Cardiac hypertrophic risk markers of left ventricle and left atrium in chronic heart failure due to aortic and mitral valve disease

Abstract

Background

Chronic valvular heart disease leads to systolic dysfunction and left atrial enlargement that ultimately results in heart failure.

Purpose

To investigate prognostic importance of Echocardiography and plasma natriuretic peptide levels that increase as a compensatory response and can be used as predictive markers for cardiac hypertrophy.

Material and Methods

The patients were divided into three groups: 51 with left ventricle hypertrophy due to aortic valve disease; 126 with left atrial enlargement due to mitral valve dysfunction; and 76 with both conditions. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) plasma levels were measured in all three respective groups showing dilated cardiomyopathy.

Results

The mean left ventricular end-diastolic dimension at 64.3 ± 1.6 mm (P < 0.00) and left atrial dimension at 58.3 ± 3.7 mm (P < 0.00) were significantly high. However, patients with both conditions showed significantly high values for left ventricular end-diastolic dimension (63.3 ± 3 mm, P < 0.00) and left atrial dimension (54.9 ± 4 mm, P < 0.00) when compared with controls. A significant positive correlation was found between plasma natriuretic peptides levels and dilated cardiomyopathy. The mean values of ANP were 173 ± 46.6 pg/mL (P < 0.00), 140.4 ± 42.4 pg/mL (P < 0.00), and 295.1 ± 67.5 pg/mL (P < 0.00), significantly high in all three respective disease groups. The levels of BNP were also significantly high at 189 ± 44.5 pg/mL (P < 0.00), 166.6 ± 36.6 pg/mL (P < 0.00), and 323 ± 69.1 pg/mL (P < 0.00) in the disease groups with left ventricular hypertrophy, left atrial enlargement, and the disease group showing both characteristics, respectively.

Conclusion

Significant positive associations were found between left ventricle hypertrophy and left atrial enlargement with ANP and BNP.

Keywords

Left ventricle hypertrophy left atrial enlargement atrial natriuretic peptide brain natriuretic peptide aortic valve mitral valve

Introduction

Valvular heart disease (VHD) has remained the leading cause of death in industrialized countries including Pakistan. The most frequent forms of VHD are aortic stenosis and mitral regurgitation (1). The left ventricular pressure overload also occurs due to aortic valve dysfunction. When the heart faces a hemodynamic burden, it undergoes a compensatory mechanism. The recruitment of neurohormones increase contractility due to augment muscle mass to bear the extra load (2). Thus, the compensation for hemodynamic overload leads to increase in myocardial mass. This increase in the mass of myocytes occurs due to hypertrophy rather than hyperplasia. However, the increase in myocyte width occurs due to the parallel addition of sarcomeres. Therefore, wall thickness increases in response to pressure overload due to aortic valve dysfunction. This remodeling results in an increase in ratio of wall thickness/chamber dimension which finally leads to concentric hypertrophy (3). Aortic stenosis is the most important stimulus for left ventricular hypertrophy (LVH). However, beside the severity of aortic stenosis, LV response also depends on multiple factors including age, gender, co-existing coronary artery disease (CAD), and hypertension. Regurgitation in the aortic valve also influences the response of LV remodeling (4). However, in chronic conditions of mitral valve stenosis or regurgitation, it may results in left atrial remodeling and enlargement. Left atrial enlargement (LAE) also increases the risk of atrial fibrillation (5). Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are the two closely related natriuretic peptides (NPs) expressed in human heart (6). The expression of both hormones is strongly associated with various cardiac associated diseases. NPs act to decrease blood volume by increasing natriuresis and decreasing vascular resistance. The plasma levels of both NPs (hormones) are used as prognostic markers for cardiac hypertrophy and heart failure (HF) (7). Moreover, echocardiography, chest X-ray, and physical examination are commonly used clinical practices. However, diagnosis on the basis of ANP and BNP provides supportive information for the identification of LVH and LAE (8). NT-proBNP and serum uric acid also play key roles in various cardiovascular diseases. In addition, the increased NT-ProBNP and uric acid can also be used as hallmarks for cardiac hypertrophy (9). The production of serum uric acid increases through xanthine oxidase (XO) during cardiac hypertrophy which also enhances the generation of reactive oxygen species (ROS). However, the inadequate level of ROS was also found in cardiomyocytes apoptosis during VHD (10). The increased production of serum uric acid through xanthine oxidase (XO) during cardiac hypertrophy increases the generation of ROS especially superoxide anions, hydrogen peroxide, and water. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) are antioxidant enzymes in humans (11), constituting first line of defense system against oxidative stress and removal of excessive ROS. SOD operates primarily and catalyzes the conversion of the superoxide anion into hydrogen peroxide within the cells and in extracellular matrices. Hydrogen peroxide is neutralized by catalase and GPx. In addition, GPx can also convert lipid peroxyl radicals to non-toxic alcohols (12).

