Elevated mean pulmonary artery pressure in patients with mild-to-moderate mitral stenosis: a useful predictor of worsening renal functions?/Hafif ve orta derecede mitral darligi bulunan hastalarda artmis ortalama pulmoner arter basinci bozulan böbrek fonksiyonlarini göstermede yararli bir belirteç olabilir mi?

Headnote

ABSTRACT

Objective: Renal dysfunction commonly accompanies the course of cardiac disorders and strongly associates with increased morbidity and mortality. Elevated central venous pressure is related to worsening renal function in patients with heart failure. However, predictors of worsening renal function in mitral stenosis-whose pathophysiologic process is similar to heart failure with regard to right heart dysfunction-are unknown. This study aimed to evaluate whether clinical and echocardiographic parameters might predict worsening renal function in patients with mild-to-moderate mitral stenosis.

Methods: The current study has a prospective cohort design. Sixty consecutive patients (9 male, 51 female, mean age 50±13 years) with mild-to-moderate mitral stenosis were followed up for 34±13 months (range 1-60) and their renal functions were monitored. Worsening renal function was defined as a decline in glomerular filtration rate of ≥ 20% on follow-up. In order to presence or absence of worsening renal functions, study patients divided into two groups. Statistical analysis was performed using the Chi-square, Independent samples t / Mann-Whitney U tests, univariate and multivariate Cox proportional hazards analyses, receiver operating characteristic (ROC) and Kaplan-Meier curve analyses.

Results: Worsening renal function was observed in 14 patients (23%). In univariate analysis, male gender, mean pulmonary artery pressure (mPAP), peak tricuspid regurgitation velocity, systolic pulmonary artery pressure, digitalis and antiplatelet usage, right atrial size, and TEI index were determined to be predictors of worsening renal function. In a multivariate Cox proportional hazards model, mPAP (HR=1.136, 95% CI: 1.058-1.220, p<0.001) and male gender (HR=4.110, 95% CI: 1.812-9.322, p=0.001) were associated with increased risk of worsening renal function during the follow-up period. In ROC curve analysis, the optimal cut-offvalue of mPAP to predict worsening renal function was measured as more than 21 mmHg, with 78.6% sensitivity and 58.7% specificity (AUC 0.725, 95% CI 0.595-0.838). According to the Kaplan-Meier curve, a significant difference was found between those who had mPAP of >21 mmHg, and those who did not have, in terms of worsening renal function (p=0.006), and the difference between the groups increased after 30 months of follow-up.

Conclusion: Elevated mean pulmonary artery pressure at the time of initial evaluation, in patients with mild-to-moderate mitral stenosis, might help to predict worsening renal function. (Anadolu Kardiyol Derg 2013; 13: 457-64)

Key words: Mean pulmonary artery pressure, mitral stenosis, worsening renal function, Cox proportional regression analysis, survival

ÖZET

Amaç: Böbrek fonksiyon bozuklugu, siklikla kalp hastaliklarina eslik eder ve yüksek mortalite ve morbiditeye sahiptir. Kalp yetersizligi bulunan hastalarda santral venöz basinç yüksekligi de böbrek fonksiyonlarinda bozulmayla ilgilidir. Bununla birlikte; sag kalbe ait fonksiyon bozuklugu ile kalp yetersizligi bulunan hastalarla benzer patofizyolojik özelliklere sahip mitral darligi bulunan hastalarda böbrek fonksiyonlarinda bozulmayi gösteren belirteçlerin neler oldugu bilinmemektedir. Bu çalismada, hafif ve orta mitral darligi bulunan hastalarda klinik ve ekokardiyografik parametrelerin bozulan böbrek fonksiyonlarini göstermedeki yerinin arastirilmasi hedeflenmistir.

