|Year : 2013 | Volume
| Issue : 4 | Page : 197-204
Prevalence, clinical characteristics and outcome of pulmonary hypertension among admitted heart failure patients
Kamilu M Karaye1, Hadiza Saidu2, Mohammed S Bala3, Isa A Yahaya4
1 Department of Medicine; Bayero University; Aminu Kano Teaching Hospital, PMB 3452, Kano, Nigeria
2 Department of Medicine; Bayero University; Kano, Nigeria
3 Department of Medicine; Aminu Kano Teaching Hospital, PMB 3452, Kano, Nigeria
4 Department of Chemical Pathology; Bayero University ; Aminu Kano Teaching Hospital, PMB 3452, Kano, Nigeria
|Date of Web Publication||4-Dec-2013|
Kamilu M Karaye
PO. Box 4445, Kano
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: There is paucity of data in Africa on the prevalence of pulmonary hypertension (PHT) and its impact on morbidity and short-term mortality in heart failure (HF) patients. The aim of this study was to assess the prevalence of PHT, its clinical characteristics and in-hospital mortality among HF patients admitted to a referral hospital in Nigeria.
Methods: The study was carried out on serially-admitted HF patients who satisfied the inclusion criteria, in a Nigerian tertiary health center. PHT was defined as the presence of mean pulmonary artery pressure (mPAP) of ≥25 mmHg, assessed using Doppler echocardiography and Chemla formula.
Results: A total of 80 admitted HF patients were studied serially. 53 of them (66.25%) had PHT while the remaining 27 (33.75%) had normal mPAP. mPAP was 38.31 ± 12.23 mmHg and 16.39 ± 5.48 mmHg (P < 0.001) for subjects with and without PHT, respectively. The most common cause of HF was hypertensive heart disease (HHD) (28 patients; 35%). Subjects with PHT had relatively lower systolic blood pressure (SBP) (P = 0.044), and larger left atrium (P = 0.036) and left ventricle (LV) at both end-diastole and end-systole (P = 0.036 and P = 0.008, respectively), and a trend toward lower LV ejection fraction (LVEF) (P = 0.053). There was no relationship between mPAP and N-terminal pro-B type natriuretic peptide (P > 0.05). A total of 12 HF patients (15.0%) died, out of whom 8 (66.7%) had PHT. Cardiogenic shock (P = 0.044) and trans-mitral flow velocities ratio (P = 0.023) were the independent determinants of in-hospital mortality.
Conclusion: PHT was common among the admitted HF patients, and was associated with worse morbidity indices, and a trend toward higher mortality. We recommend that HF patients be screened for PHT, and its presence should be taken into consideration in the management and prognostication of affected patients.
| Abstract in Spenish|| |
Fond : Il est la rareté des données en Afrique sur la prévalence de l'hypertension pulmonaire (PHT) et son impact sur la morbidité et la mortalité à court terme chez les patients d'insuffisance cardiaque (IC). Le but de cette étude était d'évaluer la prévalence des PHT, ses caractéristiques cliniques et mortalité à l'hôpital chez les patients HF admis dans un hôpital spécialisé au Nigeria.
Méthodes : L'étude a été réalisée sur des patients de HF-admis en série qui ont satisfait aux critères d'inclusion, dans un centre de santé tertiaires nigérian. PHT a été définie comme la présence de la pression de l'artère pulmonaire moyenne (PAPM) ≥ 25 mmHg, évalués en utilisant l'échocardiographie Doppler et formule Chemla.
Résultats : Un total de 80 admis les patients HF ont été étudiés en série. 53 d'entre eux (66,25 %) avait PHT le 27 restants (33,75 %) avait normal PAPM. PAPM était 38,31 ± 12.23 mmHg et 16.39 ± 5,48 mmHg (P < 0.001) pour les sujets avec et sans PHT, respectivement. La cause la plus fréquente de HF a été Cardiopathie hypertensive (HHD) (28 patients ; 35 %). Sujets avec PHT avaient relativement abaisser la pression artérielle systolique (SBP) (P = 0.044) et l'oreillette gauche plus gros (P = 0.036) et le ventricule gauche (VG) à fin-diastole et systole-fin (P = 0.036 et P = 0.008, respectivement) et une tendance à la fraction d'éjection inférieure LV (FEVG) (P = 0.053). Il n'y n'avait aucune relation entre PAPM et le peptide natriurétique de type B-pro N-terminal (P > 0.05). Un total de 12 patients HF (15,0 %) sont morts, dont 8 (66,7 %) avaient des PHT. Choc cardiogénique (P = 0.044) et le ratio cours / flux trans-mitrale vitesses (P = 0.023) étaient des déterminants indépendants de mortalité hospitalière.