Herein we hypothesized that echocardiography may provide an important prognostic information as a marker of LVH and LAE due to cardiac valve disease. In addition, ANP and BNP are also potent markers for the diagnosis of LVH and LAE which provide supportive information with echocardiography and clinical examination.

Material and Methods

Study population

In the present study, samples were collected from patients referred to Lady Reading Hospital, Peshawar, Pakistan between August 2019 and December 2019 for the evaluation of symptomatic LVH and LAE. The patients with history of myocardial infarction, other established Coronary Artery Diseases (CAD), complicated diabetes, and renal failure were excluded from the study. A total of 1000 patients with VHD were selected with severe stenosis, regurgitation, and combined disease condition. After screening, 253 patients (mean age of men = 43.4 ± 12.4, mean age of women = 46 ± 11.7 years) were selected for further clinical investigation showing LVH, LAE alone, or both. In addition, data were also collected from 188 normal individuals (mean age of men = 45 ± 10.9 years, mean age of women = 46.9 ± 10.7 years) which were used as a control (Table 1). The severity of chronic heart failure (CHF) was assessed using New York Heart Association (NYHA) classification criteria in the patients with aortic and mitral valve diseases 13).

Table 1.

Clinical characteristics of patients vs. controls.

	Aortic valve disease		Mitral valve disease		Aortic valve + mitral valve disease
	Left ventricle		Left atrium		Left ventricle + left atrium
	Patient	Control	Patient	Control	Patient	Control
Age (years)	50.3 ± 9.1	48.7 ± 9.5	43.2 ± 12.6	44.8 ± 10.8	47.6 ± 12.3	45.3 ± 11.7
M/F	41/10	37/10	38/88	30/56	46/30	33/22
Systolic BP (mmHg)	126.7 ± 14.5	125.7 ± 1.8	125.4 ± 12.1	124.9 ± 12	125.7 ± 13.3	124.7 ± 12.9
Diastolic BP (mmHg)	81.7 ± 7.5	80.8 ± 6.4	80.9 ± 7.3	81.2 ± 6.8	82.3 ± 6.8.5	81.7 ± 7.2
BMI (kg/m²)	23.3 ± 1.6	22.8 ± 1.4	24.1 ± 1.2	23.1 ± 1.4	23.8 ± 1.1	22.9 ± 1.7

Values are given as mean ± SD.

BMI, body mass index; BP, blood pressure.

