Pathophysiological Characterization of Isolated Diastolic Heart Failure in Comparison to Systolic Heart Failure FREE

Congestive heart failure (HF) is a major cause of morbidity and mortality in the United States and is the leading cause of hospitalization in older patients.¹ Several epidemiologic studies have recently shown that more than 50% of older patients who present with symptoms of HF have preserved left ventricular (LV) systolic function.^1- 6 This syndrome has been presumptively termed diastolic heart failure (DHF).^2,7- 10 However, clinical criteria for HF are not specific. There are other conditions, which are particularly common in elderly patients, that cause similar signs and symptoms. This is further confounded by normal age-related changes in cardiovascular function, the absence of a practical, definitive diastolic function test, and relative lack of information regarding the pathophysiology of DHF. These issues have led to doubts regarding whether patients with DHF have "real" HF^11- 12 and may have created barriers to progress in characterization and treatment of this important disorder of older patients.^8,13- 14

To address whether DHF represents real HF and to characterize the pathophysiology of this syndrome, we compared 3 groups of subjects: older patients with symptoms of HF, a normal ejection fraction, and no other identifiable cause for their symptoms (isolated DHF); age-matched healthy controls; and age-matched typical patients with classic systolic heart failure (SHF). Detailed physiologic testing was performed in 4 domains pivotal to the pathophysiology of the classic HF syndrome: LV structure and function, exercise performance, neuroendocrine function, and quality of life.

As previously described,^15- 17 SHF was defined as HF with severely reduced systolic function (LV ejection fraction ≤35%), and isolated DHF was defined as HF with normal systolic function (LV ejection fraction ≥50%, no segmental wall motion abnormalities) and no evidence of significant coronary, valvular, infiltrative, pericardial, or pulmonary disease. The clinical diagnosis of HF was based on previously described criteria¹⁵ that included an HF clinical score of 3 or greater from NHANES I (National Health and Nutrition Examination Survey I),¹⁸ as well as those criteria used by Rich et al¹⁹ (history of acute pulmonary edema, or the occurrence of at least 2 of the following with no other identifiable cause and with improvement following diuresis: dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema, or exertional fatigue).

A total of 573 patients were identified by review of 1998 clinic visit and hospital discharge records from the Wake Forest University Medical Center, Winston-Salem, NC, to potentially fulfill inclusion/exclusion criteria. These patients were contacted for a screening visit. Thirty-nine percent refused to participate and 10% were deceased. The screening visit included, in the following order, a history and physical examination by a board-certified cardiologist, spirometry, electrocardiogram, rest echocardiogram, and bicycle exercise echocardiogram.¹⁵ If an exclusion criterion was found at any stage, the screening visit was terminated. The echocardiogram and exercise test were used only for excluding unsuspected valvular or ischemic heart disease and for confirming that the subject met prescribed ejection fraction criteria. The exercise test also served to familiarize the subjects with the testing environment and did not include expired gas analysis. None of the primary outcomes of the study (LV function, exercise function, neuroendocrine function, and quality of life) were measured at this visit. This visit resulted in additional exclusions due to conditions not apparent during the initial records review, including significant ischemic heart disease (6%); valvular heart disease (3%); other medical problems (chronic pulmonary disease, anemia, renal failure, cancer, uncontrolled hypertension, debilitating stroke or arthritis; 12% for all combined); or because they were found to not have symptoms of HF by the above criteria (9%). Key demographic variables (age, sex, race) for excluded patients were similar to those for included patients (70 [SD, 3] years; 52% women; 13% African American). The remaining 21% met all criteria and entered the study. There were 60 patients with SHF and 59 patients with isolated DHF.

Age-matched healthy controls (n = 28) were recruited from the community and were screened to exclude those who had any chronic medical illness; were receiving any chronic medication; had symptoms or abnormal physical examination results; had abnormal results on the screening exercise, echocardiogram, or spirometry test; or who were regularly exercising.