Yöntemler: Bu çalisma prospektif kohort bir dizayna sahiptir. Hafif ve orta derecede mitral darligi bulunan, ortalama yaslari 50±13 yil olan, 9'u erkek 51'i kadin 60 hastada böbrek fonksiyonlari ortalama 34±13 ay (1-60 ay) takip edilmistir. Takip boyunca, glomerüler filtrasyon oraninda %20'den fazla azalma görülmesi böbrek fonksiyonlarinda bozulma olarak kabul edilmistir. Hastalar böbrek fonksiyonlarinda bozulma gelisip gelismemesine göre iki gruba ayrildi. Istatistiksel analiz olarak Ki-kare, bagimsiz gruplarda t/Mann-Whitney U testleri, tek ve çok degiskenli Cox orantisal risk analizleri, ROC ve Kaplan-Meier egrisi analizleri kullanildi.

Bulgular: Çalismaya alinan 14 hastada (%23) böbrek fonksiyonlarinda bozulma tespit edilmistir. Yapilan tek degiskenli analizlerde; erkek cinsiyet, ortalama pulmoner arter basinci, pik triküspit regürjitasyon akimi, sistolik pulmoner arter basinci, dijital ve antitrombositlerin kullanimi, sag duraatriyum boyutlari ve TEI indeksi'nin böbrek bozukluklarinda bozulmayi gösterdigi saptanmistir. Çok degiskenli orantisal Cox risk modeli analizleri de, takip döneminde erkek cinsiyet ve ortalama pulmoner arter basincinin böbrek fonksiyonlarinda bozulma riskindeki artis ile iliskili oldugunu göstermistir. ROC analizinde, mPAP için kötülesen böbrek fonksiyonunu gösteren optimal cut-offdegeri % 78,6 duyarlilik ve %58,7 özgüllük ile (AUC 0,725, %95 CI 0,595-0,838) >21 mmHg olarak ölçüldü. Kaplan-Meier egrisi ile degerlendirmelerde, mPAP > 21 mmHg olanlar ve olmayanlar arasinda renal fonksiyonlarda kötülesme açisindan görülen fark anlamliydi (p=0,006). Gruplar arasindaki bu fark 30 aylik takip sonrasinda daha da artti.

Sonuç: Hafif ve orta derecede mitral darligi bulunan hastalarda, ilk degerlendirmede ölçülen artmis ortalama pulmoner arter basinci, bozulan böbrek fonksiyonlarini göstermede yararli olabilir. (Anadolu Kardiyol Derg 2013; 13: 457-64)

Anahtar kelimeler: Ortalama pulmoner arter basinci, mitral darligi, böbrek fonksiyon bozuklugu, Cox orantisal hazard regresyon analizi, sag kalim

Introduction

The incidence of acute rheumatic fever, and consequently of rheumatic valvular heart diseases, in developed countries has declined over the past decade. Although the occurrence of rheumatic heart diseases, including rheumatic mitral stenosis (MS), has declined in developed countries, it has remained a significant public health problem in developing ones (1). Symptoms of MS usually occur after a latent period following an initial acute rheumatic fever episode. This period might take more than 15 years. During this asymptomatic period, mitral valve area (MVA) reduces gradually. Clinical symptoms suggestive of MS occur when MVA of less than 2 cm2, and the appearance of the diastolic pressure gradient between the leftatrium and leftventricle, have resulted in a transmitral peak velocity of greater than 1 m/sec. Rates of 5-, 10- and 15-year survival with sole medical therapy (without surgery) were 44%, 32%, and 19%, respectively (2).

It is well known that renal dysfunction frequently accompanies the course of cardiac disorders and is strongly associated with morbidity and mortality (3-6). Worsening renal function (WRF) most commonly occurs in heart failure (HF) as a result of a complex interaction between the heart and kidneys. Recently published studies in HF have clarified its pathophysiology and underlined the importance of venous congestion, which can also be observed in MS due to increased right heart afterload (7-9). The relation between venous congestion and renal dysfunction has been shown in experimental studies (10, 11). These studies suggest that iatrogenically induced hypervolemia, and increase in renal vein pressure, lead directly to renal insufficiency independent of cardiac output or renal blood flow. This has also been shown to be a reversible phenomenon because lowering of renal vein pressure immediately improves urine output and glomerular filtration rate (GFR) (10, 11). Experimental studies have also indicated that temporary renal vein compression results in reduced sodium excretion, reduced GFR, and reduced renal blood flow (12-14). Increased venous congestion also causes an increase in renal interstitial pressure, which might lead to a hypoxic state of the renal parenchyma (15-18). Prolonged increases in plasma volume also attenuate several vascular reflexes, leading to an impaired arterial responsiveness, thereby further impairing the effective renal blood flow (19-22).