Echocardiography

Standardized study protocol was followed for echocardiography (14). The analysis of all echocardiography was performed at the Echocardiography Core Laboratory LRH, Peshawar Pakistan. Cardiac atrial, vertical, and area of valves were quantitatively evaluated through echocardiography. The threshold values of mass/height^2.7 > 46.7 g/m^2.7 in women and 49.2 g/m^2.7 in men were used for consideration of LVH (15). The presence of concentric LV geometry was assured by relative wall thickness > 0.420 (16). An invasively validated method of taking the mean aortic valve gradient into account was used for the calculation of Circumferential End-Systolic Stress (CESS) (17). The average of > 3 beats in sinus rhythm and > 15 beats in patients with atrial fibrillation was considered for the heart rate. LV mass × CESS × heart rate product (LV mass–wall stress–heart rate product) was used to calculate myocardial oxygen demand (18). Mid-wall shortening and stress-corrected mid-wall shortening were estimated using previously reported validated equations (19). The product of LV mass–wall stress–heart rate was used for the estimation of Stress-corrected LV myocardial oxygen demand (18). The upper 95% confidence interval [CI] limit calculated previously from collected normotensive New York population (>2.13 × 106 g kdyne/cm² bpm) was used for the identification of high LV mass–wall stress–heart rate product (20). The area of the aortic valve adjusted for pressure recovery in the aortic root was measured to assess the severity of aortic stenosis (21). LV stroke volume was calculated by Doppler and indexed for body surface area. The estimation of LV diastolic function was performed by calculating the peak early and atrial transmitral filling velocities, their ratio, and left atrial anteroposterior diameter.

Biochemical analysis

The blood samples collected form patients were chilled and centrifuged for measurements of ANP and BNP. ANP and BNP were measured with fluorescence immunoassay (Biocompare, San Francisco, CA, USA; Catalogue Numbers: MBS264010 for ANP and MBS2512090 for BNP).

Statistical analysis

The data were expressed as mean ± standard error (SE). Statistical analyses were performed among different groups using SPSS 21 (IBM Corp., Armonk, NY, USA). P < 0.005 was considered significant.

Results

Baseline clinical and echocardiographic characteristics

A total of 253 patients were found to demonstrate high predictive values for the presence of LVH and LAE compared with normal individuals. Aortic valve dysfunction is one of the prevalent adult valve diseases which cause progressive pressure overload and finally leads to life-threatening complications including LVH. It develops in a considerable proportion of patients before the onset of symptoms. According to the NYHA classification, the patients were found in class III and class IV. Among these, 91.7% patients were found in class III while 8.3% patients were found in class IV (Fig. 1).

Fig. 1.

New York Heart Association classification of patients showing 91.7% patients in class III and 8.3% patients in class IV.

Left ventricular end-diastolic dimension was found to be significantly high at 64.3 ± 1.5 mm (P < 0.00) in 51 (20%) patients due to aortic valve disease showing LVH. In addition, LAE is one of the earliest manifestations of mitral valvular dysfunction. Clinically, LA size has been used as a good prognostic marker for adverse cardiac function and its outcomes. LA dimension was found significantly high at 58.3 ± 3.7 mm (P < 0.00) in 126 (50%) patients. Furthermore, combined aortic and mitral valvular dysfunction is the third most common functional valvular disease. However, patients characterized by both aortic and mitral valves dysfunction, showing both LVH and LAE, have also been found in 76 (30%) patients. The average left ventricular end-diastolic dimension and LA dimension found in these patients were also significantly high at 54.9 ± 4 mm and 63.3 ± 3 mm, respectively (P < 0.00; Table 2).

Table 2.

Demographic data of patients with valvular heart disease with LVH, LAE, and LVH + LAE.

	Disease groups
	LVH	LAE	LVH + LAE	P value
Aortic root dimension (mm)	31.3 ± 4	30.6 ± 3.4	30.7 ± 3.4	0.978
Left atrial dimension	33.0 ± 2.8	58.3 ± 3.7	54.9 ± 4.0	<0.000*
Left ventricular end-diastolic dimension (mm)	64.3 ± 1.6	40.4 ± 4.5	63.3 ± 3.0	<0.000*
Left ventricular end-systolic dimension (mm)	44.0 ± 3.7	43.5 ± 3.0	43.6 ± 3.0	0.988
IVS thickness (mm)	11.1 ± 0.9	11.2 ± 0.7	11.1 ± 0.7	0.998
LVPW thickness (mm)	10.8 ± 0.7	10.7 ± 0.8	10.8 ± 0.6	0.989
Right ventricle dimension (mm)	26.4 ± 2.5	26.4 ± 1.6	27.0 ± 1.4	0.988
Fractional shortening (%)	26.1 ± 4.3	25.8 ± 3.8	25.8 ± 3.9	0.889
ANP (pg/mL)	173 ± 46.6	140.4 ± 42.4	295.1 ± 67.5	<0.000*
BNP (pg/mL)	189 ± 44.5	166.6 ± 36.6	323 ± 69.1	<0.000*

Values are given as mean ± SD.

