Systolic and Diastolic Dyssynchrony in Patients With Diastolic Heart Failure and the Effect of Medical Therapy

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1 Journal of the American College of Cardiology Vol. 49, No. 1, by the American College of Cardiology Foundation ISSN /07/$32.00 Published by Elsevier Inc. doi: /j.jacc EXPEDITED REVIEWS Systolic and Diastolic Dyssynchrony in Patients With Diastolic Heart Failure and the Effect of Medical Therapy Jianwen Wang, MD, PHD, Karla M. Kurrelmeyer, MD, Guillermo Torre-Amione, MD, PHD, Sherif F. Nagueh, MD Houston, Texas Objectives Background Methods Results Conclusions The purpose of this study was to determine the prevalence of systolic and diastolic dyssynchrony in diastolic heart failure (DHF) patients and identify the effects of medical therapy. The prevalence of systolic and diastolic dyssynchrony in DHF patients is unknown with no data on the effects of medical therapy on dyssynchrony. Patients presenting with DHF (n 60; 61 9 years old, 35 women) underwent echocardiographic imaging simultaneous with invasive measurements. An age-matched control group of 35 subjects and 60 patients with systolic heart failure (SHF) were included for comparison. Systolic and diastolic dyssynchrony were assessed by tissue Doppler and defined using mean and SD values in the control group. Systolic dyssynchrony was present in 20 patients (33%) with DHF and 24 patients (40%) with SHF and was associated in both groups with significantly worse left ventricular (LV) systolic and diastolic properties (p 0.05 vs. control group and patients without systolic dyssynchrony). Diastolic dyssynchrony was present in 35 patients (58%) with DHF and 36 patients (60%) with SHF and had significant inverse correlations with mean wedge pressure and time constant of LV relaxation. In DHF patients, medical therapy resulted in significant shortening of diastolic time delay (39 23 ms to ms; p 0.02) but no significant change in systolic interval (p 0.15). Shortening of diastolic time delay correlated well with shortening after therapy (r 0.85; p 0.001). Systolic dyssynchrony occurs in 33% of DHF patients, and diastolic dyssynchrony occurs in 58%. Medical therapy results in significant shortening of the diastolic intraventricular time delay which is closely related to improvement in LV relaxation. (J Am Coll Cardiol 2007;49:88 96) 2007 by the American College of Cardiology Foundation Systolic dyssynchrony in patients with congestive heart failure and depressed ejection fraction (EF) is associated with increased morbidity and mortality, even when it occurs in the presence of a normal QRS duration (1). Treatment of dyssynchrony by atrial synchronized biventricular pacing See page 106 leads to an improvement in left ventricular (LV) function and symptomatic status (2). The presence of mechanical dyssynchrony in patients with normal EF has not been directly examined, but there have been 2 published studies that are relevant to this topic. In the first report, the presence of dyssynchrony in patients with congestive heart failure and EF 40% was investigated. That study showed that systolic dyssynchrony is not uncommon in patients with From the Department of Cardiology and Methodist DeBakey Heart Center, The Methodist Hospital, Houston, Texas. Manuscript received June 8, 2006; revised manuscript received July 25, 2006, accepted August 14, EF 40% (3). In the second study, the presence of a prolonged QRS duration was associated with worse outcome in patients with congestive heart failure and normal EF (4). However, those 2 studies are limited in their conclusions, as they pertain to congestive heart failure patients with normal EF: one study included patients with depressed EF and the other used QRS duration as a surrogate for mechanical dyssynchrony (3,4). Therefore, the topic of systolic and diastolic dyssynchrony in patients with congestive heart failure and normal EF remains to be directly addressed, including the impact of mechanical dyssynchrony on cardiac systolic and diastolic function in this population. In addition, it is important to identify safe and effective therapeutic measures for this abnormality in patients with diastolic heart failure, given the high prevalence as well as the morbidity and mortality of this disease (5). In that regard, there are few studies that have examined the effects of medical and nonmedical treatment in patients with diastolic dysfunction and normal EF. Those studies evaluated patients with coronary artery disease (6), aortic stenosis

