Unexplained Pulmonary Hypertension in Elderly Patients* Brian P. Shapiro, MD; Michael D. McGoon, MD, FCCP; and Margaret M.

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1 CHEST Unexplained Pulmonary Hypertension in Elderly Patients* Brian P. Shapiro, MD; Michael D. McGoon, MD, FCCP; and Margaret M. Redfield, MD Original Research PULMONARY HYPERTENSION Background: Idiopathic pulmonary arterial hypertension (IPAH) preferentially affects young women. However, a subset of patients with IPAH is elderly. Our objective was to compare elderly (age > 65 years) vs younger persons with unexplained pulmonary hypertension (PH) and a presumptive diagnosis of IPAH. Methods: Clinical, echocardiographic, hemodynamic, and survival data were collected on consecutive patients with suspected IPAH after evaluation in a large tertiary center PH clinic. Results: Of 197 patients (mean age SD, years; 80% female), 48 patients (24%) were elderly. Elderly and younger patients had similar symptom severity, systolic pulmonary artery (PA) pressure ( mm Hg vs mm Hg, respectively; p 0.21), and severity of right ventricular enlargement and dysfunction. Elderly patients had higher pulmonary capillary wedge pressure (PCWP) [ mm Hg vs mm Hg; p < ] and more frequently failed (56%) to meet hemodynamic criteria for IPAH (PH with PCWP < 15 mm Hg) than did younger patients (19%). Elderly patients also had higher systemic systolic (p < ) and pulse (p < ) pressures and more cardiovascular disease. Among those patients with normal PCWP, elderly patients had worse survival than young patients (p 0.007). Among those patients with elevated PCWP, elderly patients had lower PA pressures (p 0.04) and better survival (p 0.02). Conclusions: Elderly patients with clinically suspected IPAH often fail to meet hemodynamic criteria for IPAH due to elevated PCWP. Studies to define the proper diagnostic strategy and the safety and efficacy of pulmonary vasodilators in elderly patients with unexplained PH are needed. (CHEST 2007; 131:94 100) Key words: diastolic heart failure; idiopathic pulmonary arterial hypertension; pulmonary capillary wedge pressure; ventricular interdependence Abbreviations: A mitral inflow late diastolic filling velocity; CI cardiac index; E mitral inflow early diastolic filling velocity; EF ejection fraction; HF heart failure; IPAH idiopathic pulmonary arterial hypertension; LV left ventricular; NYHA New York Heart Association; PA pulmonary artery; PCWP pulmonary capillary wedge pressure; PH pulmonary hypertension; RA right atrial; RV right ventricular Idioipathic pulmonary arterial hypertension (IPAH) is a diagnosis of exclusion and preferentially affects young and middle-aged women. Despite their advanced age, symptomatic elderly patients who undergo echocardiography and are found to have significant pulmonary hypertension (PH), a normal ejection fraction (EF), and no left-sided valve disease may still be given a preliminary diagnosis of *From the Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN. Grant support was provided by the Miami Heart Research Institute. IPAH prior to right-heart catheterization if no other cause of PH is apparent. The objective of this study was to compare the clinical, hemodynamic, echocardiographic, and prognostic characteristics of elderly The authors have no conflicts of interest to disclose. Manuscript received June 23, 2006; revision accepted September 4, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Margaret M. Redfield, MD, 200 First St SW, Rochester, MN 55905; Redfield.Margaret@mayo.edu DOI: /chest Original Research

2 vs younger persons with significant and unexplained PH after careful clinical evaluation at a PH clinic. Study Patients Materials and Methods This study was approved by the Mayo Institutional Review Board. Using the Mayo PH Clinic database, consecutive patients given a presumptive diagnosis of IPAH after clinical evaluation and undergoing right-heart catheterization between July 1987 to For editorial comment see page 5 November 2003 were identified retrospectively (n 197). All patients had undergone echocardiography and an extensive evaluation to rule out PH associated with recognized causes. While evaluation was otherwise consistent with the revised PH classification system, 1 patients with HIV or drug-induced PH were not included. 2,3 Patients with an EF 50%, significant mitral or aortic valve disease, or congenital heart disease were excluded. Data were obtained from review of the patient record. Medications initially prescribed specifically for the treatment of PH were recorded. Functional assessment was ascertained from the 6-min walk distance and clinician s assessment of New York Heart Association (NYHA) class. Survival status as of September 2004 was determined through the Mayo Clinic registration database and a decision support tool (Accurint; LexisNexis; Philadelphia, PA) as previously described. 