*The mean difference is significant at the 0.05 level.

ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; LAE, left atrial enlargement; LVH, left ventricular hypertrophy.

The levels of ANP and BNP due to LVH and LAE

CHF including cardiac hypertrophy is increasing worldwide. The natriuretic peptides are used as markers for the diagnosis and treatment of cardiac function. However, in the present study, the levels of both ANP and BNP are elevated compared with the controls. The patients with LVH due to aortic valve dysfunction were found to have significantly high levels of ANP and BNP (173 ± 46.6 pg/mL and 189.3 ± 44 pg/mL, P < 0.00). LAE also occurs due to impaired function of the mitral valve. However, the levels of natriuretic peptides gradually increase in a compensatory mechanism. In the present study, the plasma concentrations of ANP and BNP have been reported with a significant increase up to 140.5 ± 42.4 pg/mL and 166.6 ± 36.6 pg/mL, respectively (P < 0.00). In the present findings, the number of patients with LAE due to mitral valve disease is substantially high compared to other disease groups. Furthermore, patients revealed both LVH and LAE due to aortic and mitral valve disease. However, both plasma levels of ANP and BNP were also significantly high in these patients at 295.1 ± 67.5 pg/mL and 323±69.1 pg/mL, respectively (p < 0.00). In addition, the plasma levels of ANP and BNP in this disease group (aortic and mitral valves) showed significant increase in the plasma concentration of patients having only LVH or LAE (Table 2). Furthermore, there was linear positive correlation between LVH and LAE with both the markers of ANP and BNP shown in Fig. 2. In addition, the levels of both ANP and BNP were also compared within the three respective disease groups (Table 3).

Fig. 2.

Regression analysis of disease groups with ANP and BNP. (a) LVH vs. ANP. (b) LVH vs. BNP. (c) LAE vs. ANP. (d) LAE vs. BNP. (e) LVH vs. ANP. (f) LVH vs. BNP. (g) LAE vs. ANP. (h) LAE vs BNP. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; LAE, left atrial enlargement; LVH, left ventricular hypertrophy.

Table 3.

The baseline characteristics of aortic and mitral valve patients showing LVH, LAE, and both conditions of LVH and LAE.

		ANP		BNP
Subtypes of disease group		Mean difference at 95% CI	P value	Mean difference at 95% CI	P value
LVH (n = 51)	LAE	32.54240*	<0.000*	22.759085	0.072
	LHV + LAE	–122.06680*	<0.000*	–134.989879*	<0.000*
	CLV + CLA	163.48740*	<0.000*	176.788789*	<0.000*
	CLA	161.90707*	<0.000*	176.999687*	<0.000*
	CVA	161.39664*	<0.000*	176.161748*	<0.000*
LAE (n = 126)	LVH	–32.54240*	<0.000*	–22.759085*	0.072
	LHV + LAE	–154.60920*	<0.000*	–157.748964*	<0.000*
	CLV	130.94500*	<0.000*	154.029703*	<0.000*
	CLA	129.36467*	<0.000*	154.240602*	<0.000*
	CLV + CLA	128.85424*	<0.000*	153.402663*	<0.000*
LHV + LAE (n = 76)	LVH	122.06680*	<0.000*	134.989879*	<0.000*
	LAE	154.60920*	<0.000*	157.748964*	<0.000*
	CLV	285.55420*	<0.000*	311.778667*	<0.000*
	CLA	283.97387*	<0.000*	311.989565*	<0.000*
	CLV + CLA	283.46344*	<0.000*	311.151627*	<0.000*
CLV (n = 47)	LVH	–163.48740*	<0.000*	–176.788789*	<0.000*
	LAE	–130.94500*	<0.000*	–154.029703*	<0.000*
	LHV + LAE	–285.55420*	<0.000*	–311.778667*	<0.000*
	CLA	–1.58033	1.000	0.210898	1.000
	CLV + CLA	–2.09075	1.000	–0.627041	1.000
CLA (n = 86)	LVH	–161.90707*	<0.000*	–176.999687*	<0.000*
	LAE	–129.36467*	<0.000*	–154.240602*	<0.000*
	LHV + LAE	–283.97387*	<0.000*	–311.989565*	<0.000*
	CLV	1.58033	1.000	–0.210898	1.000
	CLV + CLA	–0.51042	1.000	0.837939	1.000
CLV + CLA (n = 55)	LVH	–161.39664*	<0.000*	–176.161748	<0.000*
	LAE	–128.85424*	<0.000*	–153.402663	<0.000*
	LHV + LAE	–283.46344*	<0.000*	–311.151627	<0.000*
	CLV	2.09075	1.000	0.627041	1.000
	CLA	0.51042	1.000	0.837939	1.000

