Increased Myocardial Stiffness in Patients with High Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B HFpEF

Abstract

Background:

Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle-age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF.

Methods:

Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers [NT-proBNP (>40 pg/ml) or TnT (>0.6 pg/ml)] were recruited, along with 61 age- and sex- matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3D-echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion.

Results:

There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (e.g., PCWP: LVH: 13.4 ± 2.7, vs. control: 11.7 ± 1.7 mmHg, P<0.0001). The LV was less distensible in LVH than controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (PCWP – RAP), LV myocardial stiffness was nearly 30% greater in LVH compared to controls (LVH stiffness constant: 0.053 ± 0.027, vs. controls: 0.042 ± 0.020, P=0.028).

Conclusions:

LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than age- and sex- matched controls, and thus appears to represent a transitional state from a “normal healthy-heart” to HFpEF. Although, LV myocardial stiffness of LVH patients is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high risk individuals.

Clinical Trial Registration:

URL: https://clinicaltrials.gov/ct2/show/NCT03476785 and https://clinicaltrials.gov/ct2/show/NCT02039154; ClinicalTrials.gov Identifier: NCT03476785 and NCT02039154

Introduction

There are over 6.5 million patients with heart failure, with 960,000 new cases year in the United States.¹ Approximately half of all elderly patients with a diagnosis of heart failure have a normal appearing ejection fraction above 0.50, a condition referred to as “heart failure with a preserved ejection fraction (HFpEF)”.² This multifactorial condition is associated with several abnormalities in diastolic function including impaired relaxation, increased chamber stiffness as well as compromised ventricular-arterial coupling all of which can also develop to some degree with healthy ageing.^3–5 However, to date, no effective therapy for HFpEF has been found, and thus strategies to prevent HFpEF must be investigated to enable healthy ageing.

To elucidate the mechanism of developing HFpEF, two key observations should be emphasized: a) both aging and sedentary behavior are high risk conditions;^{6, 7} and b) that in contrast to sedentary seniors, healthy middle aged hearts have sufficient plasticity to restore more youthful compliance.^{8, 9} Indeed, we have recently demonstrated that age-related cardiac and vascular stiffening can be substantially prevented by exercise training 4–5 days/week⁷, and can even be reversed in previously sedentary middle aged adults.¹⁰ The purpose of this study was to identify a subgroup of individuals who are at particularly high risk for developing HFpEF, and to examine their underlying myocardial substrate to determine if there was evidence of cardiovascular structural abnormalities that are present in middle age, and might be amenable to modification by exercise training.

Data from the Dallas Heart Study has identified potential high risk markers for the development of heart failure.¹¹ In a representative, population based sample of adults with no previous heart failure, individuals with LVH and elevations in biomarkers reflecting subclinical myocardial injury (cardiac troponin T; cTnT) or neuro-hormonal activation due to hemodynamic stress (NT-proBNP) had a markedly increased risk of developing clinical heart failure, approximately 50% of which was HFpEF.¹¹ However, it is unknown if these individuals also have increased LV stiffness, a hallmark characteristic of HFpEF.

We hypothesized that individuals with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness, compared to healthy controls and therefore identify a group who demonstrate the earliest signs of HFpEF, as a manifestation of “Stage B” (the presence of structural changes without frank heart failure) of this disease. To test this hypothesis, we performed a comprehensive invasive and non-invasive assessment of cardiovascular structure and systolic/diastolic function in patients with LVH and elevated biomarkers, compared to healthy controls.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Participant Population and Study Design

