KM and AA: The significance of rate pressure product in heart failure patients.

The significance of rate pressure product in heart failure patients.

KM Karaye, 1

AA Akintunde, 2

[1] Departments of Medicine, Bayero University & Aminu Kano Teaching Hospital, Kano, Nigeria

[2] Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Nigeria

Correspondence to:Dr Kamilu M Karaye Departments of Medicine, Bayero University Aminu Kano Teaching Hospital, Kano, Nigeria e-mail: kkaraye@yahoo.co.uk

Abstract

Introduction: The rate pressure product (RPP) is a strong determinant of myocardial oxygen consumption, and relates strongly to important indices for morbidity and cardiovascular mortality. Its significance in Black-African subjects with heart failure (HF) has however not been well described. This study therefore aimed to assess the significance of RPP among admitted HF patients in 2 Nigerian centres.

Methods: Admitted HF patients in the 2 centres were serially recruited after satisfying all inclusion criteria. RPP was calculated by multiplying heart rate by systolic blood pressure at admission. Subjects were classified into 2 groups based on RPP <10,000 (log10 <4.0) (group 1) or above (group 2), which is a cut-off value above which there is increased risk of myocardial ischemia.

Results: 100 subjects were recruited from the 2 centres with a mean age of 47.3+/-19.5 years, and 53% were females. 35% of the subjects were in group 1 while 65% were in group 2. N-Terminal B-type Natriuretic Peptide (NTBNP), serially measured in only 37 subjects (12 in group 1; 25 in group 2), was significantly higher in group 1 as compared with group 2 (p=0.016). Group 1 also had lower interventricular septal thickness(IVST) (p=0.007) as compared with group 2 subjects. RPP correlated strongly with IVST (r=+0.510, p<0.001), left ventricular posterior wall thickness (LVPWT) (r=+0.399, p<0.001) and LV end-diastolic dimension (LVEDD) (r=-0.202, p=0.045). Log10 >4.0 was strongly associated with IVST (95%confidence interval (CI): 1.061-1.528, p=0.009) and NT-BNP (CI:0.999-1.000, p=0.026). There was however no significant relationship (p>0.05) between RPP and in-hospital mortality, severity of dyspnoea, gender, age, body weight, LV ejection fraction or presence of atrial fibrillation/flutter.

Conclusion: This study confirms the close relationship that exists between a determinant of myocardial oxygen consumption (RPP), and indices for LV wall tension (IVST, LVEDD and NT-BNP), in Black-Africans with HF.

Introduction

Myocardial oxygen consumption is an important indicator of the workload on the heart.1 Major determinants of myocardial oxygen demand are left ventricular systolic pressure, radius, mass, contractility, and heart rate.2 Although myocardial oxygen consumption is difficult to measure directly, the rate-pressure product (RPP) (heart rate X systolic BP) is a strong correlate of myocardial oxygen consumption and is an easy parameter to measure.

Heart rate and blood pressure have been found to increase significantly in most ischemic episodes, indicating that increased myocardial oxygen demand plays a significant role in its own right, in the pathogenesis of myocardial ischemia during daily life.1,3 Studies have shown that ischemic episodes, even if painless, predict cardiac morbidity and mortality.4,5 Subjects admitted for heart failure (HF) are at high risk for morbidity and mortality, and the number of HF deaths has increased steadily despite advances in treatment for many reasons. Multivariate analysis of clinical variables has helped to identify the most significant predictors of survival, and prognostic models have been developed and validated, but there are still gaps in knowledge.6 Although the RPP relates strongly to important indices for cardiovascular morbidity and mortality, its significance in Black-African subjects with HF has not been well described. We hypothesise that it will be associated with indices that increase cardiac workload in HF patients. This study therefore aimed to assess the significance of RPP among admitted HF patients in two Nigerian referral hospitals.

Materials and methods

The study was carried out in the medical wards of Aminu Kano Teaching Hospital, Kano, and Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Nigeria. Before the commencement of the study, the Research Ethics Committees of the study centres reviewed and approved the study protocol. The study conformed to the ethical guidelines of the Declaration of Helsinki; on the principles for medical research involving human subjects.7 Signed informed consent was obtained from all study subjects.

Admitted HF subjects who had satisfied the inclusion criteria were consecutively recruited, and the subjects were then followed up longitudinally till time of discharge or demise. Subjects were included if they had HF, were at least 18 years of age, had satisfactory images on trans-thoracic echocardiography, were admitted to the medical wards of the study centres and gave informed consent.