However, the prognostic significance of WRF and its clinical and echocardiographic determinants in MS are still unknown. In this study, we aimed to evaluate the clinical and echocardiographic parameters which might predict WRF in mild-to-moderate MS.

Methods

Study design

This study has a prospective cohort design.

Study population

Eighty consecutive patients with mild-to-moderate rheumatic MS, who were enrolled as part of another study, were prospectively considered in three participating centers between January 2006-January 2011 (23). Twenty patients (with similar age and gender distribution) from the original cohort declined to participate during the follow-up period. Patients with another severe accompanying valvular disorder, history of coronary artery disease, depressed ejection fraction, history of cardiac surgery, previous diagnosis of pulmonary disease, or previous diagnosis of chronic renal failure, were excluded from the study. Patients with a mitral valve area of < 1cm2 were also excluded, because these patients required surgical treatment at the time of evaluation. Patients with severe MS who declined surgery were also excluded because these patients already had low cardiac output (authors of this manuscript were considered that this might influence renal functions earlier than expected and could obscure other parameters' significance in determining worsening renal function). Therefore, 60 consecutive patients were enrolled. Patients were evaluated at every 6 months, unless any clinical deterioration and increase in symptoms were observed. The GFR of each participant was followed up at each visit.

The study protocol had been approved by the institutional ethics committee, and written informed consents were taken from all participants of this prospective observational cohort.

GFR assessment

The GFR was calculated according to the Modification of Diet in Renal Disease (MDRD) formula (86.3 x sCr-1.154 x age-0.203, female: MDRDx0.742, black or non-white: MDRDx1.212). Worsening of renal function was defined as a decline in GFR of ≥ 20% on follow-up.

Clinical examinations

Clinical parameters including age, gender, height, weight, body surface area, body mass index, and presence and dura tions of comorbid disorders such as hypertension, diabetes mellitus, hyperlipidemia, smoking, characteristics of cardiac rhythm, and applied treatment as antiplatelets, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors / angiotensin receptor blockers (ARB), diuretics, calcium channel blockers, digitalis, and warfarin were carefully evaluated and recorded.

Echocardiography

Echocardiographic examinations were performed with a cardiac ultrasound system (Vivid 7, GE Healthcare, Wauwatosa, WI, US) to evaluate chamber quantification with a defined protocol (11, 24) by a physician who was unaware of patients' renal function. Resting heart rate was 55-85 bpm in all patients during echocardiographic examination. All echocardiograms were recorded and coded by echocardiographers without identities to eliminate interobserver variability. Recorded and coded data were put into random order by computer assistance and evaluated off-line by an expert echocardiographer. MVA was calculated by the two-dimensional planimetry method, and if the image quality was not sufficient, the Doppler pressure half time method was used (25). Transmitral gradients were calculated by the modified Bernoulli equation (26). Accompanying valvular regurgitations were quantified according to recent guidelines and categorized as mild-moderate (27). The modified Bernoulli equation derived from the tricuspid regurgitation jet velocity and estimated right atrial pressure from inferior vena cava collapsibility was used in determining systolic pulmonary artery pressure (sPAP) (28). Mean pulmonary artery pressure (mPAP) was calculated by the Masuyama method (29). Tricuspid annulus velocities (via tissue Doppler), right ventricular outflow timevelocity integral, Tei index, ejection times, intervals, and tricuspid annular plane systolic excursion were measured accordingly in all patients (30-33). Echocardiographic parameters at the time of initial evaluation were used in statistical analysis, as predictors of WRF during follow-up.