2 JACC Vol. 49, No. 1, 2007 January 2/9, 2007:88 96 Wang et al. Dyssynchrony in DHF 89 (7), and hypertrophic cardiomyopathy (8,9), but to our knowledge none examined patients with isolated diastolic heart failure (DHF). We hypothesized that both systolic and diastolic dyssynchrony occur in this population, possibly related to conduction system disease, myocardial pathology of hypertrophy and fibrosis, abnormal coronary flow reserve related to hypertrophy, and increased afterload. Therefore, treatment aimed at each of the above targets may improve dyssynchrony, cardiac function, and symptomatic status. In that regard, medical therapy that decreases afterload, improves myocardial blood flow, and reduces interstitial fibrosis may be effective. We therefore undertook this study to examine the prevalence of dyssynchrony in patients presenting with DHF as well as the effects of medical therapy on this abnormality. Abbreviations and Acronyms DHF diastolic heart failure EF ejection fraction ESP end-systolic pressure ESV end-systolic volume LA left atrial LV left ventricular PCWP pulmonary capillary wedge pressure SHF systolic heart failure SW stroke work TD tissue Doppler Methods Patient population. Consecutive patients with the clinical diagnosis of congestive heart failure by the Framingham criteria (10) who were already scheduled for cardiac catheterization underwent transthoracic echocardiographic imaging simultaneous with invasive measurements. All patients had an EF 50% by 2-dimensional (2D) echocardiography. Patients with atrial fibrillation (n 10; these patients were excluded from the study to avoid the confounding effect of variation in RR cycle length in computing timing intervals), more than mild valvular stenosis or regurgitation, and/or inadequate echocardiographic images (n 5) were excluded. In addition to the clinical status and EF, diastolic dysfunction and DHF were diagnosed if mean pulmonary capillary wedge pressure (PCWP) was 12 mm Hg and/or the time constant of LV relaxation ( ) was 48 ms (11). Sixty patients were enrolled in this study. There were 40 patients (66%) with hypertension, 15 (25%) with diabetes mellitus, and 8 (13%) with coronary artery disease. None of the patients had wall motion abnormalities on 2D echocardiography. In addition, we included 2 other groups for comparison: a group of 35 normal subjects, who were age and gender matched to patients with DHF, and 60 patients with systolic heart failure (SHF) with EF 50%. Subjects in the control group were referred to the echocardiographic laboratory for evaluation of a cardiac murmur and had a normal echocardiogram and no history of cardiovascular disease. All measurements of LV systolic and diastolic function were also normal. The control group was identified a priori and was not selected based on any of the measurements in the heart failure groups. Patients with SHF were age and gender matched to the DHF group and likewise had simultaneous hemodynamic and echocardiographic measurements. Echocardiographic studies. All of the examination procedures were carried out to provide a comprehensive echocardiographic examination that would enable assessment of LV systolic and diastolic function using several indices. Twodimensional images were acquired in the parasternal views. Apical views were acquired, and pulse-doppler was used to record transmitral and pulmonary venous flow in the apical 4-chamber view (12). Tissue Doppler (TD) was applied to record myocardial velocities at the septal, lateral, anterior, and inferior walls, with adjustment of depth and sector width to achieve frame rates of 100 frames/s. Echocardiographic images were stored digitally and analyzed offline. Echocardiographic analysis. The analysis was performed offline without knowledge of clinical status. LV volumes, mass, EF, and left atrium (LA) maximum volume were measured per American Society of Echocardiography recommendations (13). Stroke volume was derived as the difference between end-diastolic (EDV) and end-systolic (ESV) volumes. End-systolic pressure (ESP) was derived as: 0.9 systolic blood pressure (14). Mid-wall fractional shortening was computed (15), and its relation to end-systolic circumferential wall stress (16) was evaluated. All Doppler measurements represent the average of 3 beats. Mitral inflow was analyzed for peak E (early diastolic) velocity, peak A (late diastolic) velocity, E/A ratio, and deceleration time (DT) of E velocity. Pulmonary artery systolic pressure was calculated using the tricuspid regurgitation jet and right atrial pressure estimation using inferior vena cava diameter and respiratory collapse in addition to hepatic venous flow (12). From the pulmonary vein flow signals, the velocity, time velocity integral, and duration of peak systolic, diastolic, and atrial flows were determined. The systolic (Sa) and early diastolic (Ea) velocities at the septal and lateral areas of the mitral annulus were measured (12). For the control group, noninvasive estimates of mean wedge pressure (12) and (see the following text and reference 19) were used. Assessment of systolic and diastolic dyssynchrony. Onset (17) and peak (18) of systolic velocity and onset of early diastolic velocity (17) in the TD signal were timed using the QRS complex as the reference point. The average of 3 consecutive beats was calculated. Intraventricular systolic dyssynchrony was defined using the time difference between the shortest and longest delay between the QRS complex and onset/peak of systolic velocity among the 4 LV walls (intraobserver mean difference 3 3 ms; interobserver mean difference 6 3 ms). Likewise, intraventricular diastolic dyssynchrony was defined using the time difference between the shortest and longest delays between the QRS complex and onset of early diastolic velocity among the 4

