertensive LVH without HF.⁸

However, the difference between elderly men and women in diastolic function relative to arterial elasticity, and its relation to alterations in the cardiac structure of hypertensive patients, remains unclear. We therefore sought to determine the age- and sex-related differences in diastolic function relative to arterial elasticity among hypertensive patients with preserved LVEF and no history of HF.⁹ We enrolled hypertensive patients with LVEF ≥50% (Table 1), and their echocardiographic parameters regarding arterial elastance and LV performance were measured. There were significant differences in estimated glomerular filtration rate (eGFR) and hemoglobin levels among 3 age groups in men (both P<0.001) and women (both P<0.001) by analysis of variance. The eGFR and hemoglobin levels decreased with age in both men (r=−0.349, P<0.001, and r=−0.469, P<0.001, respectively) and women (r=−0.418, P<0.001, and r=−0.214, P=0.002, respectively).⁹ The effective arterial elastance index (EaI=[0.9×systolic blood pressure (SBP)]/stroke volume index) and operant diastolic elastance index (EdI=E/e’/stroke volume index) did not differ significantly between the sexes. However, the EdI indexed as EaI, EdI/EaI=E/e’/(0.9×SBP), a new marker for diastolic function assessment, was significantly more impaired in women than in men only in patients ≥75 years old (Table 2, t-test). Furthermore, in the patients ≥75 years old, the coefficient of variation in EdI/EaI was larger in women and the variations of EdI/EaI values were significantly different between the sexes (P=0.002, F-test), although no differences were observed in patients <75 years old. There were significant differences in left atrial volume index (LAVI), LV mass index (LVMI), and EdI/EaI between patients aged ≥75 and <75 years, but only among women (Table 2).⁹ Thus, impairment of diastolic function relative to arterial elasticity, EdI/EaI, occurred in elderly women with hypertension and was coincident with alterations in cardiac structure. Importantly, the changes in 2 indices, EdI/EaI and LAVI or LVMI, coincidentally occurred at different time points between the sexes. Because this study was a retrospective database study, we did not have any invasive hemodynamic data. Furthermore, it was essential to exclude patients with coronary artery disease and atrial fibrillation, because in these comorbidities, the indices may be underestimated.

Table 1. Laboratory Data and Comorbidities in Hypertensive Participants and the 3 Age Groups (Modified From Hoshida et al⁹)

	All		P value	Group A: <65 years		P value	Group B: 65 years≤age<75 years		P value	Group C: ≥75 years		P value
	Men (n=267)	Women (n=212)		Men (n=85)	Women (n=48)		Men (n=89)	Women (n=81)		Men (n=93)	Women (n=83)
Age, years	69.4±10.1	70.9±10.0	0.099	57.8±6.4	57.1±7.2	0.554	69.6±2.7	69.6±3.0	0.956	79.8±4.1	80.2±4.3	0.472
eGFR, mL/min/1.73 m2	64.7±19.8	66.1±21.0	0.447	73.6±19.6	81.0±22.9	0.051	64.9±19.8	66.2±16.2	0.627	56.3±16.3	57.3±19.3	0.704
Hemoglobin, g/dL	13.7±1.8	12.6±1.5	<0.001	14.8±1.3	12.7±1.7	<0.001	13.7±1.7	13.0±1.1	0.003	12.8±1.8	12.1±1.5	0.003
Comorbidity, n (%)
Diabetes mellitus	60 (22)	43 (20)	0.320	20 (24)	13 (27)	0.403	21 (24)	15 (19)	0.267	19 (20)	15 (18)	0.419
Hypercholesterolemia	104 (39)	99 (47)	0.054	39 (46)	20 (42)	0.387	32 (36)	40 (49)	0.053	33 (35)	39 (47)	0.081

Data are mean±standard deviation or number of participants (percentage). eGFR, estimated glomerular filtration rate.

Table 2. Between-Sex and Between-Age Differences in Cardiac Dimensions and Diastolic Function Adjusted by Arterial Elastance (Modified From Hoshida et al⁹)

	<65 years	P value (A vs. B)	65 years≤age<75 years	P value (B vs. C)	≥75 years	P value*
	Group A		Group B		Group C
LAVI
Men	24.7±8.4 (34.0)	–	27.0±9.0 (33.5)	–	27.9±10.3 (36.9)	0.061
Women	26.1±8.7 (33.3)	1	25.5±8.0 (31.6)	0.002	30.2±9.7 (32.2)	0.001
P value (M vs. W)†
F-test	0.387		0.144		0.301
t-test	0.372		0.229		0.129
LVMI
Men	96.6±23.2 (24.0)	–	104.4±25.2 (24.1)	–	104.6±25.3 (24.2)	0.051
Women	95.9±27.6 (28.8)	0.621	94.8±19.3 (20.3)	0.008	103.0±23.5 (22.8)	0.019
P value (M vs. W)†
F-test	0.063		0.007		0.250
t-test	0.512		0.011		0.672
EdI=E/e’/SVI
Men	0.274±0.103 (37.7)	1	0.288±0.114 (39.5)	0.145	0.319±0.119 (37.2)	0.022
Women	0.277±0.087 (31.3)	1	0.264±0.088 (33.3)	<0.001	0.332±0.128 (38.7)	0.001
P value (M vs. W)†
F-test	0.093		0.009		0.237
t-test	0.881		0.117		0.504
EdI/EaI=E/e’/0.9×SBP
Men	0.083±0.022 (27.5)	0.228	0.090±0.032 (35.0)	0.257	0.098±0.027 (27.1)	<0.001
Women	0.088±0.024 (27.6)	1	0.085±0.029 (33.6)	<0.001	0.108±0.036 (33.1)	<0.001
P value (M vs. W)†
F-test	0.306		0.173		0.002
t-test	0.253		0.253		0.028

