Effect of Septal Ablation on Myocardial Relaxation and Left Atrial Pressure in Hypertrophic CardiomyopathyAn Invasive Hemodynamic Study
Paul Sorajja, MD,
Rick A. Nishimura, MD*,
Steve R. Ommen, MD,
Charanjit S. Rihal, MD,
Bernard J. Gersh, MB, ChB, DPhil,
David R. Holmes, Jr, MD
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
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Abstract
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Objectives: The objective of this study was to examine the effects of septal ablation on diastolic function with the use of invasive hemodynamics.
Background: Septal ablation is an alternative therapy for patients with obstructive hypertrophic cardiomyopathy (HCM). However, its beneficial effect on diastolic function, by relieving the systolic contraction load, may be countered by adverse effects from the infarction on left ventricular mechanics.
Methods: Using high-fidelity, micromanometer-tipped catheters, we examined 40 HCM patients by taking direct measurements of the left ventricular outflow tract (LVOT) gradient, time constant of myocardial relaxation (tau), and left atrial pressure (LAP) before and after septal ablation.
Results: Although there was an overall reduction in LVOT gradient, septal ablation resulted in variable changes in myocardial relaxation and left atrial pressure. In 20 patients (50%), LAP increased. The magnitude of LVOT gradient reduction directly correlated with the effects of septal ablation on LAP (R = 0.58; p < 0.0001). Those patients with a greater decrease in the LVOT gradient had better improvement in direct LAP. Furthermore, those patients with a larger decrease in left ventricular outflow tract gradient had a beneficial enhancement of ventricular relaxation, as measured by tau (R = 0.43; p = 0.006). Thus, the beneficial enhancement of relaxation was directly related to improvement in LAP (R = 0.75; p < 0.0001).
Conclusions: Septal ablation results in variable effects on left ventricular filling pressure, which are dependent upon the magnitude of reduction in the LVOT gradient. These effects are mediated in part by effects of ablation on myocardial relaxation. These findings shed insight into the pathophysiologic effects of septal reduction therapy in patients with HCM.
Key Words: hypertrophic cardiomyopathy • septal ablation • diastole
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Abbreviations and Acronyms
| | EDP = end-diastolic pressure | | HCM = hypertrophic cardiomyopathy | | LAP = left atrial pressure | | LV = left ventricle | | LVOT = left ventricular outflow tract | | tau = time constant of myocardial relaxation |
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Diastolic dysfunction is a prominent, complex phenomenon in patients with hypertrophic cardiomyopathy (HCM) that arises from an interplay of multiple interrelated factors. Ventricular relaxation plays a major role in diastolic filling and is dependent upon myocardial nonuniformity, perturbations in sarcomere inactivation, and altered loading conditions (1–4). Each of these components can be exacerbated by obstruction of the left ventricular outflow tract (LVOT), which leads to symptoms of heart failure and, in some studies, impaired survival (1–5). Likewise, as a therapeutic target, alleviation of LVOT obstruction could alter diastolic function in patients with HCM. However, few studies have directly examined the effect of septal reduction on myocardial relaxation and overall diastolic function of the left ventricle (6–8).
Percutaneous septal ablation is an alternative therapy that has been shown to relieve LVOT obstruction in patients with HCMs, leading to significant improvement in both symptoms and objective measures of functional capacity (9–12). Nonetheless, despite its early success, there has been concern regarding the consequences of induction of a myocardial infarction in patients with HCM (13,14). Infarction of myocardium may exacerbate diastolic dysfunction as the result of an increase in myocardial stiffness as well as enhancement of ventricular nonuniformity.
These detrimental effects may be of particular importance in patients with HCM who have hypertrophied noncompliant ventricles and are inherently predisposed to nonuniformity of both contraction and relaxation due to abnormal myofibril structure and function. Conversely, improvement in left ventricular filling pressures might occur if a large systolic contraction load is the predominant etiology for diastolic dysfunction and can be reduced by septal ablation. Accordingly, the objectives of the present study were to examine the effects of septal ablation on diastolic function in patients with HCM using invasive hemodynamics.
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Methods
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Study population.
The Institutional Review Board approved this study. All participants provided informed consent. The study population consisted of 48 patients with obstructive HCM (LVOT gradient either  40 mm Hg at rest and/or 50 mm Hg during provocation) and normal sinus rhythm who presented to the Mayo Cardiac Catheterization Laboratory for septal ablation. Patients who had undergone a previous surgical myectomy, were diagnosed with moderate or greater aortic valvular disease, had significant intrinsic mitral disease, had left ventricular ejection fraction <50%, had coronary artery stenosis >30%, or had pacemaker dependency (before or after septal ablation) were not included.
