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The Prognostic Impact of Pulse Pressure in Acute Heart Failure: Insights from the HEARTS Registry

Background Low pulse pressure predicts long-term mortality in chronic heart failure, but its prognostic value in acute heart failure is less understood. The present study was designed to examine the prognostic value of pulse pressure in acute heart failure. Methods Pulse pressure was tested for its impact on short- and long-term mortality in all patients admitted with acute heart failure from October 2009 to December 2010 in eighteen tertiary centers in Saudi Arabia (n = 2609). All comparisons were based on the median value (50 mmHg). Heart failure with reduced ejection fraction was defined as less than 40%. Results Low pulse pressure was associated with increased short-term mortality in the overall population (OR = 1.61; 95 CI 1.17, 2.22; P 0.004 and OR = 1.51; 95% CI 1.13, 2.01; P = 0.005, for hospital and thirty-day mortality, respectively), and short-term and two-year mortality in the reduced ejection fraction group (OR = 1.81; 95% CI 1.19, 2.74; P = 0.005, OR = 1.69; 95% CI 1.17, 2.45; P = 0.006, and OR = 1.29; 95% CI 1.02, 1.61; P = 0.030 for hospital, thirty-day, and two-year mortality, respectively). This effect remained after adjustment for relevant clinical variables; however, pulse pressure lost its predictive power both for short-term and long-term mortality after the incorporation of systolic blood pressure in the model. Conversely, low pulse pressure was an independent predictor of improved survival at two and three years in heart failure with preserved ejection fraction (OR = 0.43; 95% CI 0.24, 0.78, P = 0.005 and OR = 0.49; 95% CI 0.28, 0.88; P = 0.016, respectively). Conclusion In acute heart failure with reduced ejection fraction, the prognostic value of low pulse pressure was dependent on systolic blood pressure. However, it inversely correlated with long-term survival in heart failure with preserved ejection fraction.


Introduction
P ulse pressure (PP) is a blood pressure (BP) component that measures the pulsatility dynamics of the left ventricle (LV) throughout the cardiac cycle, and is influenced by two main parameters: stroke volume and aortic elasticity [1], [2]. In the Framingham study, elevated baseline PP carried a significant future risk for coronary artery disease [3] and heart failure (HF) [4]. In addition, it independently predicted an overall cardiovascular-related mortality in several studied populations [5e7].
The prognostication of PP across the spectrum of HF syndromes is variable. In chronic symptomatic HF with reduced ejection fraction (HFrEF), low PP was predictive of all-cause mortality [8e12]. A similar observation was found in HFrEF following acute coronary syndromes [13], [14]. However, post-hoc analyses from two recognized randomized trials revealed a reverse pattern in asymptomatic HFrEF [15], [16]. Moreover, PP in HF with preserved EF (HFpEF) is less understood owing to the lack of reports. Available evidence emerges from three large-scale registries with variable conclusions, where direct [9], U-shaped [11], and neutral [8] relationships with long-term survival were described.
Few reports have focused on PP and mortality rates following an acute HF (AHF) hospitalization, and as such, independent inverse relationships between PP and extended mortality rates were described, especially in HFrEF [9], [11], [17]. All evidence about PP in HF seems to emphasize on extended survival rates, and there remains a literature gap on the clinical utility of admission PP for predicting hospital mortality. The aim of this study is to examine the prognostic value of PP on short-and long-term outcomes in both phenotypes of AHF, using data from the Heart Function Assessment Registry Trial in Saudi Arabia (HEARTS). We hypothesized that low PP will be associated increased mortality in patients presenting with AHF.

Methods
The HEARTS protocol had been previously described [18], [19]. Briefly, HEARTS is a prospective registry that enrolled 2609 consecutive patients aged 18 years and above with a primary admission diagnosis of AHF. Eighteen tertiary care centers in different regions of Saudi Arabia participated in this registry. Enrollment took place between October 2009 and December 2010, with clinical follow-up through January 2013. The definition of HF was based on the European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic HF [20]. The study was approved by the institutional review board at each participating hospital and complied with the Declaration of Helsinki. An informed written consent was obtained from all enrolled subjects.
BP was recorded on the first encounter in the emergency department. Measurements were done over the brachial artery with standard automated oscillometric devices or manual sphygmomanometers, depending on the practice of the participating institution. PP was calculated as the difference between systolic BP (SBP) and diastolic BP (DBP). Comparisons were assessed according to the PP median value (50 mmHg). LV systolic function was reported in categorical values as either normal (50%) or reduced (mild; 40e49%, moderate; 30e39%, and severe; < 30%), with the cutoff definition for HFrEF as 40%. We described patients' baseline characteristics, therapies, hospital course, and hospital outcomes. The primary endpoints were hospital, thirty-day, one-, two-, and three-year mortality. We obtained the vital status following hospital discharge by telephone interview, and then verified these data as needed with the use of hospital records.