The study protocol was approved by the Wake Forest University Institutional Review Board and written informed consent was obtained from all patients. The outcome measures of exercise capacity, LV function, neuroendocrine function, and health-related quality of life were obtained during a single visit. Tests were performed in the morning and participants had not eaten food or ingested caffeine for more than 4 hours. Subjects with SHF and DHF were ambulatory outpatients who had been stable and well-compensated for at least 6 weeks. Testing was performed and results were analyzed by individuals blinded to subject groups and other clinical information.

Exercise Testing Protocol. Exercise testing was performed with patients in the upright position on an electronically braked bicycle, with expired gas analysis and venous lactate measurement under continuous electrocardiographic and blood pressure monitoring.^15- 17 Participants were encouraged to exercise to exhaustion. Peak values were averaged from the final 30 seconds of the exercise test. Ventilatory anaerobic threshold was assessed by standardized methods using ventilatory equivalents.¹⁵ A 6-minute walk test was performed as described by Guyatt et al.²⁰

Echocardiography. Echo-Doppler examinations were performed using a Sonos 5500 ultrasound imaging system with a multiple frequency transducer (Hewlett-Packard, Palo Alto, Calif).^9,21- 22 Standard 2-dimensional images were obtained in the parasternal long and short axes, and in the apical 4- and 2-chamber views. Pulsed-wave Doppler tracings of mitral valve inflow were recorded at the leaflet tips.^21- 22 Left ventricular volumes and Doppler tracings were analyzed using a digital echocardiography workstation as previously described.^9,21- 22

Neurohormones. Before exercise testing and after at least 15 minutes of quiet, supine rest, venous blood samples were drawn into prepared, chilled EDTA vacutainers, placed on ice, and then centrifuged; plasma was then separated. Aprotinin (25 µL per milliliter of plasma) was added to the plasma tested for natriuretic peptides and 100 µL of sodium metabisulfite was added to the plasma tested for catecholamines. Samples were then stored at −70°C. Commercially available radioimmunoassays (Phoenix Pharmaceuticals Inc, Mountain View, Calif) were used for both C-terminal atrial natriuretic peptide (ANP) and for brain natriuretic peptide-32 (BNP). Norepinephrine was separated and purified by alumina solid-phase extraction and analyzed by high-pressure liquid chromatography with electrochemical detection as previously described.²³

Quality of Life. The standardized Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) was administered to assess general health limitations. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), a condition-specific measure, was administered to assess the impact of HF on the patients' well-being.^24- 26

All outliers were included after verification of unadjusted data. The study was designed a priori to compare DHF with normal controls and DHF with SHF. Adjustments for sex and body surface area were made using analysis of covariance when groups were compared for outcome variables. Logarithmic transformation was used for nonnormally distributed variables that were highly skewed (eg, norepinephrine, ANP, BNP). SAS v8.0 was used for all analyses. All reported P values are 2-sided, with .05 considered significant.

The 3 groups were well matched for age (Table 1). A higher percentage of the DHF group was women compared with the control group and the SHF group; this is similar to the percentages reported in the community from the Cardiovascular Health Study² and other population-based studies.^1,3 All statistical comparisons of physiologic data (LV function, exercise function, and quality of life; Table 2, Table 3, and Table 4) were adjusted for sex, and LV volumes and mass (Table 2) also included adjustment for body surface area. However, these adjustments did not alter any of the overall results of intergroup comparisons for outcomes.

New York Heart Association (NYHA) class was similarly distributed between DHF and SHF groups (median, class II; interquartile range, I-III). The majorities of both the DHF and the SHF groups were NYHA class II at the time of testing. The DHF group had a higher prevalence of hypertension and higher systolic, diastolic, and pulse blood pressures compared with SHF and controls.