Middle-aged (45–64 years) participants with LVH were recruited from the Dallas Heart Study (DHS), a population based, probability sample of the Dallas community,¹² enriched by review of hospital electrocardiography and echocardiography data bases to identify patients with asymptomatic LVH. In total 3,597 potential candidates were screened, 814 individuals met the initial inclusion criteria for our study including an ejection fraction >50% and documented LVH by MRI (125g/m²) or echocardiography (LV septum >11 mm) without exclusion criteria. One hundred forty who expressed an interest in the study underwent phone screening. Eighty-three subjects were tested for elevated biomarkers: either an elevated high sensitivity troponin (>0.6 pg/ml), or NT-proBNP (>40 pg/ml). Participants were excluded if they had signs or symptoms of heart failure, ischemic heart disease, prior myocardial infarction or stroke, greater than moderate valvular heart disease, COPD, sleep apnea syndrome, or were unable to exercise. Eventually, forty-six participants with LVH and elevated biomarkers were enrolled in this study, with sample size determined a priori (Figure 1). After informed consent was obtained, 24 hr ambulatory blood pressure monitoring was performed in all volunteers.

Figure 1. LVH Study Consort Diagram.

LVH, left ventricular hypertrophy; ECG, electrocardiography

All healthy control participants in this study were drawn by design from a previously published study with a detailed description of the subject population available eleswhere.¹⁰ In brief, sixty-one healthy, sedentary, middle-aged (45–64 years) participants were recruited from the Dallas Heart Study,¹³ Texas Health Resources, and the University of Texas Southwestern Medical Center, and through local media between September 2012 and February 2014. Participants had no comorbidities and were considered sedentary (did not meet physical activity guidelines [30 minutes, 3 days per week]).

The experimental procedures were explained to all participants, with informed consent obtained as approved by the institutional review boards of University of Texas Southwestern Medical Center at Dallas and Texas Health Presbyterian Hospital Dallas. All procedures conformed to the standards set by the Declaration of Helsinki. Trials were registered prospectively on ClinicalTrials.gov ( NCT03476785 and NCT02039154).

Cardiopulmonary exercise testing

Maximal oxygen uptake (VO₂ max) was measured using a modified Astrand-Saltin treadmill protocol and the Douglas bag technique; gas fractions were analyzed by mass spectrometry, and ventilatory volumes were analyzed by a Tissot spirometer, as previously reported.¹⁴ VO₂ max was defined as the highest oxygen uptake measured from at least a 30-second Douglas bag.

Hemodynamics

All experiments were conducted in the morning in a quiet environmentally controlled laboratory with an ambient temperature of 25°C. Subjects had a light breakfast at least two hours before data collection commenced and were asked to refrain from heavy exercise and caffeinated or alcoholic beverages for at least 24 hours prior to the day. A 6-F balloon-tipped, fluid filled catheter (Swan-Ganz catheter, Baxter, Deerfield, IL) was placed through an antecubital vein into the pulmonary artery using fluoroscopic guidance. Intravascular pressures were referenced to atmospheric pressure, with the pressure transducer (Transpac IV, Abbott, Chicago, IL) zero reference point set at 5.0 cm below the sternal angle. After at least 20-minutes of quiet supine rest, baseline data were collected. Analog waveforms were sampled at 250 Hz and the digital waveforms were analyzed off line using customized software (Biopac Systems Inc., Santa Barbara, CA). The steady-state mean pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) were measured using three separate measurements during a quiet, held end expiration (~ 5 seconds), excluding the V waves.¹⁵ Because external constraint influences ventricular volumes and pressure, LV end-diastolic transmural pressure-volume relationships were constructed using estimated transmural pressure (TMP= PCWP–RAP).¹⁶

Cardiac filling and thus LVEDP was decreased by 2-sequential levels of lower body negative pressure (LBNP) of −15 mmHg and −30 mmHg as previously described.¹⁷ Five minutes into each level of cardiac unloading, 3 separate measurements of mean PCWP and RAP were obtained at end-expiration. After release of the LBNP and confirmation of return to hemodynamic baseline with repeat measurements, cardiac filling was increased by 2-sequential levels with a rapid infusion of 15 and 30 ml/kg warm (37℃) isotonic saline at 200 ml/min. Hemodynamic measurements were obtained as previously described.

Echocardiography

The LV was imaged by 3-dimensional echocardiography (iE33; Phillips Medical System) at all loading conditions during the study. LV end-diastolic volume (LVEDV) was analyzed offline (Qlab 9.0; Phillips Medical System) by an experienced cardiologist who was blinded to filling pressures. The typical error of the LV volume measurement in our laboratory, expressed as a coefficient of variation, is 10% (95% confidence interval, 8%–12%).