Minimum sample size was estimated at 71 (at 95% confidence level), using a validated sample size formula for observational studies (see below), using a prevalence of HF of 10%, with an approximate combined bed capacity of 140 for medical patients, and confidence limits of 5%.8

Sample size (n) = [DEFF*Np(1-p)]/[(d2/Z21-α/2*(N-1)+p*(1-p)]

Where:

Population size (N) = 140

Hypothesized frequency of outcome factor (in-hospital mortality for HF) in the population (p) = 10.1%8 Confidence limits as % of 100 (d) = 5% Design effect (for cluster surveys-DEFF) = 1 However 115 HF patients were serially recruited concurrently from both centres over 6 months to improve power of the study, but 15 subjects were dropped because they did not have complete data.

Definitions of study terms

HF was defined according to the recommendations of European Society of Cardiology (ESC).9 RPP was calculated by multiplying heart rate (HR) and systolic blood pressure (SBP), at the time of admission. Subjects were classified into group 1 if RPP was <10,000 or group 2 if the RPP was higher. High RPP value has been found to be associated with increased risk of myocardial ischemia.10

Among patients with systemic hypertension, hypertensive heart disease (HHD) was diagnosed after excluding ischemic heart disease (IHD), and if echocardiography had revealed abnormal left ventricular (LV) geometry without regional wall motion abnormalities, with or without increased left atrial (LA) size, or diastolic or systolic LV dysfunctions. IHD was diagnosed if the subject had all of the following: positive history of typical angina or acute myocardial infarction, and/or typical electrocardiographic (ECG) abnormalities of acute myocardial infarction (MI) or myocardial ischemia, and ventricular regional wall motion abnormality on 2D echocardiography. Acute MI was defined according to the recommendations of the joint ESC/American Heart Association (ESC/AHA) Committee.11 The diagnoses of rheumatic mitral regurgitation and aortic regurgitation were based on the presence of valvular regurgitation in two planes on Doppler echocardiography and with the following features on 2D echocardiography: thickened and retracted leaflets and subvalvar apparatus, restricted leaflet mobility, and poor coaptation of the leaflets in systole/diastole respectively, which could be worsened by the dilatation of the valve annulus.12 Rheumatic mitral stenosis was defined as the presence of thickened and/or calcified mitral leaflets and subvalvar apparatus, and narrowed ‘fish-mouth’ orifice of the mitral valve (MV) in the short-axis view measurable with planimetry (with valve area of ≤2.0cm2) or Doppler echocardiographic techniques (the diastolic pressure half-time method or the continuity equation).12 Rheumatic aortic stenosis was defined as the presence of thickened or calcified and immobile aortic valve cusps, with commissural fusion causing a narrowed orifice (valve area of ≤1.5cm2), and almost invariably occurring with rheumatic MV disease.12 Dilated cardiomyopathy (DCM) was defined as the presence of dilated LV (with or without dilatation of the other 3 cardiac chambers) with global systolic (LV ejection fraction (LVEF) ≤45%) and diastolic dysfunction.13 Peripartum cardiomyopathy (PPCM) was defined as an idiopathic cardiomyopathy presenting with HF secondary to LV systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of HF is found. It is a diagnosis of exclusion. The LV may not be dilated but the LVEF is nearly always reduced below 45%.14 Other diseases were also defined according to standard criteria.

Evaluation of subjects

Clinical evaluation of HF patients and investigations were carried out within the first 48 hours after hospital admission. Demographic data, relevant aspects of history and physical signs, duration and outcome of admission (either discharge or death), medications, co-morbid conditions, complications, and in-hospital mortality or discharge were recorded in a questionnaire. Investigations recommended for the management of patients with HF were carried out as appropriate.9 These included a 12-lead ECG at rest, transthoracic echocardiogram and N-terminal pro-B-type natriuretic peptide (NT-BNP). Other investigations were carried out if and when indicated, as appropriate.