Statistical Analysis
Categorical data were summarized with absolute numbers and percentages. Numeric data were summarized with mean and standard deviation or the median and interquartile range. Comparisons between the groups were performed using the Chisquare test or Fisher's exact test for categorical variables and the independent sample T-test or ManneWhitney U test for continuous variables. We

Baseline Demographics
Generally, patients with low PP were younger and had greater male predominance. Further, they were more likely to have a previous history of HF, and less likely to be diabetic, hypertensive, or dyslipidemic. On the other hand, the high PP patients had higher rates of previous atherosclerotic events, anemia, chronic renal insufficiency, and chronic lung diseases (P < 0.05 for all comparisons) ( Table  1). Patients with elevated PP had a significantly higher prevalence of hypertensive cardiomyopathy and lower rates of idiopathic dilated cardiomyopathy (P < 0.001 for group comparison). Uncontrolled hypertension was the main exacerbating factor for AHF in the high PP group, while medication and dietary noncompliance were higher in the opposing group (P < 0.001 for all comparisons) ( Table 2). The high PP group had higher average SBP and DBP values (150.2 vs. 108.9 mmHg; P < 0.001, and 78.0 vs. 70.5 mmHg; P < 0.001, respectively) and lower rates of severely reduced EF (P < 0.001 for group comparison). Among patients undergoing coronary angiogram in the same admission (n ¼ 749), normal studies were more often reported in the low PP group (P ¼ 0.001) ( Table 3). Fig. 1 demonstrates all differences in medication use between the groups. There was a trend of higher use of statins and lower use of aldosterone antagonists in the high PP group on admission and at discharge (P < 0.01 for all comparisons). In addition, the requirement of inotropic support with dobutamine and dopamine was greater in patients with low PP, while the need for nitroglycerin infusions was higher in the other group (P < 0.001 for all comparisons).

Primary Endpoints
In crude analysis, patients having low PP experienced higher rates of hospital recurrence of HF, shock state, and ventricular arrhythmias (P < 0.001 for all comparisons), as well as higher requirements for intra-aortic balloon pumps, implantable cardioverter defibrillators, and cardiac resynchronization therapy (P < 0.05 for all comparisons). Furthermore, they had higher rates of hospital and thirty-day mortality (7.9 vs. 5.0%; P ¼ 0.004, and 9.6 vs. 6.6%; P ¼ 0.005, respectively), but not after one, two, or three years (Table 4). In univariate regression analysis, low PP was associated with greater short-term mortality in the overall population, and short-term and two-year mortality in HFrEF. Furthermore, initial multivariate analyses revealed PP was predictive of both short-and long-term mortality in the overall population and HFrEF, but not HFpEF. However, the stepwise introduction of SBP, but not DBP, to adjustment models eliminated this mortality association, but showed an independent inverse correlation with long-term mortality in HFpEF only (OR ¼ 0.43; 95% CI 0.24, 0.78; P ¼ 0.005 and OR ¼ 0.49; 95% CI 0.28, 0.88; P ¼ 0.016 for twoand three-year mortality, respectively) ( Table 5 and Fig. 2). Of note, a subgroup analysis on HFpEF patients only showed higher rates of diabetes mellitus, hypertension, dyslipidemia, and chronic renal insufficiency in the high PP group (P < 0.001 for all comparisons) (See online supplementary material, Table S1).