Conclusion : PHT est fréquente chez les patients hospitalisés de HF et a été associée à la pire des indices de la morbidité et une tendance vers une mortalité plus élevée. Nous recommandons que les patients HF projeté pour PHT, et sa présence devrait κtre prise en considération dans la gestion et le pronostic des patients affectés.
Mots-clés : Insuffisance cardiaque, mortalité, Nigeria, hypertension artérielle pulmonaire
Keywords: Heart failure, mortality, Nigeria, pulmonary hypertension
|How to cite this article:|
Karaye KM, Saidu H, Bala MS, Yahaya IA. Prevalence, clinical characteristics and outcome of pulmonary hypertension among admitted heart failure patients. Ann Afr Med 2013;12:197-204
|How to cite this URL:|
Karaye KM, Saidu H, Bala MS, Yahaya IA. Prevalence, clinical characteristics and outcome of pulmonary hypertension among admitted heart failure patients. Ann Afr Med [serial online] 2013 [cited 2020 Sep 20];12:197-204. Available from: http://www.annalsafrmed.org/text.asp?2013/12/4/197/122685
| Introduction|| |
Heart failure (HF) and pulmonary hypertension (PHT) are common syndromes globally, with significant morbidity and mortality. Although data from large-scale community-based studies are lacking in Sub-Saharan Africa (SSA), hospital-based studies have shown that HF was responsible for upto 10% of medical admissions with prevalence of in-hospital mortality of 10.1%, while PHT was recorded in upto 47% of subjects with right HF. ,
The prevalence of PHT in left-heart disease increases with the severity of functional impairment. Forty to seventy percent of patients with isolated diastolic dysfunction, and upto 60% of those with left ventricular systolic dysfunction were found to have PHT at presentation. , In patients with left heart disease, the mortality rate was higher in patients with PHT (28%), than those without (17%) at
28 months.  In addition, a recent community-based study has shown that patients with PHT caused by left-heart disease fared poorly (mean survival
4.2 ± 0.1 years), similar to those with respiratory diseases (4.1 ± 0.3 years) and those without an identified cause for their PHT (4.3 ± 0.3 years). By contrast, patients with pulmonary arterial hypertension, most of whom were prescribed disease-specific treatment, had the best survival
(82% survival at the conclusion of the study).  Studies carried out in various parts of the world have shown that PHT and pulmonary artery systolic pressure (PASP) can strongly predict death and provide incremental and clinically relevant prognostic information in subjects with HF, followed-up for several months, independently of known predictors of outcomes. ,
However, there is paucity of data in SSA on the prevalence of PHT and its impact on morbidity and short-term mortality in HF patients.
The aim of the present study was to assess the prevalence of PHT, its clinical characteristics and in-hospital mortality, among admitted HF patients in a referral hospital in Nigeria.
| Materials and Methods|| |
The study was prospective and descriptive in design. Before the commencement of the study, the Research Ethics Committee of the study center reviewed and approved the study protocol, which conformed to the ethical guidelines of the Declaration of Helsinki; on the principles for medical research involving human subjects.  Signed informed consent was obtained from all study subjects.
HF patients were included in the study if they were atleast 18 years of age, had satisfactory images on trans-thoracic echocardiography for the assessment of PASP, no pulmonary valve stenosis and were admitted to the medical wards of the study center. Minimum sample size was estimated at 48 (at 95% confidence level), using a validated sample size formula for observational studies (see below), using a prevalence of HF of 10% among all patients admitted to the medical wards of a tertiary health center in Nigeria, with a bed capacity of 72, and confidence limits of 5%. 
Sample size (n) = [DEFF * Np (1 − p)]/[(d2 /Z2 1-α/2 * (N − 1) + p * (1 − p)]
Population size (N) = 72
Hypothesized frequency of outcome factor in the population (P) = 10%
Confidence limits as % of 100 (d) = 5%
Design effect (for cluster surveys-DEFF) = 1
However, 80 HF patients were serially recruited after satisfying the inclusion criteria, to improve the power of the study.