Statistical analysis

All statistical procedures were performed using SPSS software version 15.0 (SPSS Inc., Chicago, IL). Continuous variables were expressed as mean±standard deviation or median (interquatile range) in the presence of abnormal distribution, categorical variables as percentages. Comparisons between groups of patients were made by use of a Chi-square test for categorical variables, an independent samples t-test for normally distributed continuous variables, and the Mann-Whitney U test when the distribution was skewed. Univariate Cox proportional hazards analysis was used to quantify the association of variables with worsening renal function. Variables found to be significant at the p <0.1 level in univariate analysis were used in a multivariate Cox proportional hazards model with a forward stepwise method in order to determine the independent predictors of WRF. Receiver operator characteristic (ROC) curve analysis was performed to identify the optimal cut-offpoint of mPAP (at which sensitivity and specificity would be maximal) for the prediction of WRF. Areas under the curve (AUC) were calculated as measures of the accuracy of the tests. We compared the AUC by use of the Z test. Kaplan-Meier curves were used to show the development of WRF in two patient subgroups, defined as having no increased (≤21 mmHg) or increased (>21 mmHg) mPAP based on a cut offvalue. A p-value of 0.05 was considered as statistically significant.

Results

Baseline clinical characteristics and echocardiographic parameters

Sixty mild-to-moderate MS patients were followed up for a mean period of 34±13 months (range 1-60). The mean age of the study population was 50±13 years (85% females, 15% males). The mean MVA and mean transmitral gradient of the study population were 1.6±0.2 cm2 and 6.4±2.9 mmHg, respectively. Comparison of patients' baseline clinical characteristics and echocardiographic parameters, according to the presence of WRF, has been shown in Table 1 and Table 2. Worsening renal function on follow-up was more frequent in patients of male gender, or with a history of digitalis use (p=0.025 and p=0.044, respectively. Maximum tricuspid regurgitation velocity (TR max velocity), sPAP and mPAP were higher in patients with worsening renal function (p <0.05). Other baseline clinical and echocardiographic parameters were similar between groups (Table 1 and 2).

Regression analyses for the development of worsening renal function

Results of the univariate and multivariate Cox proportional hazards analyses have been shown in Table 3. Male gender, mPAP, TR max velocity, sPAP, digitalis and antiplatelet agent usage, right atrial diameter, and Tei index were found to be univariate predictors of WRF. In the multivariate Cox proportional hazards model, mPAP (HR=1.136, 95% CI: 1.058-1.220, p<0.001) and male gender (HR=4.110, 95% CI: 1.812-9.322, p=0.001) were associated with an increased risk of WRF during follow-up.

ROC curve for mPAP to predict worsening renal function

According to the ROC curve analysis, the optimal cut-offvalue of mPAP to predict WRF was measured as more than 21 mmHg, with 78.6% sensitivity and 58.7% specificity (AUC 0.725, 95% CI 0.595-0.838, Fig. 1). On the other hand, mPAP of >36.21 mmHg was found to have 100% specificity for WRF on follow-up, though sensitivity was low (14.3%).

Survival analysis

According to the Kaplan-Meier curve, a significant difference was found between those who had mPAP of >21 mmHg, and those who did not, in terms of worsening renal function (p=0.006), and the difference between the groups became bigger after 30 months of follow-up (Fig. 2).

Discussion

In this study, we aimed to evaluate whether clinical and echocardiographic parameters might predict WRF in patients with mild-to-moderate mitral stenosis. Male gender, mPAP, TRmax velocity, sPAP, digitalis and antiplatelet agent usage, right atrial diameter and TEI index were found to be univariate predictors of worsening renal function. However, even after controlling these parameters, we demonstrated that only mPAP and male gender were independently associated with an increased risk of WRF during follow-up in patients with mild-to-moderate mitral stenosis.