The diagnosis of HCM was based on typical clinical features with ventricular myocardial hypertrophy occurring in the absence of any other cardiac or systemic disease that could have been responsible for the hypertrophy (15,16). The magnitude of myocardial hypertrophy was assessed with M-mode and 2-dimensional transthoracic echocardiography with the use of standard techniques. Doppler echocardiography was used to ascertain the peak LVOT gradient (17). Mitral regurgitation was graded semiquantitatively with the use of Doppler echocardiography and color-flow imaging (grade I, mild; grade II, moderate; grade III, moderate-severe; grade IV, severe) (18).
Hemodynamic evaluation.
Before receiving septal ablation, each patient underwent a comprehensive hemodynamic evaluation with cardiac catheterization completed under conscious sedation in the fasting state. Transeptal puncture with placement of an 8-F Mullins sheath was performed for direct measurement of left atrial pressure (LAP) and left ventricular (LV) pressure. Simultaneous ascending aortic pressures with 6-F guide catheters were obtained via retrograde femoral access. Calibrated, high-fidelity, micromanometer-tipped catheters (Millar Instruments, Houston, Texas) were placed into the cardiac chambers. Rapid acquisition (5-ms intervals) digital records were obtained from 3 to 5 end-expiratory cardiac cycles (19).
The following LV variables were measured: minimum diastolic pressure, LV end-diastolic pressure (EDP), mean LV diastolic pressure (measured during LV diastolic filling period), LV pre-A pressure, and the rate of increase (i.e., positive) and decrease (i.e., negative) in LV pressure (dp/dt) (19). From the left atrium, the following variables were measured: mean LAP, peak A wave pressure, peak V wave pressure, and V wave height. V wave height was defined as the pressure difference between the peak V wave and the nadir of the x descent in the left atrial pressure tracing (Fig. 1) (19).
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Figure 1 Method for Pressure Recording Analysis
Left atrium (LA), left ventricle (LV), and ascending aorta (Ao) demonstrating the hemodynamic variables used for characterization of diastolic function. (a) Minimum LV pressure; (b) LV pre-A pressure; (c) end-diastolic pressure, LV end-diastolic pressure; (d) LV diastolic filling period; (e) LA peak A wave pressure; (f)
V wave height; (g) LA peak V wave pressure; (h) isovolumic relaxation period.
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The time constant of myocardial relaxation (tau) was calculated by use of a zero asymptote method as described by Weiss et al. (20). As described previously, tau is defined as the negative inverse of the slope of the natural logarithm of pressure versus time during the isovolumic relaxation period. After a period of stabilization after septal ablation (>15 min), this hemodynamic evaluation was repeated with the same methodology. Baseline cardiac medications were continued unchanged throughout the study. No intravenous or oral fluid administration was performed during the procedure apart from that required to deliver intravenous sedatives and analgesics.
Septal ablation procedure.
Septal ablation was performed in all patients with the use of previously described techniques (21,22). In brief, an oversized, over-the-wire angioplasty balloon was placed in the septal perforator artery from a left coronary guide catheter using standard methods. After balloon inflation, angiographic and echocardiographic contrast was injected through the balloon catheter to identify the perfusion bed of the septal perforator. After delineation of the targeted myocardium with contrast, 1 to 2 ml of desiccated ethanol was infused over the course of 3 min to 5 min followed by a normal saline flush. For patients with <50% reduction in either the resting or provoked LVOT gradient, other septal arteries were targeted and treated in similar fashion. As a precaution against the development of atrioventricular block, all patients underwent temporary pacemaker placement during the procedure. Hemodynamic evaluations were completed in each patient during normal sinus rhythm.
Data analysis.
To facilitate comparisons of hemodynamic variables before and after septal ablation, only patients who remained in sinus rhythm were examined. Eight patients (17%) who underwent baseline evaluation were not further analyzed because of the need for continuous pacing after septal ablation. Significant resting obstruction was defined as an LVOT gradient at rest of 40 mm Hg. Simple regression analyses were performed with Statview 4.0 (SAS Institute, Cary, North Carolina). Comparisons of continuous variables were made with a 2-sample t test when the variable distributions were normally distributed, and a Wilcoxon rank sum or Mann-Whitney U test otherwise. Paired t tests or Wilcoxon rank sum test was used for within-group comparisons; unpaired t tests or Mann-Whitney U test was used for between-group comparisons. Continuous variables are reported with one standard deviation. Statistical significance was set at p < 0.05.