Definitions of study terms
HF was defined according to the recommendations of European Society of Cardiology (ESC).  PHT was defined as the presence of mean pulmonary arterial pressure (mPAP) of ≥25 mmHg at rest.  mPAP was estimated from PASP using the Chemla formula as: mPAP = (0.61 Χ PASP) +2 (mmHg).  PASP was estimated using continuous wave Doppler echocardiography, which was used to measure the maximum velocity of the tricuspid regurgitant jet (v), with which the trans-tricuspid pressure gradient was calculated using the modified Bernoulli equation (4v2 ) [Figure 1].  Right ventricular systolic pressure (RVSP) was then estimated by adding the trans-tricuspid pressure gradient to the right atrial pressure (RAP) [Figure 1].  RVSP was then equated to the PASP, given that pulmonary valve stenosis was excluded.  RAP was estimated using the diameter and collapse of the inferior vena cava (IVC) during spontaneous respiration. In this method, IVC diameter ≤2.1 cm that collapses >50% with a sniff suggests a normal RAP of 3 mm Hg (range 0-5 mm Hg), whereas an IVC diameter >2.1 cm that collapses <50% with a sniff suggests a high RA pressure of 15 mm Hg (range 10-20 mmHg). In indeterminate cases in which the IVC diameter and collapse do not fit this paradigm, an intermediate value of 8 mm Hg (range, 5-10 mm Hg) was used.  Mild PHT was defined as mPAP of 25.0-34.9 mmHg, moderate PHT as mPAP of 35.0-44.9 mmHg, and severe PHT as mPAP ≥45.0 mmHg. 
|Figure 1: Estimation of pulmonary artery systolic pressure using continuous wave Doppler echocardiography|
Click here to view
Among patients with systemic hypertension, 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 either a positive history of typical angina or acute myocardial infarction (MI), and/or typical electrocardiographic (ECG) abnormalities of acute MI or myocardial ischemia, and ventricular regional wall motion abnormality on 2D echocardiography. Acute MI was defined according to the recommendations of the joint European Society of Cardiology/American Heart Association (ESC/AHA) Committee.  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.  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 ≤2.0 cm 2 ) or Doppler echocardiographic techniques (the diastolic pressure half-time method or the continuity equation).  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 ≤1.5 cm 2 ), and almost invariably occurring with rheumatic MV disease.  Dilated cardiomyopathy (DCM) was defined as the presence of dilated LV (with or without dilatation of the other 3 cardiac chambers) with global systolic (LVEF ≤45%) and diastolic dysfunction (DD).  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%.  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 h 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.  These included a 12-lead ECG at rest, trans-thoracic echocardiogram and N-terminal pro-B-type natriuretic peptide (NT-BNP). Other investigations were carried out if and when indicated, as appropriate.
In addition, NT-BNP was measured in an apparently healthy control group, which comprised of 34 volunteers from among medical students and doctors, and laboratory staff, after obtaining informed consent. This was to generate a normative data on NT-BNP as well as to compare with the HF subjects. To be eligible, the controls had to be at least 18 years of age, apparently healthy, and without history of systemic hypertension, diabetes, renal failure, stroke or failure of any major body organ.
Plasma concentration of 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. All laboratory investigations were carried out in the laboratories of the study center.
Frequencies, ranges and means with standard deviations were used to describe patients' characteristics. Chi-squared, Fisher's exact, and Student's t-tests were used to compare categorical and continuous variables as appropriate. To assess for the determinants of in-hospital mortality, univariate and multivariate logistic regression models were applied. Pearson's correlation (r) was also used to determine the relationship between mPAP and a number of variables. Estimates were computed as odds ratios (OR) with 95% confidence (95% CI) limits. 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 80 HF patients were recruited serially, among whom 31 (38.75%) were males while
49 (61.25%) were females. Five other HF patients were excluded from the study because of unsatisfactory echocardiographic images. The mean age of all patients was 45.90 ± 19.93 years, with a range of 18-91 years while their mPAP was 30.91 ± 14.73 mmHg. PHT was recorded in 53 subjects (66.25%) while the remaining 27 (33.75%) had normal mPAP. Their baseline and clinical characteristics are presented in [Table 1].
A total of 12 HF patients (15.0%) (male:female (M:F) ratio = 1:2) suffered in-hospital mortality, out of whom 8 (66.67%) had PHT. Subjects with PHT who died spent 12.5 ± 6.7 days on admission, had a mean age of 45.0 ± 22.9 years and mPAP of 41.05 ± 13.87 mmHg, while those who died and had no PHT spent 16.3 ± 10.2 days on admission (P > 0.05), had a mean age of 53.5 ± 26.4 years (P > 0.05) and mPAP of 19.08 ± 6.78 mmHg (P = 0.015). In the univariate regression analysis, the following variables were significant determinants of in-hospital mortality: systolic blood pressure (SBP) (B = 0.963; 95% CI = 0.931-0.996; P = 0.030); diastolic BP (B = 0.954; 95% CI = 0.916-0.994; P = 0.025); trans-mitral flow velocities ratio (E:A waves) (B = 0.396; 95% CI = 0.161-0.972; P = 0.043) and presence of cardiogenic shock (B = 0.069; 95% CI = 0.017-0.286). After controlling for confounding factors however, only cardiogenic shock (B = 0.096; 95% CI = 0.010-0.939; P = 0.044) and the E:A waves ratio (index of LV diastolic dysfunction [LVDD]) (B = 0.207; 95% CI = 0.053-0.803; P = 0.023) maintained their statistical significance.