3 90 Wang et al. JACC Vol. 49, No. 1, 2007 Dyssynchrony in DHF January 2/9, 2007:88 96 LV walls (intraobserver mean difference 4 3 ms; interobserver mean difference 5 3 ms). Right heart catheterization. Medex transducers were balanced before acquisition of hemodynamic data, with the zero level at the mid-axillary line. Pressure measurements were acquired at end-expiration and represent the average of 5 cardiac cycles. The position of the PA catheter was verified by fluoroscopy, and pulmonary capillary wedge pressure (PCWP) was determined using changes in pressure waveform and, when needed, O 2 saturation. Cardiac output was derived by thermodilution, where 3 cardiac cycles with 10% variation were averaged. The time constant of LV relaxation ( ) was computed using the previously validated equation IVRT/(Ln ESP Ln PCWP) (19), where IVRT is isovolumetric relaxation time as measured by Doppler, and PCWP was obtained by invasive measurements. In addition, was calculated using the noninvasive estimation of mean PCWP (12) at baseline and follow-up. Assessment of LV systolic properties. The LV systolic properties were examined as reported in a recent study (20). The LV systolic performance was assessed using stroke work (SW), calculated as the product of stroke volume and mean arterial pressure. The LV systolic function was examined using EF and the relationship between SW and LV end-diastolic volume. The ratio of ESP to ESV was used an index of LV contractility (21). The relation between midwall fractional shortening and circumferential wall stress was used to gain insight into myocardial contractility. Statistics. Demographic and echocardiographic variables were compared between the control group and patients with SHF and DHF using analysis of variance with the Holm- Sidak method for pairwise comparisons. This methodology was used to compare the 3 groups of SHF and DHF (see subsequent). Changes in hemodynamic and echocardiographic measurements with medical therapy were compared with paired t tests. Linear regression analysis was used to relate hemodynamic and echocardiographic measurements to Doppler indices of dyssynchrony. A p value of 0.05 was considered significant. Results Patients with SHF and DHF were similar to the control group with respect to age and gender distribution. However, DHF and SHF patients had significantly higher LV mass, LA volume index, E/Ea ratio, and PA systolic pressure as well as a longer Ar duration in pulmonary venous flow and a shorter DT (Table 1). For time delay measurements by TD, significantly longer systolic and diastolic intraventricular delays were noted in patients with SHF and DHF. Cardiac function in DHF patients with and without dyssynchrony. In the DHF group, there were 20 patients (33%) with systolic dyssynchrony (time delay 35 ms, which exceeds the mean 2 SD in the control group). The same patients were identified whether the time to onset or the time to peak systolic velocity was used. Of the 20 patients with systolic dyssynchrony, 15 had a systolic intraventricular time delay of 60 ms. The QRS duration was significantly longer in these 20 patients than in the remaining 40 ( vs ; p 0.05) but with a wide overlap between the 2 groups. A weak correlation was present between the QRS duration and the systolic time delay (r 0.33; p 0.04). The septum was the most delayed region in 2 patients, the inferior wall in 3, the anterior wall in 4, and the lateral wall in 11 (55%). Several significant differences in LV systolic and diastolic parameters were observed in DHF patients with systolic dyssynchrony. These patients had significantly lower SW (Fig. 1), EF, ESP/ESV ratio, SW/EDV ratio, mid-wall fractional shortening (Fig. 2), and Sa velocity. Mean PCWP was significantly higher, and was significantly longer (Table 2). Clinical and Echocardiographic Summary of the 3 Groups: Control, SHF, and DHF Table 1 Clinical and Echocardiographic Summary of the 3 Groups: Control, SHF, and DHF Control (n 35) SHF (n 60) DHF (n 60) Age (yrs) Gender (M/F) 14/21 24/36 25/35 Heart rate Blood pressure (mm Hg) /68 8* 90 13/ /86 19 EF (%) LV EDV (ml) LV mass (gm/m 2 ) 81 21* LA volume (ml/m 2 ) 18 6* Deceleration, time (ms) * Pulmonary veins (Ar-A) (ms) 1 10* E/Ea ratio (average) 5 3* PA systolic pressure (mm Hg) 23 3* Systolic intraventricular delay (ms) 12 10* Diastolic intraventricular delay (ms) 10 9* *p 0.05 versus DHF and SHF groups; p 0.05 versus control and DHF group; p 0.05 versus DHF group. Ar-A difference in duration between Ar velocity in pulmonary venous flow and A velocity in mitral inflow; DHF diastolic heart failure; EDV end-diastolic volume; EF ejection fraction; LA left atrial; LV left ventricular; PA pulmonary artery; SHF systolic heart failure.