4 Right-Heart Catheterization Right-heart catheterization was performed by a flow-directed pulmonary artery (PA) catheter using hemodynamic and fluoroscopic guidance with oxygen saturation measurements in the wedged position. Measurements were obtained at end-expiration and averaged over three to five beats. Systemic pulse pressure (systolic diastolic BP), pulmonary arteriolar (vascular) resistance ([mean PA pressure mean pulmonary capillary wedge pressure (PCWP)] cardiac index [CI]), and systemic vascular resistance ([mean arterial pressure mean right atrial (RA) pressure] CI) [indexed] were calculated and expressed in Wood units meters squared. The transpulmonary pressure gradient (mean PA pressure mean PCWP) was calculated. Echocardiography Assessment of left ventricular (LV) diastolic dimension, EF, and LV mass were performed as previously described. 5,6 The mitral inflow early diastolic filling velocity (E) and mitral inflow late diastolic filling velocity (A) and their ratio (E/A) were obtained from pulsed Doppler recordings. Continuous-wave Doppler imaging was used for measurement of the tricuspid regurgitant velocity, and PA systolic pressure was estimated as previously described. 2 Right ventricular (RV) enlargement and dysfunction were graded semiquantitatively as mild, moderate, moderate-to-severe, severe, or as unspecified RV enlargement or dysfunction. Statistical Analysis Continuous variables were described as mean SD. Group comparisons were made using the Student t test. Categorical variables were evaluated by a 2 analysis. Linear regression was used to examine the association of continuous variables. Kaplan- Meier survival curves were constructed and compared using the log-rank test. A p value 0.05 was considered statistically significant. To evaluate potential interactions between age, hemodynamic profile, and outcome, Cox proportional hazards modeling was used with age group, hemodynamic profile, and an age hemodynamic profile interaction term in the model. Results Characteristics of Elderly vs Young Patients With Unexplained PH There were 197 consecutive patients with a presumptive diagnosis of IPAH prior to right-heart catheterization. The mean age was years (80% female), and 48 patients (24%) were 65 years old. The percentage of elderly patients was greater (27%) in the last half (from 1996 to 2003) than the first half (from 1987 to 1995) of the study (11%, p 0.05). Elderly patients had a similar sex distribution (Table 1) but more cardiovascular disease. The NYHA classification was similar between groups, but elderly patients had a lower 6-min walk distance. The PCWP was higher in the elderly group (Table 1). The PA systolic and mean pressures were similar in elderly and younger patients, but diastolic PA pressure, the transpulmonary gradient, and pulmonary arteriolar resistance were lower in the elderly group. RA pressure and CI were similar between groups. Systolic BP and pulse pressure were higher in the elderly group, while systemic vascular resistance was similar between groups. The ratio of the PA systolic to systemic systolic pressure was lower in the elderly patients. The LV EF, end-diastolic diameter, and mass index were similar between groups (Table 1). There were no large or hemodynamically significant pericardial effusions in either group. The expected agerelated decrease in the E/A ratio was not apparent in the elderly patients, suggesting the presence of elevated filling pressures (pseudonormalization of the E/A ratio). 7 The degree of RV enlargement and dysfunction was similar between groups. Characteristics of Patients by Hemodynamic Criteria for IPAH Fifty-five patients (28%) had an elevated PCWP ( 15 mm Hg) and thus did not meet hemodynamic criteria for IPAH. Patient characteristics according to hemodynamic group are shown in Table 2. Patients with elevated PCWP were older. PCWP was related to age (Fig 1, left), with a rightward shift in the age distribution of patients with elevated PCWP (Fig 1, right). PCWP did not correlate with PA systolic pressure (r 0.12, p 0.08). Patients with CHEST / 131 / 1/ JANUARY,