Analysis of Hemodynamic Data

Cardiac output (Qc) was measured with the C₂H₂ rebreathing method.¹⁸ Heart rate was monitored continuously via an electrocardiograph (ECG), and stroke volume (SV) was calculated from cardiac output divided by heart rate. Blood pressure was measured at the brachial artery during cardiac output measurements. Arm cuff systolic and diastolic blood pressure (sBP and dBP) was measured by electrosphygmomanometry, with a microphone placed over the brachial artery to detect Korotkoff sounds. Lean body mass was measured by dual energy X-ray absorptiometry (DEXA). Due to the significant difference in body size between the two groups, the relationship between LVEDV and body size parameters were examined in order to determine the best method of the normalization. The correlation factor between LVEDV and body size parameters: height: R²=0.26, P<0.001; body mass: R²=0.31, P<0.001; body surface area: R²=0.33, P<0.001; BMI: R²=0.12, P<0.001; and lean body surface area: R²=0.39, P<0.001) was determined. The lean body surface area (= root square of height (cm) × lean body mass (kg) / 3600) yielded the greatest fit to LVEDV amongst these body size parameters and thus was used to scale all chamber volume measurements. The effective arterial elastance (Ea), representing afterload was calculated using 0.9 x systolic blood pressure divided by SV.¹⁹ A constant for LV chamber stiffness was modeled using commercially available software (SigmaPlot version 12.0, Systat Software Inc, San Jose, CA), which uses an iterative technique to solve the following exponential equation: P = P_∞ [ Exp {a (V-V₀) −1}],²⁰ where P is transmural pressure, P_∞ is pressure asymptote of the curve, V is LVEDV, V₀ is the equilibrium volume at which P is assumed to be 0 mm Hg, and a is the constant that characterizes chamber stiffness. The averages of the individual LV myocardial stiffness constants for all the participants within each group are reported and denoted as individual stiffness.¹⁶ PCWP and SV data were used to construct Frank-Starling curves. The SV, mean arterial pressure (MAP), and 3-dimensional LVEDV data were used to calculate preload recruitable stroke work relationships ( PRSW = [ SV × MAP ] / LVEDV ),²¹ where the slope was used as an index of global systolic function.

Statistical Analysis

Continuous variables are expressed as mean ± SD, and categorical variables are expressed as n (%). Nonparametric data were analyzed by Wilcoxon test. A chi-square test used for categorical variables. P-value of < 0.05 was considered statistically significant. Statistical analysis was performed using JMP ver. 11.0 (SAS Institute Inc., Cary, NC).

Results

Baseline characteristics

Participant characteristics are summarized in Table 1. Both groups exhibited similar demographics by design, including age and sex (P=0.184 and P=0.358, respectively). LVH participants had a larger body habitus (larger BSA, BMI, lean mass, and lean BSA) than control participants. Systolic and diastolic BP from ambulatory blood pressure monitoring in the LVH group was greater than controls (LVH vs. control group: systolic BP: 132.6±14.4 vs. 121.4±7.4 mmHg, P<0.0001; diastolic BP: 79.3±8.1 vs. 72.9±5.8 mmHg, P<0.0001), while HR was similar between the groups (P=0.828). There were significant differences in both interventricular septum and posterior wall thicknesses between the two groups (both P<0.0001). Peak oxygen uptake (peak VO₂) scaled to body mass was lower in the LVH group compared to the controls (LVH vs. control group: 25.2 ± 5.5 vs. 29.2 ± 5.1 ml/min/kg, P=0.0001), while unscaled peak VO₂ was comparable (LVH vs. control group: 2.26±0.62 vs. 2.41±0.76 L/min, P=0.416).

Table 1.