LV Function. The LV mass/volume ratio was markedly increased in the DHF group compared with the SHF group and controls (Table 2). Doppler early diastolic filling velocity was increased in the SHF group compared with the DHF group and controls. Atrial filling velocity was increased in both the DHF and SHF groups compared with controls. Early deceleration time was decreased in the SHF group and was similar in the DHF group compared with controls.

Exercise Performance. All subjects gave an exhaustive exercise effort and had a peak respiratory exchange ratio of 1.05 or greater; in 87% of subjects it was 1.10 or greater (Table 3). Peak workload, exercise time, and oxygen consumption were markedly reduced in the patients with DHF and SHF compared with healthy controls. In general, impairments were not quite as severe in the DHF group as in the SHF group.

Ventilatory anaerobic threshold and peak lactate level, both measures of submaximal exercise performance that are relatively independent of effort, were also markedly abnormal in the DHF and SHF groups compared with controls. While SHF patients appeared slightly more impaired than DHF patients, this was not statistically significant. There were similar findings for 6-minute walk distance (Table 3).

Heart rate was similar in patients with DHF and SHF at peak and at specific submaximal workloads. Peak exercise pulse pressure was increased in the DHF group compared with both the SHF group and controls.

Neuroendocrine Function. Mean (SE) norepinephrine level was similar in the DHF (306 [64] pg/mL) and SHF (287 [62] pg/mL) groups (P = .56) and in both was markedly increased compared with controls (169 [80] pg/mL) (P = .007 and .03, respectively) (Figure 1). The mean (SE) BNP level was significantly increased in both the DHF (56 [30] pg/mL) and the SHF (154 [28] pg/mL) groups compared with controls (3 [38] pg/mL) (P = .02 and .001, respectively). The mean ANP level was also significantly increased in both the DHF and the SHF groups (34 [39] and 92 [98] pg/mL, respectively) compared with controls (14 [10] pg/mL) (P = .02 and .001, respectively). Both natriuretic peptides were increased significantly more in the SHF group than in the DHF group. These data trends were not altered meaningfully after adjustment for age, sex, and/or medications. Thus, patients with DHF had substantial neuroendocrine activation.

Quality of Life. General life functioning scores, as assessed by the standardized SF-36, were not different between the DHF and SHF groups except for general health status (Table 4). For both the DHF and SHF groups, scores were lower (ie, worse quality of life) than benchmarks for a general population sample of men and women aged 65 to 74 years.²⁵ Benchmark values for the MLHFQ were obtained from the SOLVD (Studies of Left Ventricular Dysfunction) Prevention Trial,²⁴ based on 172 subjects without overt heart failure, classified as NYHA class I (mean [SD] ejection fraction, 28% [5%]). Patients with DHF and SHF both had mean scores that were substantially above the benchmark of 10 (ie, reduced quality of life). Scores on the MLHFQ were worse in patients with SHF than in those with DHF. Thus, patients with DHF had substantially reduced general and symptom-specific quality of life.

In this study, we found that despite markedly different degrees of LV systolic function, elderly patients with presumed DHF had key pathophysiologic abnormalities that were qualitatively similar to those of patients with classic SHF, including severely reduced exercise performance, substantial neuroendocrine activation, and reduced quality of life. These data support the hypothesis that isolated DHF is a form of "real" heart failure.

Data from the present study complement those from 2 other recent reports in validating DHF as a true clinical HF syndrome.^9,27 The first showed that most patients with this syndrome have ejection fractions within the normal range, even during acute exacerbations.⁹ The second showed that most patients with HF symptoms and a normal ejection fraction have abnormal diastolic function as assessed by invasive measurements.²⁷

While numerous large trials have established specific therapies for SHF, such trials are lacking for DHF. The finding of similar key pathophysiologic abnormalities in DHF compared with SHF suggests the possibility that therapies that have been successful for SHF may have a role in therapy for DHF.