Table 1

Baseline characteristics of the HF subjects

Characteristic Log10 RPP<4.0 N=35 Log10 RPP≥4.0 N=65 p-value
Females 20(57.1) 33(50.8) 0.542
Age(years) 48.2±19.3 46.7±19.8 0.723
Systolic BP(mmHg) 91.5±13.1 123.4±27.3 <0.001*
Diastolic BP(mmHg) 59.6±13.1 80.9±18.6 <0.001*
Hear rate (per min) 94.1±16.2 112.4±27.3 <0.001*
In-hospital deaths 6(17.1) 8(12.3) 0.506
Smoking 1(2.9) 5(7.7) 0.332
Diabetes mellitus 2(5.7) 7(10.8) 0.400
AF or A. Flutter 7(20.0) 6(9.2) 0.129
Stroke/TIA 3(8.6) 4(6.2) 0.651
NYHA 3.23±0.77 3.26±0.67 0.824
Body weight (Kg) 58.7±10.0 59.8±13.2 0.698
Anti-log10NTBNP(pg/ml) 5620.8±3056.6 3366.3±2274.2 0.031*
Log10Creatinine 1.99±0.22 2.04±0.33 0.474
PCV(%) 37.7±6.3 34.7±9.2 0.134
ACE-I/ARB 9(25.7) 39(60) 0.001*
Beta-blockers 3(8.6) 2(3.1) 0.229
Digoxin 21(60) 33(50.8) 0.377

Table 2

Echocardiographic features of the HF subjects

Variable Log10 RPP<4.0 N=35 Log10 RPP≥4.0 N=65 p-value
LA (mm) 46.9±15.3 45.3±10.0 0.621
IVSd (mm) 8.7±2.1 10.3±2.9 0.003*
PWTd (mm) 9.0±2.7 10.2±2.9 0.059
LVEDD (mm) 59.9±12.8 56.0±12.4 0.145
LVESD (mm) 47.1±15.9 44.4±14.0 0.383
LVEF (%) 37.1±17.3 44.2±19.5 0.074
MV E:A ratio 1.72±0.84 1.69±0.90 0.888

Table 3

Correlates of log10 RPP among the heart failure subjects

Variable R p-value
Age (yrs) +0.053 0.598
Anti-log10NT-BNP(pg/ml) -0.263 0.115
Left atrium diameter(mm) -0.052 0.638
IVSd (mm) +0.488 <0.001*
PWTd (mm) +0.364 <0.001*
LVEDD (mm) -0.205 0.042*
LVESD (mm) -0.154 0.131
LVEF (%) +0.173 0.085

Plasma NT-BNP was measured using a highly sensitive and specific immunoassay based on double-antibody sandwich technique on Elecsys 2010 immunology analyzer (Roche Diagnostics, Mannheim, Germany).

Echocardiography was carried out by the investigators according to standard recommendations, while ECG was recorded by a trained technician but interpreted by the investigators.15,16 All laboratory investigations were carried out in the laboratories of the study centres.

Statistical analysis

Proportions, ranges and means with standard deviations were used to describe patients’ characteristics. RPP and other assessed continuous variables were explored for the presence of skewness, which was appropriately corrected with logarithmic (log10) transformation. Chi-squared, Fisher’s exact, Student’s T and Mann-Whitney tests were used to compare categorical and continuous variables as appropriate. To assess the determinants of increased RPP, univariate and multivariate logistic regression models were developed. Pearson’s correlation (r) was also used to determine the relationship between RPP and a number of variables. A p-value of <0.05 was considered significant. The statistical analysis was carried out using SPSS version 16.0 software.

Results

A total of 100 subjects were studied; 84% of them in the Kano Centre and the remaining 16% in the Ogbomoso centre. Mean age of all patients was 47.3±19.5 years (range=18-91 years); comprising of 47 males (47%) and 53 (53%) females. Subjects were classified into groups 1 and 2, and compared with each other, based on the RPP cut off value of less or greater than 10,000 (equivalent log10 = 4.0) respectively. The mean log10 RPP for subjects in group 1 was 3.92±0.05 while that for group 2 was 4.13±0.09 (p<0.001). Baseline and clinical characteristics of these two groups are presented in Table 1, while echocardiographic variables are presented in Table 2. Table 3 shows the correlates of log10 RPP while Table 4 shows the aetiologies of HF among the subjects.