Baseline Characteristics

	Controls (n=61)		LVH (n=46)	P value
Age, years	52.4 ± 5.2		53.6 ± 5.7	0.184
Gender, Male	29 (47.5%)		26 (56.5%)	0.358
Height, cm	169.6 ± 9.7		172.3 ± 10.7	0.217
Body Mass, kg	75.3 ± 14.3		89.9 ± 15.7	<0.0001
Race/Ethnicity				<0.0001
Caucasian	48 (78.7%)		24 (52.2%)
Asian	6 (9.8%)		0
Hispanic	4 (6.6%)		3 (6.5%)
African American	1 (1.6%)		19 (41.3%)
American Indian	2 (3.3%)		0
Comorbidities				-
Hypertension	0		37 (80.4%)
Diabetic Mellitus	0		5 (10.9%)
Hyperlipidemia	0		15 (32.6%)
Smoking history	0		1 (2.2%)
Medications				-
ACE-inhibitors/ARB	0		27 (58.7%)
Ca2+ channel blocker	0		8 (17.4%)
Beta-blocker	0		7 (15.2%)
Diuretics	0		10 (21.7%)
BSA, m2	1.88 ± 0.23		2.06 ± 0.23	0.0001
Lean Body Mass, kg	50.7 ± 11.0		56.3 ± 11.6	0.0084
BMI, kg/m2	26.0 ± 3.2		30.1 ± 3.9	<0.0001
Lean Body Surface Area, m2	1.54 ± 0.21		1.64 ± 0.21	0.015
LV wall thickness
Interventricular Septum	9.1 ± 1.1		13.0 ± 1.4	<0.0001
Posterior Wall	8.6 ± 1.2		10.2 ± 8.6	<0.0001
BNP, pg/ml	N/A		44.6 [35.2–51.7]	-
cTnI, pg/ml	N/A		2.0 ± 2.1	-
ABPM sBP, mmHg	121.4 ± 7.4		132.6 ± 14.4	<0.0001
ABPM dBP, mmHg	72.9 ± 5.8		79.3 ± 8.1	<0.0001
ABPM HR, beats/min	73.6 ± 8.2		74.0 ± 11.2	0.828
Peak VO2, L/min	2.41 ± 0.76		2.26 ± 0.62	0.416
Peak VO2, ml/min/kg	29.2 ± 5.1		25.2 ± 5.5	0.0001

Continuous data are shown as mean ± SD. LVH, left ventricular hypertrophy; ACE-inhibitors, angiotensin converting enzyme-inhibitors; ARB, angiotensin receptor blocker; BSA, body surface area; BMI, body mass index; BNP, brain natriuretic peptide; cTnI, cardiac troponin T; ABPM, Ambulatory Blood Pressure Monitoring; sBP, systolic blood pressure; dBP, diastolic blood pressure; HR, heart rate, VO2, oxygen uptake.

Hemodynamic parameters

Hemodynamic parameters for each group are shown in Table 2. Under resting conditions in the laboratory, although the PCWP and RAP were both greater in LVH participants compared to control group (LVH vs. control group: PCWP: 13.4 ± 2.7 vs. 11.7 ± 1.7 mmHg, P<0.0001; and RAP: 10.0 ± 2.3 vs. 8.6 ± 1.5 mmHg, P=0.002), the transmural filling pressure (PCWP – RAP) was comparable between the groups (LVH vs. control group: 3.3 ± 1.1, vs. 3.1 ± 0.8 mmHg, P=0.261).

Table 2.

Hemodynamics

	Controls (n=61)		LVH (n=46)	P value
sBP, mmHg	108.4 ± 8.6		124.7 ± 11.4	<0.0001
dBP, mmHg	68.7 ± 6.5		76.9 ± 8.8	<0.0001
HR, beats/min	65.6 ± 8.2		69.3 ± 10.5	0.155
Cardiac Output, L/min	4.8 ± 0.8		5.6 ± 1.2	0.0002
SV, ml	74.0 ± 15.5		81.7 ± 18.6	0.015
SVR, dynes s/cm5	1404.4 ± 231.1		1378.2 ± 318.8	0.505
Ea, mmHg/ml	1.4 ± 0.3		1.5 ± 0.4	0.417
PCWP, mmHg	11.7 ± 1.7		13.4 ± 2.7	<0.0001
RAP, mmHg	8.6 ± 1.5		10.0 ± 2.3	0.002
Transmural pressure, mmHg	3.1 ± 0.8		3.3 ± 1.1	0.261
LVEDV, ml	94.6 ± 20.6		98.4 ± 22.8	0.181
LVEDV index, ml/m2	61.4 ± 10.3		58.6 ± 12.3	0.308
Central PWV, cm/s	722.8 ± 140.3		768.9 ± 128.5	0.027