The kidney and the heart are two closely interrelated organs. It is well known that any disorder affecting one of the two deteriorates the other's functional status. Deterioration of this close interrelation between these two organ systems is known as "cardio-renal syndrome," and studies in HF have clarified the pathophysiological mechanisms behind this syndrome. It has been thought that renal dysfunction in HF is attributable to low cardiac output, which consequently causes reduction in blood flow and renal perfusion pressure (9, 34). Decreased cardiac output also activates the renin-angiotensin-aldosterone system and the sympathetic nervous system, which in turn causes congestion and constriction in afferent arterioles. These results in further decreases in renal perfusion pressure (34). Theoretically, the above-mentioned pathophysiological mechanism is valid; however, recent studies suggest different mechanisms. Heywood et al., (35) have shown that renal dysfunction is similar in patients with systolic and diastolic dysfunction; this result suggests mechanisms other than low cardiac output. Recently published HF studies have explained the role of venous congestion in renal dysfunction (7-9, 36, 37). Some other studies have suggested right atrial and central venous pressure, rather than cardiac index, as the main predictors of worsening renal function (37, 38). Increased oxidative stress and inflammation in the tubule-interstitium developed after venous congestion may also have a role in renal dysfunction (39).

Renal dysfunction may also potentially complicate the course of rheumatic MS. Just like in HF, right ventricular dysfunction secondary to increased right heart afterload, and venous congestion, are also common findings of MS. However, the potential role of echocardiography in predicting WRF in MS is unknown. In this study, we investigated clinical and echocardiographic indices of WRF in MS. In our study, mPAP was found to be an independent predictor of WRF. Systolic PAP and TR max velocity were other predictors in univariate analysis, though they lost their significance after multivariate analysis. On the other hand, in this study, echocardiographic indices of MS severity including transmitral gradients and valve area, as well as leftatrial diameters, had no influence in predicting WRF. These findings were consistent with the above-mentioned data derived from HF studies, which proved the role of venous congestion and right ventricular dysfunction in WRF. It is notable that cardiac output may have a potential role in worsening renal function; however, we excluded patients with severe MS since these patients needed intervention at the time of evaluation. In our study, right ventricular diameter was within normal range and did not differ between groups. This was also true for TAPSE and Tei indices. These findings suggest that right ventricular systolic function was relatively preserved at the time of evaluation; however, an afterload mismatch of the right ventricle, in the form of increased pulmonary pressure, was already there. This increased afterload seemed to bring about right ventricular diastolic dysfunction, which in turn increased right atrial pressures and caused venous congestion. Increased transverse right atrial diameter, observed in this study, supports this hypothesis (Table 2). The right atrial area was also increased in patients with WRF, though it could not reach statistical significance (p=0.101). We think invasive measurement of right atrial pressure might clarify this hypothesis.

Study limitations

Although a lack of invasive measurements was the major limitation of our study, we did not consider invasive assessment, since it might cause ethical problems if performed in cases of mild-to-moderate MS. Central venous pressure and inferior vena cava diameters, which remain other important study limitations, were also not recorded in our study. Because right ventricular systolic function was preserved, this issue was overlooked. Male gender was also found to be a predictor of WRF; however, it is better not to generalize about this, since there were relatively few male patients in the cohort, which is another limitation of this study. The number of patients enrolled in this study was another limitation; therefore, our findings should not be generalized. These findings should be supported by further studies conducted with a sufficient number of patients.

Conclusion

Increased mPAP at the time of evaluation, in patients with mild-to-moderate MS, seems to predict WRF during follow-up; hence, we think close monitoring of these patients, particularly those with mPAP of > 36.2 mmHg-which as a rule designates very high specificity in test results-may be useful in terms of renal function.

Conflict of interest: None declared.

Peer-review: Externally peer-reviewed.

Authorship contributions: Concept - M.B.Y., C.Z., A.Z.; Design - M.B.Y., G.A., G.B.; Supervision - M.B.Y., I.T., O.O.T.; Resource - I.T., M.B.Y.; Material - G.A.; Data collection&/or Processing - G.A., G.B.; Analysis &/or interpretation - A. Z.; Literature search - C.Z., I.E.; Writing - C.Z., A.Z.; Critical review - O.O.T., M.B.Y., A.Z.; Other - I.E.

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