4 JACC Vol. 49, No. 1, 2007 January 2/9, 2007:88 96 Wang et al. Dyssynchrony in DHF 91 Figure 1 Relationship Between Left Ventricular EDV and Stroke Work The relationship in the control group is shown by the solid line and solid circles (r ; p 0.001). The relationship in patients with diastolic heart failure (DHF) and systolic dyssynchrony (r ; p 0.001) is shown by the dotted line and open circles. The relationship in patients with DHF but without systolic dyssynchrony (r 2 0.9; p 0.001) is shown by the dashed line and solid squares. The DHF patients without systolic dyssynchrony and the control group had similar linear relationships. This relationship was shifted downward in patients with DHF and systolic dyssynchrony. EDV end-diastolic volume. There were 35 patients (58%) with diastolic dyssynchrony (time delay 35 ms). The 20 patients with systolic dyssynchrony had evidence of diastolic dyssynchrony. In addition, there were 15 patients with isolated diastolic dyssynchrony. A weak correlation was present between the QRS duration and diastolic time delay (r 0.3; p 0.05). The septum was the most delayed region in 3 patients, the inferior wall in 6, the anterior wall in 8, and the lateral wall in 18 (51%). In general, hemodynamic and echocardiographic indices of LV systolic properties were similar between patients with DHF and no dyssynchrony and those with isolated diastolic dyssynchrony. Figure 3 shows the correlation between the diastolic time delay and mean PCWP and. A strongly significant correlation is present between diastolic dyssynchrony and each of these 2 measurements. In addition, several significant correlations were noted between the diastolic time delay and LV mass (Fig. 4) as well as Doppler and 2D measurements of LV diastolic function, including DT (r 0.63; p 0.01), Ar A duration (r 0.61; p 0.01), LA volume (r 0.59; p 0.01), LV mass/edv ratio (r 0.85; p 0.01), and E/Ea ratio (r 0.71; p 0.01). Cardiac function in SHF patients with and without dyssynchrony. In the SHF group, there were 24 patients (40%) with systolic dyssynchrony (definition based on the control group as in preceding), with 18 patients having an intraventricular time delay of 60 ms. A weak correlation was present between the QRS duration and the systolic time delay (r 0.34; p 0.035). The septum was the most delayed region in 3 patients, the inferior wall in 5, the anterior wall in 5, and the lateral wall in 11 (46%). As expected, patients with SHF had abnormal LV systolic and diastolic function (Table 3), with the worst function observed in the 24 patients with systolic dyssynchrony. There were 36 patients (60%) with diastolic dyssynchrony (definition as in preceding), with 12 patients having isolated diastolic dyssynchrony. A weak correlation was present between the QRS duration and the diastolic time delay (r 0.36; p 0.03). The septum was the most delayed region in 5 patients, the inferior wall in 8, the anterior wall in 7, and the lateral wall in 16 (44%). Overall, LV diastolic function was worse in the patients with diastolic dyssynchrony compared with those without (Table 3). The diastolic intraventricular time delay was significantly related to LV mass (r 0.59; p 0.01), EDV (r 0.6; p 0.01), and mass/volume ratio (r 0.63; p 0.01). Effect of medical therapy for DHF on LV function and systolic and diastolic dyssynchrony. Patients were treated for DHF with intravenous diuretics (n 60), beta-blockers (n 15), calcium-channel blockers (verapamil or diltiazem; n 20), angiotensin-converting enzyme inhibitors (n 25), and/or angiotensin-receptor blockers (n 10). Repeat imaging was performed 3 to 15 days after the initial studies. Table 4 shows a summary of the changes with therapy. Systemic blood pressure decreased significantly, whereas no significant change was noted in EF, LV mass, and LA volume index in the overall group. Doppler measurements indicated a decrease in LV filling pressures and an improvement in LV relaxation. A nonsignificant decrease in the systolic intraventricular time delay was noted (31 25 ms to ms; p 0.15). On the other hand, the diastolic intraventricular time delay became significantly shorter (39 23 ms to ms; p 0.02). Figure 2 Relationship Between Mid-Wall Fractional Shortening and Circumferential Wall Stress Patients with diastolic heart failure (DHF) and systolic dyssynchrony are shown by open circles, whereas patients with DHF but without dyssynchrony are shown by solid circles. The data points for patients with DHF and systolic dyssnchrony were outside the lower 95% prediction interval for the control group.