Diastolic heart failure is a heterogeneous disorder. As suggested by Caruana et al¹¹ and by Banerjee et al,¹² many patients with clinically presumed DHF were found during subsequent screening examinations to have potentially confounding medical disorders or were found to not have HF. The patients with DHF included in this study had isolated DHF, as we and others have defined it,^8,15- 16 a more "pure" subset of DHF. In the population-based Cardiovascular Health Study, isolated DHF accounted for 42% of older individuals with HF and a normal LV ejection fraction.² Furthermore, demographic and other characteristics of the patients with DHF in the present study were similar to those in population-based studies.^2,5- 7 Thus, the results of the present study may well be generalizable.

For most, but not all, variables, impairments were somewhat worse for SHF than for DHF. This quantitative gradient of pathophysiological abnormality from healthy controls to DHF to SHF parallels the mortality gradient in epidemiologic studies.^7,28

Two variables that were abnormal in patients with DHF but not in those with SHF were increased LV mass/volume ratio and exercise pulse pressure. These findings, along with other recent reports,^16,30 lend support to a potential role of increased vascular stiffness in the pathogenesis of DHF.

Exercise intolerance is the primary symptom of chronic HF, regardless of etiology. The objective measurements in the present study confirm results from prior smaller studies and show that elderly patients with DHF have severely reduced peak and submaximal exercise performance.^16,31 Submaximal exercise performance is relatively independent of patient motivation and is more relevant than peak performance to activities of daily living. In this regard, impairments in ventilatory anaerobic threshold and 6-minute walk distance were similar in patients with DHF and those with SHF.

The "neurohormonal hypothesis" has become central to our understanding of the pathophysiology and therapy of classic SHF.³² The severity of neuroendocrine activation is closely related to onset of SHF,³³ symptomatic status,^34- 35 progression,³³ survival,³⁶ and response to therapy. Norepinephrine and BNP are among the most widely studied neurohormones in SHF. In the present study, both were increased in patients with DHF compared with healthy controls. Norepinephrine was increased to a similar degree in patients with DHF and in those with SHF. Level of BNP was not as severely increased in patients with DHF as in those with SHF. These relationships were unchanged after adjustment for medications as well as sex. These data indicate that neuroendocrine activation, a pivotal feature of HF pathophysiology, is present in patients with isolated DHF.

There are relatively few data available for cardiac peptides in patients with DHF, and a variety of BNP analytic techniques have been used, complicating interstudy comparisons.^37- 40 The BNP measurements in the present study were made in well-compensated, stable, ambulatory outpatients. Thus, the absolute levels of BNP would be expected to be lower than those reported from hospitalized patients with acute, decompensated congestive HF. Some patients with DHF in the present study had BNP levels near those of the controls. However, this was true for the patients with SHF as well, as could be expected in well-compensated patients, and emphasizes the importance of intrastudy controls for direct comparison. In addition, mean BNP level was increased nearly 20-fold in patients with DHF compared with controls.

Patients with DHF had severe impairments on the MLHFQ compared with standards from the SOLVD study^24- 25 for nonovert HF, and on the SF-36 compared with benchmarks for the general population. Scores for most items on the SF-36 were similar in patients with DHF and those with SHF. However, on the MLHFQ, which emphasizes physical functioning and symptoms, patients with DHF had less-severe impairments than did those with SHF.

This study has limitations. Although demographic variables were similar to those reported in epidemiologic studies, our study was not population-based and therefore the potential for selection bias cannot be excluded. Two newer techniques for assessment of diastolic function—color M-mode and tissue Doppler—were not widely available at the time of the study.

Patients with isolated DHF have similar key pathophysiologic characteristics compared with patients with typical SHF, including severely reduced exercise capacity, neuroendocrine activation, and impaired quality of life. Thus, such patients have "real" HF. Furthermore, these findings suggest that therapies that have been successful for SHF may have a role in the therapy for DHF. Future randomized clinical trials will be needed to determine how best to manage patients with this common and disabling disorder.