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Results
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Patient population.
Mean age of the study population was 59 ± 12 years (Table 1). Eight patients had a history of atrial fibrillation but were in normal sinus rhythm during the study. The baseline LVOT gradient was either 40 mm Hg at rest (n = 27) or 50 mm Hg with provocation in all patients. Mean LAP at baseline was 17.7 ± 7.2 mm Hg, with 33 patients (83%) having LAP >10 mm Hg. The baseline LAP (R = 0.49; p = 0.001), peak V wave (R = 0.57; p = 0.0001), and V wave height (R = 0.57; p = 0.0001) all were related to the severity of the LVOT gradient. The median dose of ethanol administered was 1.8 ± 0.5 ml.
The LVOT gradient reduction and left atrial pressure.
Septal ablation significantly reduced the resting LVOT gradient (60.8 ± 41.4 mm Hg to 10.8 ± 15.7 mm Hg; p < 0.0001) (Table 2). For the 13 patients with significant LVOT gradients who presented only with provocation, ablation reduced the provoked gradient from 112 ± 45 mm Hg to 20 ± 32 mm Hg (p < 0.0001). The mean reduction in the resting LVOT gradient was –83.2 ± 21.8%, including 32 patients who had a reduction of >80%.
Although reduction in the LVOT gradient occurred in the majority of patients, the effects of septal ablation on LAP were variable with a broad range of effect (–12 mm Hg to +18 mm Hg) (Fig. 2). There was no significant change in LAP in the overall population. The LAP increased after septal ablation in 20 patients (50%). In the remaining patients, there was either no change (n = 4, or 10%) or a decrease in LAP (n = 16, or 40%). The effect of septal ablation on LAP was directly related to the magnitude of reduction in LVOT gradient (R = 0.58; p < 0.0001). The relation of LVOT gradient reduction and LAP change remained evident (R = 0.52; p = 0.006) in analyses that excluded patients who had significant resting LVOT obstruction.
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Figure 2 Effect of Septal Ablation on the LVOT Gradient
(A) Change in left ventricular outflow tract (LVOT) gradient with septal ablation, (B) change in left atrial pressure (LAP) with septal ablation, and (C) the relation between change in LVOT gradient and change in LAP with septal ablation. Septal ablation resulted in variable effects on left atrial pressure, which correlated with the extent of LVOT gradient reduction. Closed circles = patients with resting LVOT gradients of 40 mm Hg; open circles = patients with resting LVOT gradients of <40 mm Hg.
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Myocardial relaxation.
Mean tau at baseline was 59 ± 15 ms, with 38 patients (95%) having tau >35 ms. After septal ablation, there was a mild prolongation of tau to 61 ± 13 ms in the overall study population (p = 0.16 vs. baseline). Septal ablation resulted in an increase in tau in 22 patients (55%), and either no change (n = 2, or 5%) or a decrease (n = 16, or 40%) in tau in the remaining patients. Similarly, minimum left ventricular pressure increased in 20 patients (50%), and remained either unchanged (n = 2, or 5%) or decreased (n = 18, or 45%) after septal ablation in the remaining patients.
The magnitude of reduction in the LVOT gradient was directly related to the effect of septal ablation on myocardial relaxation, as gauged by change in tau (R = 0.43; p = 0.006) and change in minimum left ventricular pressure (R = 0.56; p = 0.0002) (Figs. 3 and 4). Furthermore, the effect of septal ablation on myocardial relaxation was directly related to the change in LAP (Fig. 3). The regression coefficient for change in tau versus change in LAP was R = 0.75 (p < 0.0001). Overall, both worsening of myocardial relaxation (measured by tau) and an increase in LAP occurred in 18 patients (45%).
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Figure 3 Effect of LVOT Gradient Reduction on Myocardial Relaxation and Left Atrial Pressure
The effect of septal ablation on minimum left ventricular pressure (A) and the time constant of mycardial relaxation (tau) (B) varied according to the extent of left ventricular outflow tract (LVOT) gradient reduction. Furthermore, the effects on minimum left ventricular pressure and tau were directly related to the changes in left atrial pressure from septal ablation (C and D). Closed circles = patients with resting LVOT gradients of 40 mm Hg; open circles = patients with resting LVOT gradients of <40 mm Hg.