Etiology of HF is described in [Table 2]. It shows that the most common cause of HF in all subjects was HHD and majority of these patients (53.57%) (i.e., 15/28) had no PHT (P = 0.006).
|Table 2: Etiology of heart failure in subjects with and without pulmonary hypertension |
Click here to view
Echocardiographic features of subjects in both groups are presented in [Table 3]. Further analysis shows that mild PHT was recorded in 30 (56.60%) subjects, moderate PHT in 11 (20.76%), and severe PHT in the remaining 12 HF subjects (22.64%).
Correlation between mPAP and various hemodynamic and cardiac structural variables was statistically significant for the following variables only: New York Heart Association (NYHA) functional classes III and IV (r = +0.225; P = 0.045); SBP (r = -0.235; P = 0.041); RV outflow tract proximal end-diastolic diameter (RVOTd) (r = +0.283; P = 0.017) and LA (r = +0.229; P = 0.041).
NT-BNP was assessed in only 37 patients because of its high cost (paid for by the investigators and the Study Center); 26 of them had PHT (anti-Log 10 of the mean NT-BNP = 3002.43 ± 905.27 pg/ml) while the remaining 11 had no PHT (anti-Log10 of the mean = 2666.29 ± 522.90 pg/ml) (P > 0.05). In addition, 34 subjects were recruited as controls for the NT-BNP assay; evenly divided between the sexes (17 males and 17 females). Their mean age was 25.50 ± 6.20 years (range of 19-42 years), and the mean of NT-BNP was 24.70 ± 2.50 pg/ml. NT-BNP levels were significantly higher in the HF groups as compared with the control group (P < 0.001).
Echocardiography was carried out by the principal author, Kamilu M. Karaye, on the majority of included patients (73/80) while the remaining (7/80) were carried out by Hadiza Saidu (in order to minimize inter-observer variability).
| Discussion|| |
The present study has prospectively assessed the prevalence and clinical characteristics of PHT and its impact on in-hospital mortality, among admitted HF patients, in a tertiary health center in Nigeria. In addition, NT-BNP was measured in the HF subjects and compared to a control group irrespective of body weight.
We found that PHT was common, seen in 66.3% of all the patients. This result is lower but comparable with that of Aronso et al., who reported a prevalence of PHT of 76% among subjects with acute decompensated HF in the "Vasodilation in the Management of Acute Congestive Heart Failure" (VMAC) trial.  Butler et al. however, reported an even higher prevalence of PHT of 88% among admitted subjects with advanced HF undergoing evaluation for heart transplantation, suggesting that prevalence of PHT rises as HF severity worsens. 
In comparison with subjects without PHT, our results have shown that subjects with PHT had lower SBP, and larger LA and LV, while their lower LVEF narrowly failed to achieve statistical significance (P = 0.053). These findings support the hypothesis that subjects with worse LV diseases had higher mPAP and prevalence of PHT. We also found positive correlation between mPAP and NYHA functional class, RV and LA sizes, and negative correlation with SBP (P < 0.05). These findings further confirm that subjects who had worse HF symptoms, worse systolic (lower SBP) and diastolic (larger LA) LV functions had higher mPAP, as well as worse RV remodeling (larger RVOT). The predominant type of PHT in the present study was therefore "PHT due to left heart disease", as classified in the Revised World Health Organisation's (WHO) recommendation.  However, we did not find significant correlation between mPAP and RV shortening fraction (RVSF) (r = -0.140; P = 0.248). This contrasts with the findings by Lindqvist et al., who reported a moderately strong negative correlation between PASP and RVSF (r = -0.53; P < 0.001), and who therefore recommended that RVSF should be included in the routine assessment of RV systolic function. 