3 Table 1 Clinical, Hemodynamic, and Echocardiographic Characteristics Based on Age* Characteristics (n 48) (n 149) p Value Clinical Age, yr Female gender 77% 81% min walk distance, m NYHA class Diabetes History of systemic hypertension Diagnosis of coronary artery disease Coronary angiography performed Ever-smoker History of atrial arrhythmia Hemodynamic PCWP, mm Hg Percentage with PCWP 15 mm Hg Systolic PA pressure, mm Hg Diastolic PA pressure, mm Hg Mean PA pressure, mm Hg Transpulmonary gradient, mm Hg CI, L/min/m Pulmonary arteriolar resistance, Wood units m RA pressure, mm Hg Systolic BP, mm Hg Pulse pressure, mm Hg Mean arterial pressure, mm Hg Systolic PA/systemic systolic pressure, % Systemic vascular resistance, Wood units m Echocardiographic Estimated systolic PA pressure, mm Hg EF, % LV end-diastolic diameter, mm LV mass index, g/m E/A ratio RV enlargement Mild-to-moderate RV enlargement Severe RV enlargement Unspecified RV enlargement RV systolic dysfunction Mild-to-moderate RV systolic dysfunction Severe RV systolic dysfunction Unspecified RV systolic dysfunction *Data are presented as mean SD or %. elevated PCWP had lower NYHA class. Systolic PA pressure was similar in the two groups, although those with elevated PCWP had a lower transpulmonary gradient and lower pulmonary arteriolar resistance but higher systemic systolic and pulse pressure and higher RA pressure. The severity of RV enlargement and dysfunction was similar. Among those with elevated PCWP, younger patients had higher PA pressure than elderly patients (mean PA pressure, mm Hg vs mm Hg, p 0.04) and lower systemic pulse pressure (57 22 mm Hg vs mm Hg, p 0.001). Analysis by CI We also examined patients with CI above and below the median level observed in the study population (CI 2.33 ml/min/m 2 vs 2.33 ml/min/m 2 ; data not shown). Age and PCWP were similar in these two groups (p 0.05 for all). However, symptoms (lower 6-min walk distance and higher NYHA class; p 0.05 for both) were more severe and survival was worse (p 0.006) in patients with a low CI, even adjusting for age, PCWP, and the age PCWP interaction term (all of which remained significant). Patients with reduced CI had higher RA pressures and more severe RV enlargement and dysfunction than the normal-ci group (p 0.05 for all). However, the relationship between age and PCWP observed in the population as a whole was observed in both the low-ci group (r 0.25, p 0.01) and the normal-ci group (r 0.38, p ). Thus, this analysis suggests 96 Original Research

4 Table 2 Clinical, Hemodynamic, and Echocardiographic Characteristics Based on PCWP* Characteristics Normal PCWP (n 142) Elevated PCWP (n 55) p Value Clinical Age, yr Age 65 yr Female gender min walk distance, m NYHA class Diabetes History of systemic hypertension Diagnosis of coronary artery disease Coronary angiography performed Ever-smoker History of atrial arrhythmia Hemodynamic PCWP, mm Hg na Systolic PA pressure, mm Hg Diastolic PA pressure, mm Hg Mean PA pressure, mm Hg Transpulmonary gradient, mm Hg CI, L/min/m Pulmonary arteriolar resistance, Wood units m RA pressure, mm Hg Systolic BP, mm Hg Pulse pressure, mm Hg Mean arterial pressure, mm Hg Systolic PA/systemic systolic pressure, % Systemic vascular resistance, Wood units m Echocardiographic Estimated systolic PA pressure, mm Hg EF, % LV end-diastolic diameter, mm LV mass index, g/m E/A ratio RV enlargement 0.29 Mild-to-moderate RV enlargement Severe RV enlargement Unspecified RV enlargement RV systolic dysfunction 0.3 Mild-to-moderate RV systolic dysfunction Severe RV systolic dysfunction Unspecified RV systolic dysfunction *Data are presented as mean SD or %. that age-related changes contribute to elevation of PCWP regardless of the CI. Management Medication use after the evaluation did not differ between elderly and younger patients nor between those with normal vs elevated PCWP (Table 3). Survival Survival data were available for all but one patient. Median follow-up in survivors was 5.0 years (range, 1.5 to 17.9 years). Survival was similar in elderly and younger patients (p 0.44) and in those with elevated or normal PCWP (p 0.42). However, when survival was compared between elderly and younger patients according to whether they met hemodynamic criteria for IPAH, a potent interaction between hemodynamic profile, age, and outcome was revealed. Among patients with normal PCWP, elderly patients had worse survival (Fig 2, left; risk ratio, 1.5; confidence limits, 1.1 to 2.0), while among patients with an elevated PCWP, elderly patients had better survival (Fig 2, right; risk ratio, 0.6; confidence limits, 0.4 to 0.9). This interaction was confirmed in the Cox proportional hazards model, in which age (p 0.002), PCWP (p 0.001), and the age PCWP interaction term (p 0.001) were all highly significant, whereas age (p 0.13) and CHEST / 131 / 1/ JANUARY,