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Figure 4 Sample Hemodynamic Tracings From 4 Patients Before and After Septal Ablation
(A) The patient was a 56-year-old woman with a marked increase in the left ventricular outflow tract gradient. After septal ablation, there were acute decreases in tau (the time constant of myocardial relaxation), minimum left ventricular pressure, and left atrial pressure. (B) Similarly, in this 62-year-old man with a left ventricular outflow tract gradient of 113 mm Hg, septal ablation resulted improvement in myocardial relaxation and left atrial pressure. (C and D) Two patients (a 71-year-old man and a 67-year-old man, respectively) who had relatively lower left ventricular outflow tract gradients. Septal ablation resulted in acute prolongation of tau and elevation in ventricular filling pressures in both of these patients. LAP = left arterial pressure; LV-MIN = minimum left ventricular diastolic pressure; other abbreviations as in Figure 1.
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Predictors of Change in LAP With Septal Ablation.
Baseline LVOT gradient, myocardial relaxation indices (tau and minimum left ventricular pressure), and ventricular filling pressures (LAP, mean diastolic pressure, LV pre-A pressure, EDP) were related to change in LAP (Table 3). The greater the LVOT gradient at rest, the greater the ventricular filling pressure, and a greater change in LAP. In addition, for patients whose baseline LAP was 20 mm Hg, the LVOT gradient decreased –69 ± 38 mm Hg and LAP change was –3.3 ± 4.8 mm Hg.
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Table 3 Regression Coefficients for the Relation Between Baseline Variables and the Dependent Variable of Change in Left Atrial Pressure After Ablation
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Conversely, for patients whose baseline LAP was <20 mm Hg, the LVOT gradient decreased –35 ± 31 mm Hg (p = 0.004 vs. baseline LAP 20 mm Hg) and LAP change was +3.5 ± 4.9 mm Hg (p < 0.0001 vs. baseline LAP 20 mm Hg). The change in LAP was not related to the pre-procedural severity of mitral regurgitation (p = 0.45 for LAP change, grade I/II vs. grade III/IV). Patients with high LVOT gradients had a decrease in LAP irrespective of the severity of mitral regurgitation (Fig. 5). Variables of myocardial hypertrophy, ventricular cavity size, and LA size were not predictive of the change in LAP after septal ablation.
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Figure 5 Change in Left Atrial Pressure and Myocardial Relaxation According to the Severity of LVOT Gradient and Baseline MR
Only 2 patients had LVOT gradient <50 mm Hg and grade III or IV mitral regurgitation. However, as shown in (A), septal ablation led to decreases in left atrial pressure in patients with gradient 50 mm Hg independently of the severity of MR, whereas those patients with LVOT gradient <50 mm Hg more commonly had increases in left atrial pressure. *p = 0.002 and **p = 0.03 for comparison versus LVOT gradient <50 mm Hg and grade I or II mitral regurgitation. Furthermore, as shown in (B), improvement in tau (the time constant of myocardial relaxation) was observed in patients with gradients 50 mm Hg independently of the severity of MR. However, prolongation of tau more frequently occurred in those patients with gradients <50 mm Hg. *p = 0.006 and **p = 0.03 for comparisons versus LVOT gradient <50 mm Hg and grade I or II mitral regurgitation. All other comparisons were not statistically significant. LVOT = left ventricular outflow tract; MR = myocardial relaxation.
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Discussion
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The principal findings of this study are as follows: 1) The effects of septal ablation on LAP are variable; 2) these effects on LAP are directly related to the magnitude of LVOT gradient reduction; 3) changes in LAP from septal ablation are mediated, at least in part, by the effects of ablation on myocardial relaxation; and 4) improvement in LAP from septal ablation may occur independently of the baseline severity of mitral regurgitation.
Diastolic dysfunction is a complex phenomenon that has been described in a variety of cardiac disease states, but its presence in HCM is associated with a complex interplay of multiple interrelated events that are unique to these patients. These processes include abnormal myocardial stiffness due to myocardial hypertrophy and interstitial fibrosis, myocardial ischemia from microvascular disease and abnormal coronary flow reserve, viscoelastic forces on the myocardium, concomitant mitral regurgitation, and prolongation of ventricular relaxation. Obstruction of the LVOT may exacerbate diastolic dysfunction by increasing myocardial ischemia, creating severe secondary mitral regurgitation, and adversely affecting ventricular relaxation (1–4). Current therapies for septal reduction, namely, surgical myectomy and percutaneous septal ethanol ablation, are highly efficacious at relieving LVOT obstruction and related mitral regurgitation. Less clear, however, is the impact of these therapies on diastolic function. In particular, septal ablation, which is being used increasingly, relies on induction of myocardial infarction for its efficacy (9–12). By simultaneously altering ventricular load and increasing nonuniformity, septal ablation potentially affects several pathophysiologic processes that contribute to diastolic dysfunction in opposite ways (4).