5 92 Wang et al. JACC Vol. 49, No. 1, 2007 Dyssynchrony in DHF January 2/9, 2007:88 96 Hemodynamic Stratified According and Echocardiographic to Presence or Absence Measurements of Systolic in DHF and Diastolic Patients Dyssynchrony Table 2 Hemodynamic and Echocardiographic Measurements in DHF Patients Stratified According to Presence or Absence of Systolic and Diastolic Dyssynchrony Control (n 35) DHF With Systolic Dyssynchrony (n 20) DHF With Isolated Diastolic Dyssynchrony (n 15) DHF Without Dyssynchrony (n 25) Stroke work (kg cm) Ejection fraction (%) Stroke work/edv (g/cm 2 ) ESP/ESV (mm Hg/ml) Mid-wall fractional shortening (%) Sa (cm/s) Mean PCWP (mm Hg) 8 2* (ms) 31 4* PA systolic pressure (mm Hg) 23 3* Deceleration time (ms) Ar-A duration (ms) 1 10* E/Ea 5 3* LA volume (ml/m 2 ) 18 6* *p 0.05 versus systolic dyssynchrony, isolated diastolic dyssynchrony, and DHF patients without dyssynchrony; p 0.05 versus isolated diastolic dyssynchrony and DHF patients without dyssynchrony; p 0.05 versus DHF patients without dyssynchrony; p 0.05 versus control group, isolated diastolic dyssynchrony and DHF patients without dyssynchrony. ESP end-systolic pressure; ESV end-systolic volume; PCWP pulmonary capillary wedge pressure; Sa systolic mitral annular velocity; other abbreviations as in Table 1. Relation of the change in LV diastolic dyssynchrony to LV relaxation and filling. A significant positive correlation was noted between the decrease in LV ESP and the shortening in diastolic time delay (r 0.71; p 0.01). In turn, the change in diastolic time delay correlated significantly with the shortening in (r 0.85; p 0.001) (Fig. 5), the increase in Ea velocity (r 0.75; p 0.01), and the decrease in E/Ea ratio (r 0.8; p 0.01). On multiple regression analysis, the decrease in ESP and the shortening of the diastolic time delay were the main determinants of the improvement in (R ; p 0.01). Discussion The present study shows that systolic dyssynchrony is not uncommon in patients with DHF, occurring in 33% of the patients. These patients were characterized by abnormal LV systolic properties and had invasive and echocardiographic indices indicative of the most advanced stage of diastolic dysfunction. At 58%, diastolic dyssynchrony appears to have a higher prevalence in this population. Importantly, medical therapy results in a significant shortening of the diastolic intraventricular time delay, which is closely related to Figure 3 Relation Between LV Diastolic Intraventricular Time Delay and LV Relaxation and Mean PCWP Relationship between maximum diastolic time delay and relaxation time constant (left) and mean wedge pressure (right) in patients with diastolic heart failure. LV left ventricular; PCWP pulmonary capillary wedge pressure.