Data are shown as mean ± SD. sBP, systolic blood pressure; dBP, diastolic blood pressure; HR, heart rate; SV, stroke volume, SV index, stroke volume index; SVR, systemic vascular resistance; Ea, effective arterial elastance; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; LVEDV, left ventricular end-diastolic volume; Central PWV, central (carotid-femoral) pulse wave velocity.

LV pressure-volume relationship

The Starling mechanism and LV preload-recruitable stroke work are shown in Figure 2 and Figure 3. The Starling mechanism curves in both groups were roughly superimposable. LV global systolic function, represented by the slope of preload recruitable stroke work, was similar in both groups, although the slope of LVH group was shifted upward and to the left as a function of their higher MAP at every level of preload. There were no significant differences in HR between those two groups during LBNP and rapid saline infusion (Group-loading condition Interaction P=0.824, Group P=0.696, loading condition P<0.0001, Controls vs. LVH subjects: baseline: 66±8 vs. 69±11 bpm; LBNP-30 (maximal unloading): 73±11 vs. 74±13 bpm; NS-30 (maximal loading): 83±8 vs. 89±20 bpm).

Figure 2. Starling mechanism (SV and PCWP relationship).

LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure, SV was scaled to lean body surface area.

Figure 3. Preload-recruitable stroke work.

LVH, left ventricular hypertrophy group; LVEDV, left ventricular end-diastolic volume.

The LV chamber was functionally less distensible than controls (smaller volume for any given transmural pressure). LV myocardial stiffness curves are shown in Figure 4; LV myocardial stiffness was nearly 30% greater in the LVH group compared to controls (LV transmural stiffness, LVH vs. control group: 0.053 ± 0.027, vs. controls: 0.042 ± 0.020, P=0.028).

Figure 4. LV transmural stiffness.

LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure; LVEDV was scaled to lean body surface area, Transmural pressure = PCWP — right atrial pressure (RAP).

Discussion

This study demonstrates that LV myocardial stiffness in patients who have both LVH and elevated biomarkers, predisposing them to developing HFpEF, is significantly higher than in healthy controls. Other abnormalities associated with this phenotype included a less distensible LV, but normal contractile function (normal pre-load recruitable stroke work). Together, these findings suggest that these patients should be considered as “stage B HFpEF” representing a transitional state from a normal healthy-heart to the pathophysiology that is observed in HFpEF. Whether lifestyle changes including exercise or pharmaceutical interventions can halt this trajectory is uncertain, and will require future study.

LV myocardial stiffness in LVH

This report is the first to quantify LV myocardial stiffness using LV pressure-volume relationships in middle-aged individuals (45–64 years old) who are at particularly high risk for the development of HFpEF. In this study, LV transmural stiffness was almost 30% greater in LVH patients compared to healthy controls, identifying a potential pathophysiologically relevant target for intervention. Recently, our group demonstrated that LV stiffening associated with sedentary aging has already become manifest by middle age,⁶ although some degree of plasticity appears to remain. In fact, two years of high intensity exercise training reversed LV stiffness in healthy, middle aged individuals without LVH.¹⁰ Thus, we speculate that high intensity exercise holds promise as a potential intervention to prevent progression to HFpEF in high risk patients, if implemented at the optimum dose and age.