In the linear regression analysis, there was statistically significant relationship between log10 RPP and interventricular septal (B=0.023; 95% confidence intervals (CI)=0.015-0.031; p<0.001) and LV posterior wall thicknesses at end-diastole (IVSd and PWTd respectively) (B=0.016; CI=0.008-0.024; p<0.001), as well as LV end-diastolic diameter (LVEDD) (B= -0.002; CI= -0.004-0.0001; p=0.042). However after controlling for confounding variables, IVSd was the only independent predictor of log10 RPP, and for every unit increase in IVSd, log10 RPP increases by 0.022, with CI of 0.009-0.034 (p=0.001). In addition, Figure 1 demonstrates the linear relationship between log10 RPP and IVSd, and shows that IVSd explains 23.8% (R2=0.238; p<0.001) of the variability of log10 RPP among the subjects. Further analysis in (Figure 2) shows the consistent linear relationship between log10 RPP and IVSd groups (group 1= IVSd <9mm; group 2=nIVSd 9-11.9mm; group 3= IVSd ≥12.0mm).

Table 4

Aetiology of HF among the HF subjects.

Aetiology All patients N=100 Log10 RPP<4.0 N=35 Log10 RPP≥4.0 N=65 p-value
HHD 43% 9(25.7) 34(52.3) 0.010*
PPCM 15% 6(17.1) 9(13.9) 0.660
DCM 14% 8(22.9) 6(9.2) 0.061
RHD 9% 5(14.3) 4(6.2) 0.175
Effusive pericarditis 7% 2(5.7) 5(7.7) 0.712
IHD 6% 3(8.6) 3(4.6) 0.427
Cor-pulmonale 5% 2(5.7) 3(4.6) 0.810
AV regurgitation 1% 0 1(1.5) -

Figure 1

Relationship between log10 RPP and interventricular septal thickness in HF patients.

Key: IVSd, interventricular septal thickness at end diastole. R2=0.238; p<0.001

icfj.2013.1.1.43-g001.jpg

Figure 2

Relationship between log10 RPP and IVSd groups.

In the binary logistic regression models testing for predictors of increased log10 RPP, IVSd (B=0.242; p=0.009) and anti-Log10 NTBNP (B=0.0001; p=0.026) were found to be the only predictors.

icfj.2013.1.1.43-g002.jpg

Discussion

The present study confirms the close relationship that exists between a determinant of myocardial oxygen consumption (RPP), and those for LV wall stress in Black-Africans with HF. The results of the regression models have shown that the main determinants of RPP among the subjects were the thickness of LV walls (interventricular septum and LV posterior wall), LV enddiastolic dimension (LVEDD) and N-terminal pro-BNP (NT-BNP). RPP also correlated significantly and positively with LV walls thickness and negatively with LVEDD. These indices are also the main determinants of LV wall stress, according to the Laplace’s law.17 NT-BNP is released mainly from ventricular myocardium in response to increased LV end-diastolic pressure (LVEDP).18 Wall stress is the force per unit cross-sectional area of muscle and is related to intra-ventricular pressure. Laplace’s law states that wall stress= pressure X radius / 2 X wall thickness.17 Hence peak wall stress relates to the amount of force and work done by the muscle during contraction, and is therefore used as an index of afterload.17

Our results have also shown that of all the determinants and correlates of RPP, the end-diastolic interventricular septal thickness was the strongest after controlling for confounding variables. The septum was responsible for up to 23.8% of the variability of RPP, and was shown to be positively predictive of RPP in a graded fashion; the thicker the septum the higher the RPP and vice versa. Therefore these results further confirm the central role that the septum plays in the determination of ventricular workload and oxygen demand, and Saleh et al rightly described it as “the motor of biventricular function”.19 The septum is a complex structure that accounts for up to 40% of LV output.19 During systole, the septum twists and shortens causing reduction in ventricular volume and forceful ejection of blood out of both ventricular cavities. In the case of the right ventricle, the septum seems to account for the major force of ejection, especially when there is pulmonary hypertension. In the absence of septal twisting due to septal damage, ventricular ejection is produced by circumferential constriction caused by contraction of the basal wall that contains predominantly transverse fibers. Such constriction may not allow delivery of enough contractile force to ensure adequate cardiac output when pulmonary vascular resistance is increased.19

In the present study, there were no significant differences in several outcome measures such as in-hospital mortality, cerebrovascular diseases, serum creatinine concentration and atrial fibrillation/flutter, between subjects who had log10RPP of 4.0 or above and those who had below the cut-off value. However a longer follow up might show significant differences in outcome measures between these two groups. This is because earlier studies among subjects with ischemic heart disease have found raised RPP to be associated with silent myocardial ischemia, and increased risk for acute myocardial ischemia and cardiovascular mortality.10,20

One of the limitations of this study is the fact that we could not assess NT-BNP in all the subjects because of limited funds for the study.

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