6 JACC Vol. 49, No. 1, 2007 January 2/9, 2007:88 96 Wang et al. Dyssynchrony in DHF 93 Figure 4 Relationship Between LV Mass Index and LV Diastolic Intraventricular Time Delay Relationship between maximum diastolic time delay and left ventricular (LV) mass index in patients with diastolic heart failure. improvement in LV relaxation. Interestingly, patients with SHF had a rather similar prevalence of systolic and diastolic dyssynchrony: 40% and 60%, respectively. Systolic dyssynchrony in patients with DHF. Patients with DHF enrolled in this study had clinical, hemodynamic, and echocardiographic findings typical of this disease (5). Therefore, we believe that we enrolled a well representative sample of this patient population. In this study, patients with systolic dyssynchrony had consistent abnormalities in LV systolic properties which were not observed in those without dyssynchrony. Specifically, LV systolic performance was reduced, as inferred from the reduced SW (Table 2). Likewise, LV systolic function was depressed, as inferred from the EF and the reduced slope of the relationship Hemodynamic According to Presence and Echocardiographic or Absence of Systolic Measurements and Diastolic in SHFDyssynchrony Patients Stratified Table 3 Hemodynamic and Echocardiographic Measurements in SHF Patients Stratified According to Presence or Absence of Systolic and Diastolic Dyssynchrony Control (n 35) between SW and EDV (Fig. 1). Finally, myocardial contractility (Fig. 2) was abnormal. Interestingly, unlike the good demarcation of the 2 groups achieved by TD, there was a wide overlap when the QRS duration was considered. The weak correlation between the QRS duration and intraventricular systolic delay parallels our observations in the group with SHF as well as other previous studies (17). Previous studies have reported that some patients with DHF have depressed systolic function, whereas other investigators did not reach similar conclusions using a more comprehensive analysis (20). However, studies (16,20,22) that examined mid-wall stress-shortening relationships have noted that a number of patients with DHF have systolic dysfunction. Interestingly, we noted in the present study that 33% of the patients with DHF have systolic dyssynchrony and evidence of depressed LV systolic properties. In addition, this subgroup of patients had worse diastolic function as inferred from hemodynamic and Doppler measurements (Table 2). Given the multiple relations at the myocardial and ventricular levels between LV systolic and diastolic function, their worse diastolic function is to be expected. Patients with SHF and systolic dyssynchrony have been shown to improve their cardiac function by biventricular pacing, as assessed by invasive and noninvasive measurements (2). We believe that the present study, which presents a comprehensive analysis of LV systolic and diastolic function, provides important insights into the prevalence and sequelae of systolic dyssynchrony in patients with DHF. This information is essential when considering the potential role of biventricular pacing in DHF patients. Diastolic dyssynchrony in DHF patients. Diastolic dyssynchrony was highly prevalent in this sample (58%) and was present without systolic dyssynchrony in 25% of the patients. Again, the duration of the diastolic time delay was SHF With Systolic Dyssynchrony (n 24) SHF With Isolated Diastolic Dyssynchrony (n 12) SHF Without Dyssynchrony (n 24) Stroke work (kg cm) * Ejection fraction (%) 64 6* Stroke work/edv (g/cm 2 ) 76 8* ESP/ESV (mm Hg/ml) * Mid-wall fractional shortening (%) 20 3* Sa (cm/s) 13 4* Mean PCWP (mm Hg) 8 2* (ms) 31 4* PA systolic pressure (mm Hg) 23 3* Deceleration time (ms) * Ar-A duration (ms) 1 10* E/Ea 5 3* LA volume (ml/m 2 ) 18 6* *p 0.05 versus SHF with systolic dyssynchrony, isolated diastolic dyssynchrony and SHF patients without dyssynchrony; p 0.05 versus isolated diastolic dyssynchrony and SHF patients without dyssynchrony; p 0.05 versus SHF patients without dyssynchrony. Abbreviations as in Tables 1 and 2.