*The mean difference is significant at the 0.05 level.

ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CI, confidence interval; CLA, control left atrial; CLV, control left ventricular; LAE, left atrial enlargement; LVH, left ventricular hypertrophy.

Discussion

VHD is one of the major cardiac complications in both men and women. Aortic stenosis and mitral regurgitation are the most frequent causes of VHD (1). The chronic condition of VHD leads to cardiac hypertrophy including LVH and LAE. LVH is the paradigm of aortic stenosis due to pressure overload characterized by progressive narrowing of aortic valve. In order to cope with the pressure overload, the ventricle triggers hypertrophic signals. These signals lead to an increase in myocyte size, left ventricular wall thickness, and mass (22). The neuroendocrine response of ANP and BNP is related to cardiac output. The levels of ANP and BNP are positively correlated with cardiac hypertrophic signals. In the present study, the statistically significant values of ANP and BNP between the patients with VHD and the controls have been observed. The high values of both the markers revealed that these markers can be used for diagnostic purposes. However, previous studies showed that these markers are also used for the diagnosis of CHF (23). Furthermore, most of the studies are concerned with the neuroendocrine response of both ANP and BNP in patients with CHF treated with different drugs. In this research study, both ANP and BNP showed a positive correlation with LVH and LAE and in combination with both LVH and LAE. It shows that the high levels of these markers are positively associated with LV systolic dysfunction. Furthermore, the baseline positive association between the echocardiographic LV end-diastolic dimension and LAE with ANP and BNP can establish a good platform to estimate the extent of cardiac hypertrophy including LVH and LAE. Both ANP and BNP provide supportive information with clinical and functional value. Therefore, CHF can be diagnosed by means of lab tests based on both ANP and BNP examination. The positive association was found between the plasma levels of both ANP and BNP with cardiac hypertrophy in different classes of NYHA classification. This further enhances the research findings that both ANP and BNP levels can be used as a potent marker for diagnosis of cardiac hypertrophy due to cardiac valve dysfunction.

The levels of both ANP and BNP have been estimated in asymptomatic patients with LV dysfunction and CHF which is likely to be useful for the clinical screening of patients (24). The progressive release of ANP and BNP into the blood stream promotes asymptomatic LV dysfunction to create CHF (25). The plasma levels of ANP and BNP can be used as diagnostic markers (25). In addition, high values of natriuretic peptides establish an avenue for the diagnosis of patients with CHF (26,27).

In conclusion, the chronic condition of VHD including aortic and mitral valves can lead to LVH and LAE. ANP and BNP hormones are secreted to overcome the pressure overload which can be used as a potent diagnostic marker for moderate to severe LV dysfunction and LAE. It can also be concluded that in addition to chest X-ray and clinical examination, both ANP and BNP provide supportive information for the diagnosis of CHF and the evaluation of its severity.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Muhammad Ishtiaq Jan

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