*Differences among all 3 age groups were appropriately assessed by 1-way analysis of variance or Kruskal-Wallis analysis. ^†Differences between sexes in each age group were assessed by F-test and t-test (Student or Welch). Data are mean±standard deviation (coefficient of variation, %). E, mitral inflow early diastolic filling velocity; e’, mitral annular early diastolic velocity measured by tissue Doppler; EaI, effective arterial elastance index; EdI, operant diastolic elastance index; LAVI, left atrial volume index; LVMI, left ventricular mass index; SBP, systolic blood pressure; SVI, stroke volume index.

Fluctuation of Dynamic Diastolic Function Relative to Static Cardiac Structure

Many patients with decompensated incident HFpEF relate a prior history of chronic exertional dyspnea or exertional intolerance, yet this earlier phase of HFpEF remains poorly characterized. Symptoms of exertional dyspnea and intolerance are highly sensitive for HF, but they are nonspecific and widely prevalent in the elderly where a number of conditions other than HF may cause or contribute to impaired functional capacity. Less is known regarding the potential for under-diagnosis of HFpEF in patients with lifestyle limiting symptoms but no clinical evidence of hypervolemia. Resting LV filling pressure is not elevated, despite marked elevations during stress such as exercise in compensated HFpEF outpatients.¹⁰ This emphasizes that congestion may only be an intermittent phenomenon in earlier HFpEF. In the patients referred to the cardiac catheterization laboratory for diagnostic evaluation of unexplained exertional dyspnea with normal resting hemodynamics, a subset of these patients display hemodynamic evidence of HF during exercise.¹¹ Furthermore, the ratio of LV filling pressure under exercise/rest was much higher than that of SBP under exercise/rest in these patients. This observation has been coupled with additional hemodynamic derangement characteristics of HF, including secondary pulmonary hypertension and impairments in heart rate and cardiac output reserve. An earlier stage of HFpEF characterized by normal resting but abnormal hemodynamics under various stresses could exist.

EdI/EaI and LAVI or LVMI were significantly higher in the older age group than in the younger age group of women, but not men. In women, alteration of cardiac structure in relation to hemodynamic changes occurs very late in life; in men, on the other hand, such alterations gradually occur. LAVI and LVMI are static parameters, and their variability during daily life might be small. On the other hand, a dynamic parameter, EdI/EaI=E/e’/(0.9×SBP) may be proportional to LV filling pressure relative to SBP, and the variability may be larger and the absolute values may be higher in elderly women than in men under various conditions. For example, among the elderly hypertensive patients (≥75 years) in our study, 13 of 83 women showed EdI/EaI values ≥0.145 (mean+standard deviation), but only 5 of 93 men showed that value (P=0.022). Furthermore, the patients exhibiting higher EdI/EaI values at rest will show further elevation of EdI/EaI values during stress. In other words, the transient markedly higher EdI/EaI values in elderly women imply that they may be intermittently exposed to higher LV filling pressure relative to SBP during daily life with various stresses. Highly fluctuating and more intensive impairment of diastolic function relative to arterial elasticity, irrespective of the steady state of cardiac structure, may predispose elderly women to pulmonary edema. Although both dynamic and static mechanisms are interrelated, the dynamic nature of LV performance and arterial elasticity are different from static behavior.

Future Directions

Age-related cardiovascular stiffening may be one of the key mechanisms in the occurrence of HFpEF.¹² Ventricular-arterial stiffening with aging is accelerated by obesity, hypertension, and changes in sex hormones.^13–15 The dynamic nature of diastolic function relative to arterial elasticity is less well appreciated and rarely considered clinically. Because patients are continuously exposed to these dynamic changes during daily life, recognition that LV filling pressure relative to systolic blood pressure fluctuates widely in HFpEF patients, even during the steady state, is clinically relevant. Because the arterial elastance-related diastolic function relative to cardiac structure may be severely impaired in patients with HFpEF, this provides new insights into the underlying mechanism of HFpEF. This marker of diastolic function assessment was independently associated with heart rate and renal function, in addition to age and LAVI in women, but not in men, in a multivariate analysis.⁹

The alteration in heart rate and/or renal function may also be a possible mechanism for exacerbation of diastolic function, leading to the occurrence of incidental HF in elderly women. The clarification of significant factors leading to the fluctuation of E/e’ and/or SBP, and the relationship between these factors and heart rate or renal function, may be a novel clue to the mechanism by which elderly women with hypertension are prone to exhibit HFpEF. A large-scale prospective study is being considered to clarify the differences between the sexes in the manner in which dynamic parameters of arterial and ventricular function, including EdI/EaI, change with age, and the differences in the course of age-linked alteration of cardiac structure.

Declaration of Interests

There are no relationships, financial or otherwise, that constitute a conflict of interest.

Acknowledgments

None.

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