7 94 Wang et al. JACC Vol. 49, No. 1, 2007 Dyssynchrony in DHF January 2/9, 2007:88 96 Changes With Medical Therapy for DHF Table 4 Changes With Medical Therapy for DHF Baseline After Medical Therapy Heart rate Systolic/diastolic blood pressure (mm Hg) / /68 16* EF (%) Deceleration time (ms) * Pulmonary veins (Ar-A) (ms) * E/Ea ratio (average of septal and lateral) * PA systolic pressure (mm Hg) * (ms) * Ea (average of septal and lateral) (cm/s) * *p 0.05 versus baseline; was derived using IVRT by Doppler, and noninvasive estimation of ESP and mean PCWP. Abbreviations as in Table 1. similar to that observed in patients with SHF enrolled in this study and previously reported by other investigators (17). There are a number of pathophysiologic mechanisms that can account for diastolic dyssynchrony in patients with DHF. They include systolic dyssynchrony, because segments with delayed contraction also show delayed expansion. Coronary artery disease is another potential reason. In 1 report, coronary artery disease was associated with diastolic dyssynchrony, which improved after mechanical revascularization (6). However, epicardial coronary artery disease was present in only 4 of the 35 patients with diastolic dyssynchrony in the present study. Therefore, other mechanisms likely play a role in the etiology of diastolic dyssynchrony in this population. The strong association between TD diastolic time delay and LV mass (and mass/volume ratio) raises the possibility that LV hypertrophy and interstitial fibrosis may be causative factors. This hypothesis, however, remains to be tested. Finally, increased afterload appears to play an important role. Previous animal studies showed that an acute Figure 5 Relation Between the Change in LV Disatolic Dyssynchrony Index and LV Relaxation With Medical Therapy Relationship between the percentage change in diastolic time delay and the corresponding percentage change in relaxation time constant after medical therapy for diastolic heart failure. LV left ventricular. increase in LV afterload leads to increased dyssynchrony which was linearly correlated with (23). In the present study, a significant correlation was present between the decrease in LV ESP and the shortening in diastolic time delay after medical therapy for congestive heart failure, raising the possibility that increased afterload may have a detrimental effect on LV relaxation, in part through increased diastolic dyssynchrony. Treatment of diastolic dyssynchrony in DHF. There are limited data on the treatment of diastolic dyssynchrony in patients with normal EF (6 9). For patients with SHF, biventricular pacing, which reduces the extent of systolic dyssynchrony, can result in an improvement in LV filling. However, the favorable effect of biventricular pacing on LV diastolic function and dyssynchrony has been observed in some but not all patients (17,24), highlighting the contribution of factors other than systolic dyssynchrony to the diastolic abnormality noted in these subjects. The effects of biventricular pacing on diastolic dyssynchrony in patients with DHF is speculative at this time. However, it may be beneficial, similar to the observations in those with depressed EF, to some but not all patients, given the multiple etiologies of diastolic dyssynchrony in patients with DHF. The correlation between diastolic dyssynchrony and LV mass raises the possibility that regression of LV hypertrophy and interstitial fibrosis, which is feasible with a number of drugs (25 29), may be of value as well. We could not address this possible etiology owing to the short follow-up of the present group. On the other hand, it is reasonable to conclude that reduction of systemic blood pressure, in and of itself, can reduce diastolic dyssynchrony, particularly in patients where the QRS duration is not prolonged. Increased afterload may contribute to dyssynchrony through its effects on myocardial blood flow. Increased systolic wall stress increases myocardial oxygen demand, which in the presence of abnormal endothelial function and coronary vasculature leads to regional heterogeneity in coronary blood flow and regional function. This mechanism is supported by previous studies using positron emission tomography which reported on the presence of abnormal regional myocardial blood flow in

8 JACC Vol. 49, No. 1, 2007 January 2/9, 2007:88 96 Wang et al. Dyssynchrony in DHF 95 patients with hypertension that was only partly determined by the degree of LV hypertrophy (30). Therefore, antihypertensive therapy can have a favorable effect on diastolic dyssynchrony that is independent of the regression of LV hypertrophy. Study limitations. We examined relatively few patients with DHF. This was due to the study design, which aimed at the inclusion of cases with hemodynamic measurements. Therefore, our observations need to be examined in a larger population of DHF patients to arrive at a more accurate representation of the prevalence of this abnormality. There are other methods that have been used to identify systolic dyssynchrony (2). Some are based on a 6- or a 12-segment model. In the present study, we did not examine these methods and therefore can not address their application in DHF patients. Strain measurements were not included for the assessment of regional function. We believe that our conclusions are unlikely to have changed with deformation measurements for the following reasons. First, in the group with DHF and systolic dyssynchrony, evidence of depressed systolic properties was unambiguously and consistently observed using several indices of pump performance, systolic function, and myocardial function. Second, strain and strain rate are dependent on preload and afterload and therefore are not the gold standard to address the issue of intrinsic myocardial contractility. Finally, the effects of tethering and translation on myocardial velocities are not germane to this study, because they primarily influence the accuracy of peak velocity measurement and not the time to onset of myocardial systolic or diastolic motion. There are a number of limitations in examining the effects of medical therapy in patients with DHF, including the fact that drugs were not controlled and different therapeutic regimens were used. 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