5 Figure 1. Left: Relationship of PCWP and age. The PCWP increased with increasing age. Right: Frequency distribution of age in the normal and elevated ( 15 mm Hg) PCWP groups. The fraction of patients in each 5-year age group is shown on the Y axis and the age group on the X axis. The age distribution of patients with elevated PCWP is shifted toward the right (older). PCWP (p 0.76) were not significant when the interaction term was not part of the model. Discussion In this series of consecutive patients with clinically apparent IPAH, elderly patients were more likely to have cardiovascular disease, increased vascular and LV diastolic stiffness, and higher PCWP. Survival for elderly vs younger patients varied according to whether they met hemodynamic criteria for IPAH (PCWP 15 mm Hg). These data underscore the need for further studies to define proper diagnostic and therapeutic strategies in elderly patients with suspected IPAH. IPAH in Elderly Patients IPAH has classically been thought to be a disease of the young with an extremely poor prognosis Earlier natural history studies 9,10 for IPAH reported a mean age of 34 to 36 years. More recent clinical studies in IPAH have included older patients with a mean age reported at 42 to 45 years. In the current study, the percentage of elderly patients evaluated for possible IPAH increased over the study period. Indeed, the mean age of patients who met both clinical and hemodynamic criteria for IPAH (accumulated here between 1987 and 2003) was 48 years, 10 years older than in a series of patients from this same institution collected between 1955 and The reasons for the increase in the mean age of patients with IPAH in clinical trials and in this study are not clear. There may be a later onset variant of the disease that is now being recognized more frequently. This may be related to increased use of echocardiography in the elderly, increases in the age of the population with patients surviving other diseases such that their PH becomes manifest, or increased physician willingness to refer elderly patients for consideration of a growing number of less complicated PH therapies. The poorer survival for elderly patients meeting traditional hemodynamic criteria for IPAH was not found in previous studies 8,12 with a younger average age than observed here and is of note. We speculate that the poorer survival in the elderly may reflect the greater prevalence of cardiovascular disease in the elderly, a different natural history of a late-onset variant of the IPAH, or that older patients have a different disease, such as heart failure (HF) with secondary PH (see below). Potential Mechanism for Increased PCWP in Elderly Patients With PH In normal hearts, the external forces which influence the LV end-diastolic pressure volume relationship include the pericardium and the RV. In normal hearts, the RV has a major effect on LV diastolic pressures (ventricular interdependence). Patients Table 3 Medical Therapy* Variables (n 48) (n 149) p Value Normal PCWP (n 142) Elevated PCWP (n 55) p Value Therapy used after evaluation Epoprostenol Endothelin antagonist Calcium-channel antagonist Other treatment *Data are presented as %. 98 Original Research

6 Figure 2. Kaplan-Meier survival curves in young ( 65 years old) vs elderly ( 65 years old) patients with normal (left) or elevated (right) PCWP. with IPAH manifest severe RV hypertrophy, dilatation, and systolic and diastolic dysfunction, conditions that should enhance ventricular interdependence and lead to elevated LV diastolic pressures. Thus, the presence of normal LV diastolic pressures in severe IPAH would seem paradoxical. Insight into this paradox was provided by Little et al, 14 who demonstrated that the effect of the RV on the LV end-diastolic pressure volume relationship is attenuated in chronic RV pressure overload. Further analysis confirmed that, as suggested by Sunagawa et al, 15 the impact of the RV on LV diastolic pressures is modulated by the relative stiffness of the interventricular septum and the LV free wall. When the septal elastance (stiffness) is similar to the LV free wall elastance, as in normal hearts, the elastance of the septal component of the LV is smaller than that of the free-wall LV component owing to the smaller size of the septum. In this setting, the marked effect of RV pressures on LV diastolic pressures is apparent. However, when the septum is stiffer than the LV free wall (as occurs in isolated chronic RV pressure overload), the effect of the RV on LV diastolic pressures is attenuated. Thus, despite severe PH and severe RV enlargement and dysfunction, most patients with IPAH have normal PCWP. However, vascular, LV systolic, and LV diastolic stiffness increase in tandem with age and particularly in women. 