Discussion
In this report, we examined the prognostic value of PP in patients admitted with AHF. PP, when measured peripherally via conventional BP measurement devices on hospital arrival, was not an independent predictor of mortality in our overall population. However, the relationship between PP and HF outcomes represents a complex interaction between several factors, such as the HF phenotype, original BP components, and coexistent comorbidities. Our data showed that the predictive value of low PP for mortality in HFrEF was dependent on SBP, while long-term mortality rates correlated independently with elevated baseline PP in HFpEF. PP was examined in multiple heterogeneous HF populations with various conclusions ( Table 6). Low PP in chronic symptomatic HFrEF was consistently shown to correlate with decreased long-term survival [8e14]. Nonetheless, there was a reverse pattern seen in asymptomatic HF patients, as reported by the Table 4. Adverse hospital events and short-and long-term mortality rates of all acute heart failure patients based on pulse pressure median value. a Adjusted for age, gender, body mass index, diabetes mellitus, smoking, hypertension, dyslipidemia, history of heart failure, anemia, heart failure etiology, heart rate, and estimated glomerular filtration rate. b Adjusted for age, gender, body mass index, diabetes mellitus, smoking, hypertension, dyslipidemia, history of heart failure, anemia, heart failure etiology, heart rate, estimated glomerular filtration rate, and systolic blood pressure. SOLVD (Study of Left Ventricular Dysfunction) [15] and SAVE (Survival and Ventricular Enlargement) [16] investigators. The exact explanation for these discrepant observations is not clear, although the presence of symptoms may be an indicator of an advanced state of HF with low cardiac output and hence lower PP. Few studies have looked into the association between PP and long-term outcomes in patients hospitalized for AHF and reported findings in line with the pattern seen with chronic symptomatic HFrEF [8], [9], [11], [17]. To the best of our knowledge, this is the first report to comment on admission PP and its correlation with hospital mortality. Our regression models revealed the predictive power of PP in HFrEF was not totally independent from original BP components, specifically SBP. The discrepancies between our study and others is likely due to several factors. Our patient population has a different ethnic background and has a younger mean age. Additionally, there were methodological differences that render our cohort incomparable, such as measuring PP at discharge [9], excluding in-hospital deaths [11], and using different PP cutoffs. Finally, the overall heterogeneity in HF syndromes may have also contributed to these differences. Physiologically, PP is thought to be a measure of both stroke volume and vascular stiffness. In early systole, the ejected blood from the LV travels across the arterial tree from large and elastic to narrow and muscular vessels. This is followed by a reflected wave against the LV during late systole, mandating extra force generation (referred to as augmentation pressure) [21]. In advanced HF, the LV fails to exert this extra pressure, explaining why low PP correlates with poor outcomes in ambulatory HFrEF. Notwithstanding, the rapid disturbance of hemodynamics in a decompensated state and the emergent use of vasoactive and inotropic agents may have diminished the prognostic impact of PP. Nonetheless, we speculate it may have independently predicted hospital mortality, had values lower than 50 mmHg been tested in patients with worse LV dysfunction.
We observed greater long-term mortality rates in patients with HFpEF and elevated baseline PP, in agreement with others [9]. Our subgroup analysis of HFpEF patients showed that higher PP was significantly associated with hypertension, diabetes mellitus, dyslipidemia, and chronic renal insufficiency, all of which are known to be associated with accelerated atherosclerosis and worse outcomes. Arteriosclerosis plays an important role in the pathophysiology and prognosis of HF. In one HF trial, a subgroup of patients underwent measurements of pulse wave velocity, a direct indicator of vascular stiffness, with elevated readings at baseline predicting decreased survival during prolonged follow-up [14]. Nonetheless, it is worthwhile to explore other potential confounders in future research, which may have an influence on HF circulatory hemodynamics, such as advanced age [22], heart rate [23], LV end-diastolic volume and mass [24], [25], and anti-HF medications [26].
Central BP is the actual pressure exerted against the LV and the true determinant of renal and brain perfusion [27]. Hence, its predictability for future risk of major adverse cardiac events and end-organ damage is more accurate [24], [28]. How reliable estimating central PP from peripheral arteries is debatable [29]. The elasticity of peripheral vessels is relatively reduced [30]. PP amplification is a compensatory mechanism that exaggerates the forward flow of blood through these narrower lumens and may overestimate the actual central PP [21]. However, this difference diminishes with aging, as the aorta and its great branches gradually lose elasticity [31], [32]. Several commercial devices noninvasively measure central PP, but they lack standardization, providing ineffective alternatives to invasive methods.
Our study suffers from several limitations. Our classification of HF was based on the guidelines published during the enrollment period, which did not include the newly-defined HF with mid-range EF as a discrete entity. There was no predefined standard method of BP measurement during enrollment of the study cohort. Although this may generate inaccurate conclusions, it reflects 'real-life' practice and eases the generalizability of our findings. We did not record readmission rates and actual cause of death during the follow-up period, which are considered standard primary endpoints in large-scale registries in cardiovascular medicine. Our sample size, although large and representative, was not enough to study PP in quartiles or quintiles, or within different strata of SBP ranges.

Conclusion
PP is a noninvasive and inexpensive tool that is readily available. In this study, it did not independently correlate with morbidity and mortality in the overall AHF population. However, its prognostic value in this domain seems to be a function of phenotype. Whereas its predictive value in HFrEF was dependent on SBP, elevated baseline PP independently correlated with decreased long-term survival in HFpEF.