LV chamber distensibility in LVH

LV volume was lower while PCWP was higher in the LVH group compared to the healthy controls at virtually all filling pressures. A rapid volume challenge with right heart catheterization has been used to unmask diastolic dysfunction and/or to diagnose HFpEF with a greater rise in PCWP in HFpEF patients than age matched controls.^{22, 23} Volume loading changes the operating range on the curvilinear LV-EDPVR to the steeper portion;²⁴ thus, the absolute increase in PCWP (or TMP) relative to infused volume could be accentuated in subjects with a steep LV-EDPVR. The LV-EDPVR reflects the net effect of several LV myocardial, anatomical, and structural properties. A descriptive summary of this hypothesis is displayed in Figure 5, which illustrates that the slope of the EDPVR is steeper in LVH patients than that in healthy controls. This myocardial stiffening is determined primarily by LV myocardial mass and myocardial composition, especially at relatively lower ventricular volumes; and pericardial constraint at higher LV volumes. According to Laplace’s Law, the load on any region of the myocardium is given as: (pressure × radius) / (2 × wall thickness). In order to reduce the wall stress in patients with LVH, LV wall thickness increases significantly. However, this physiological adaptation might lead to LV myocardial stiffening. Also, changes in intrathoracic pressure, LV pericardial constraint, and interventricular left-right interactions may influence both RV and LV diastolic pressure, which thus may impact the LV-EDPVR.²⁴ Amongst these, the pericardial constraint may be the dominant factor regulating the shape of the LV chamber stiffness curve especially at higher pressures during a rapid saline infusion. In this study, to reduce the effect of pericardial pressure on LV-EDPVR, we calculated the transmural pressure (= PCWP - RAP) as the effective LV distending pressure. The observation that even when the effect of pericardial constraint is minimized, there is still a prominent difference in myocardial stiffness between groups demonstrates that it is not the pericardium that causes the greater rise in the LV distending pressure in patients with Stage-B or Stage-C HFpEF during rapid saline infusion, but LV myocardial compliance per se.

Figure 5. Summary diagram of left ventricular end-diastolic pressure-volume relationships between LVH patients and healthy controls.

LV chamber distensibility was lower while PCWP was higher in the LVH group compared to the healthy controls. The pericardial constraint may be the dominant factor regulating the shape of the LV-EDPVR especially at higher pressure range during rapid saline infusion. In the other hand, myocardial compliance is the dominant element affecting the shape of the LV-EDPVR at lower pressure range during lower body negative pressure. In this study, to reduce the effect of pericardial pressure on LV-EDPVR, we calculated the transmural pressure (= PCWP - RAP) as an effective LV distending pressure. Indeed, the LV transmural stiffness slopes in LVH patients appeared to be greater in than healthy control subjects. These findings demonstrated that it is not the pericardium that causes the rise in the LV distending pressure, but myocardial compliance per se during rapid saline infusion.

LVH, left ventricular hypertrophy; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; LV-EDPVR, left ventricular end-diastolic pressure and volume relationship; T, LV wall stress; h, wall thickness; P, left ventricular pressure, r, radius; series 1: LVH, series 2: controls.

Concentric LVH with elevated biomarkers as a high-risk of developing future HFpEF

An emerging body of evidence suggests cardiac biomarkers may help further risk-stratify individuals into higher-risk categories for the future development of heart failure. Recently two studies have demonstrated that high-risk LVH was more strongly associated with HFrEF rather than HFpEF in the future development^{25, 26}. Both studies focused on an older cohort which may be more vulnerable to the developing systolic dysfunction due to higher co-morbidity burden. However, the relationship between high-risk LVH and HFpEF was still significantly present in both of these cohorts with a ~2–3 fold increased risk²⁵. Moreover, the lifetime HF risk by subtype for high-risk LVH in midlife is unknown. According to our inclusion criteria and LV wall thickness in this study, we specifically preselected subjects with concentric LVH, a phenotype consistent with stage-B HFpEF. Whether these patients then go on to progress to HFrEF in later life is unknown with the possibility that the first intermediary could be HFpEF. However our findings demonstrate that LV stiffness, which is an important physiologic precursor for future HFpEF development, is present in these high-risk individuals by mid-life.