6,16 We speculate that age-related increases in LV diastolic stiffness preferentially affect the LV free wall as the septum is relatively unloaded by the pulmonary circulation. When PH develops in elderly patients with age-dependent increases in LV free-wall stiffness, the septal stiffness increases as well. However, in the presence of preexisting increases in LV free-wall stiffness, there is no disparity between septal and LV free-wall stiffness, and ventricular interdependence is enhanced. Enhanced ventricular interdependence, along with the increase in LV free-wall stiffness itself, may result in elevated filling pressures in elderly patients who otherwise appear to have an isolated pulmonary arteriopathy. This mechanism is supported by the association of PCWP with age rather than severity of PH, by the evidence of increased vascular stiffness (increased pulse pressure) in patients with increased PCWP, and by the elevated RA pressures in the high PCWP group, suggesting ventricular interdependence. Agerelated impairment in RV diastolic function or pericardial compliance could also contribute. If this is indeed true, the potential for an isolated pulmonary arteriopathy to exist in the presence of elevated PCWP in elderly patients may need to be formally recognized, such that therapies for IPAH will not be withheld because strict hemodynamic criteria for IPAH are not fulfilled. However, another plausible explanation for the age-associated increase in PCWP could be that some of these patients had HF in the setting of a normal EF, a condition that may be due to severe diastolic HF with secondary PH related to chronic pulmonary venous hypertension. This is unlikely to have been the case in the majority of patients, as there was not a longstanding history of recognized HF responsive to diuretics as is the case when secondary PH develops in patients with HF and reduced EF, ie, systolic HF. However, diastolic HF can be difficult to recognize and to treat, and it remains possible that some of these patients did have diastolic HF, as might be suggested by the somewhat different outcome observed for elderly patients. Those persons 65 years old with elevated PCWP had the highest pulse pressure, suggesting more advanced cardiovascular stiffening. It is also conceivable that patients with severe diastolic HF and secondary PH related to chronic pulmonary venous hypertension may display near-normal PCWP as the RV fails and RV output decreases. In such patients, PCWP may only increase with exercise. Whether exercise testing can help distinguish if elderly patients with normal EF CHEST / 131 / 1/ JANUARY,

7 have IPAH or secondary PH related to chronic pulmonary venous hypertension (diastolic HF) is unclear. Based on previous studies of exercise hemodynamics in IPAH, with exercise one would expect patients with IPAH to display increases in PA systolic pressure, increased strain on the right ventricle, and increases in RA pressures with blunted but variable increases in RV stroke volume and cardiac output. However, increases in PCWP with exercise in IPAH have also been described and are perhaps related to worsening of ventricular interdependence with exercise. 18,19 Thus, the utility of exercise hemodynamics to discriminate between a primary pulmonary arteriopathy and secondary PH due to diastolic HF remains to be defined. Potential Limitations This study is subject to the limitations of retrospective studies in which data are collected during the course of routine care. Nevertheless, the evaluation of these patients was fairly consistent. This study may be susceptible to referral bias. PCWP measurements can be erroneous. However, there is nothing to suggest that such errors would be more frequent in elderly patients. While hemodynamic assessment of pulmonary vascular responsiveness was performed in many patients, these data were not reported since it was not consistently performed nor performed in a standardized manner. Conclusions regarding survival differences must be interpreted cautiously, as this study spanned a time of rapidly changing PH therapies as well as changes in the age distribution of patients referred to our PH clinic. Conclusions Elderly patients with PH represent a diagnostic and therapeutic challenge that appears to be increasingly common. Further studies are necessary to establish appropriate diagnostic criteria and to define the safety and efficacy of PH-targeted therapies in elderly patients with PH, particularly in the presence of elevated PCWP. References 1 Simonneau G, Galie N, Rubin LJ, et al. 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