It has been documented that circulating levels of NT-BNP and BNP correlate with mPAP, but elevations in their levels are usually not seen until mPAP is high enough to cause RV strain.  On the other hand, Goto et al. recently reported that they did not find correlation between PASP and BNP among subject with PHT, until after subjects with LV failure and LV hypertrophy were excluded.  Therefore, they suggested that presence of LV disease significantly confounds the relationship between NT-BNP or BNP and PASP or PHT.  These two studies perhaps explain our findings: Lack of relationship between mPAP and NT-BNP and lack of difference in NT-BNP between subjects with and without PHT. Majority of patients in our series had LV dysfunction, which perhaps confounded any possible relationship between mPAP and NT-BNP, although mPAP correlated positively with RV size (r = +0.238; P = 0.017). We also did not record any significant relationship between NT-BNP levels and in-hospital mortality. However, several other studies have confirmed that increased levels of NT-BNP or BNP are associated with worse long-term outcome, while decreasing levels on treatment for PHT are associated with improved outcomes. ,
Whereas several studies have demonstrated that PHT increases long-term mortality among HF subjects, there is paucity of data on the impact of PHT on in-hospital mortality among HF subjects especially in SSA. In the present study, a total of twelve HF patients died in-hospital (15.0%); eight with PHT giving a prevalence of 15.1%, while the remaining 4 had no PHT (14.8%) (P = 0.974). However, this descriptive study did not aim at comparing mortality rates between the two groups. The trend toward higher in-hospital mortality in subjects with PHT could be used in hypothesis generation in future studies. In the VMAC study, it was reported that during a follow-up of 6 months, 8.6% of subjects without PHT died, which was significantly lower than what was recorded among subjects with PHT (30.4%).  In another study among out-patients with chronic HF followed-up for about 17 months, Ghio et al. reported that mPAP among other variables (NYHA III and IV, RV ejection fraction (RVEF) and LV end-systolic diameter index) was an independent predictor of mortality.  Even among out-patients with chronic HF followed up over several months, Ghio et al. went further to show that subjects with high mPAP had to have additional low RVEF in order to have worse prognosis than subjects with normal mPAP.  In addition, Szwejkowski et al. reported that PHT predicted all-cause mortality in a heterogeneous group of patients with HF, and each 5 mmHg rise in PASP was associated with a 6% increased risk of death.  The in-hospital mortality rate in Europe, according to the EuroHeart Failure Study, was 8.1% for de novo HF, 9.1% for those presenting with pulmonary edema, and about 40% for cardiogenic shock, re-confirming the latter as an important predictor of in-hospital mortality in HF.  We have also shown in the present study that the independent predictors of overall mortality were cardiogenic shock and the trans-mitral flow velocities ratio which is an index of LVDD. LVDD has been recently reported to be common (90%) in subjects with PHT and is associated with increased mortality, irrespective of the presence of HF. 
The present study has some limitations. Firstly, we used Doppler echocardiography to estimate PASP, which could under- or over-estimate the PASP. The gold standard for the diagnosis and confirmation of PHT is right heart catheterization, which is an invasive procedure associated with some morbidity (1.1%) and mortality (0.055%).  Doppler echocardiography is non-invasive, inexpensive, and widely available. In addition, Janda et al. recently reported in a meta-analysis that the diagnostic accuracy of echocardiography for PHT was reasonably good, with a summary sensitivity and specificity of 83% and 72%, respectively. 30 Secondly; we could not measure NT-BNP in all subjects because of financial constraints. Thirdly, five patients (5/85) who had poor echocardiogram images due to co-existing chronic obstructive airway disease had to be excluded from the study. However, their exclusion could not have affected the overall results significantly given their small number. Finally, our study was hospital-based. Future studies should be community-based, and be designed to assess the impact of PHT on both short- and long-term mortality, as well as other measures of disease severity such as the NT-BNP, in the HF subjects.
| Conclusion|| |
PHT was common in the admitted HF patients, and was associated with worse parameters for morbidity, and a trend towards higher mortality as compared with subjects with normal mPAP. Community-based studies are needed to further assess the relationship between PHT and both short-and long-term mortality in SSA.
Fifteen percent of the HF patients suffered in-hospital mortality, regardless of the presence or absence of PHT, and its independent determinants were cardiogenic shock and trans-mitral flow velocities ratio.
The relationship between NT-BNP and PHT was assessed in the HF subjects perhaps for the first time in SSA, and we recorded very high values among the subjects regardless of the presence or absence of PHT, in comparison with the control group.
We recommend that assessment for PHT should be carried out in all HF patients, and its presence should be taken into consideration in the management and prognostication of affected patients.
| Acknowledgment|| |
The authors acknowledge and appreciate the contribution of the management of Aminu Kano Teaching Hospital, Kano, Nigeria, for waiving 50% of the cost of NT-BNP assays. The remaining 50% of the cost was paid by the authors.
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[Table 1], [Table 2], [Table 3]