Potential mechanisms and future study

Hypertension affecting both ventricular and vascular structure and function is an essential risk factor for developing HFpEF as a result of worsening LV myocardial stiffening from LV remodeling secondary to increased afterload. This physiology of LV diastolic dysfunction in patients with LVH is complicated; the contributing factors for this pathophysiology can be divided into intrinsic and extrinsic LV mechanisms. As intrinsic mechanisms, the relationship between LV diastolic volume and pressure are influenced by (1) the time course of active relaxation, (2) the passive deformation properties of the LV myocardium, including LV wall thickness and its composition,²⁷ and (3) an increase of the LV mass/volume ratio, which are the main causes of LV myocardial stiffning.²⁸ Extrinsic mechanisms of LV myocardial stiffening include (1) LV and RV interaction mediated by pericardial restraint, and (2) increasing central blood volume.²⁸ Both those mechanisms may lead a parallel upward-shift of the LV-EDPVR in the patients with LVH.

Current epidemiology reports emphasize that patients with HFpEF are diverse in types of cardiovascular comorbidities.^{3, 5} Since there are few effective treatments for HFpEF it is crucial to identify appropriate interventions for LV diastolic dysfunction and progression to HFpEF in high risk patients. Whether exercise training can be as effective in high-risk patients with stage-B HFpEF as it is in otherwise healthy middle aged individuals is unknown, but is currently being investigated ( NCT03476785).

Study limitations

This study has several limitations. First, there were significant differences in baseline body size between the two groups creating a challenge with scaling of volumetric parameters. However, we standardized body size using lean BSA which correlated more closely with LV chamber size than other commonly used scaling parameters. Nevertheless, despite the differences in RAP, PCWP, and body size between the two groups, LV transmural stiffness in the LVH group was significantly greater compared to healthy-controls. Second, because LVH patients had higher baseline PCWP, the total volume of infused saline was lower compared to control subjects, though this difference was abolished by appropriate scaling. Third, there were race/ethnicity differences between the two groups. Fourth, we did not study patients who had LVH, but without elevated biomarkers. We suspect, but cannot prove, that it is unlikely that such patients would have stiffer hearts than patients with LVH with elevated biomarkers. Thus although other groups of patients might also demonstrate an intermediate stage-B phenotype, we can say with some confidence that the specific patients studied here represent a particularly high risk group and should be considered for targeted preventative therapies.

Conclusion

LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than age- and sex- matched controls, and thus appears to represent a transitional state from a “normal healthy-heart” to HFpEF. Although, LV myocardial stiffness of LVH patients is greater than that of healthy controls at this early stage, further studies are required to clarify whether exercise training (or other interventions) to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high risk individuals.

Clinical Perspective.

1. What is new?

   • Left ventricular myocardial stiffness was measured invasively in patients who have both left ventricular hypertrophy (LVH) and elevated biomarkers, which predispose them to developing heart failure with preserved ejection fraction (HFpEF). We document for the first time these myocardial stiffness is significantly greater in these high risk patients than in healthy controls.
   • The left ventricular myocardial stiffness in these patients appears to represent a transitional state from a “normal healthy-heart” to HFpEF.
2. What are the clinical implications?

   • Patients with LVH and elevated biomarkers (NT-proBNP or hsTNT) should be considered as “stage-B HFpEF” representing a transitional state from a normal healthy-heart to the pathophysiology that is observed in HFpEF.
   • Further studies are required to clarify whether exercise training to improve left ventricular compliance may prevent the full manifestation of the HFpEF syndrome in these high risk individuals.

ABBREVIATIONS

LV

left ventricular

LVH

left ventricular hypertrophy

HFpEF

heart failure with preserved ejection fraction

PCWP

pulmonary capillary wedge pressure

RAP

right atrial pressure

LVEDP

left ventricular end-diastolic pressure

LVEDV

left ventricular end-diastolic volume

EDPVR

end-diastolic pressure and volume relationship

LBNP

lower body negative pressure

NS

rapid normal saline infusion

SV

stroke volume