In patients with HCM who undergo surgical or percutaneous septal reduction therapy, relief of the systolic contraction load (i.e., LVOT obstruction), may beneficially affect LV filling pressures. Although the effects of septal ablation on LAP were highly variable, the present investigation demonstrates that the effects on LAP are directly related to the baseline severity and extent of the reduction in the LVOT gradient. The relation between LVOT gradient reduction and LAP also remained evident in analyses that excluded patients without significant resting gradients. These data therefore demonstrate that the magnitude and relief of systolic contraction load directly impact the net effects of septal ablation on diastolic function. Successful reduction of high LVOT gradients with septal ablation results in a net lusitropic effect. Conversely, septal ablation that results in relatively small- or no-decreases in systolic contraction load either have no benefit or may acutely worsen diastolic dysfunction.
Variable effects on myocardial relaxation from septal ablation also help to explain the observed different effects on ventricular filling pressure. Approximately 50% of patients had acute worsening of myocardial relaxation and LAP. In some patients undergoing septal ablation, enhancement of ventricular nonuniformity by myocardial infarction therefore may overwhelm the beneficial effects on diastolic function afforded by relief of LVOT obstruction (23). Those patients with milder degrees of LVOT obstruction and diastolic dysfunction may be particularly sensitive to enhancement of ventricular nonuniformity by septal ablation, because an increase in LAP occurred more commonly in these patients. These observations suggest septal ablation may be relatively more advantageous in patients in whom there is severe LVOT obstruction and associated myocardial relaxation abnormalities that may be exacerbated by pathologic loading conditions. In those patients, septal ablation may have greater salutary effects on ventricular filling pressures.
In patients with HCM, increased systolic contraction load from LVOT obstruction may alter myocardial relaxation through enhancement of regional asynchrony or nonuniformity, myocardial ischemia, and effects on fiber shortening and intracellular calcium ion handling (4,23). Dynamic mitral regurgitation also frequently accompanies obstructive HCM, and may lead to elevation in ventricular filling pressures. In few previous studies, both pharmacotherapy and surgical myectomy for LVOT obstruction have been associated with improved myocardial relaxation and decreases in ventricular filling pressure (24–26).
In the present investigation, the extent of reduction in the systolic LVOT gradient correlated with changes in myocardial relaxation as assessed by tau and minimum LV pressure, which serves as a surrogate of ventricular diastolic suction. Moreover, the positive or negative changes in myocardial relaxation from septal ablation were directly related to the changes in LAP. Certainly, greater dynamic mitral regurgitation may be more common in those with relatively more severe LVOT obstruction.
However, decreases in LAP were observed in one-third of the patients with mild or moderate mitral regurgitation, and LAP change was not different according to the baseline severity of mitral regurgitation. A >80% reduction in the LVOT gradient occurred in >80% of patients, suggesting that improvement of dynamic mitral regurgitation occurred in the vast majority of patients. Furthermore, the authors of previous studies (27–29) have demonstrated that greater severity of mitral regurgitation results in enhanced ventricular relaxation (i.e., lower tau); therefore, relief of mitral regurgitation would not lead to lusitropic effects in the present study. In the study herein, the decrease in LAP correlated closely with a decrease in LV minimum diastolic pressure, supporting the contribution of changes in relaxation rather than mitral regurgitation. Thus, although relief of dynamic mitral regurgitation may lead to improvement in LAP, the high-fidelity measures of LV pressure decay in this study suggest that the effects of septal ablation on LAP are mediated, at least in part, by alterations in myocardial relaxation from relief of systolic contraction load.
Ideal therapy for diastolic dysfunction in patients with obstructive HCM would relieve the burden of the LVOT gradient without affecting ventricular nonuniformity or exacerbating other components of diastolic function. Although there was a net salutary effect on diastolic function in some patients, persistent or enhanced ventricular nonuniformity from septal ablation may have obviated further decrement in LAP. Surgical myectomy is considered the gold standard for septal reduction therapy, and theoretically may have a less adverse effect on ventricular nonuniformity than septal ablation (13).
Nonetheless, analogous to the present study, the clinical efficacy of surgical myectomy also has been found to be directly related to operative reduction in LVOT gradient and EDP (30). Furthermore, persistent ventricular non-uniformity has been proposed as a mechanism for continued impaired exercise capacity after surgical myectomy (31).
Study limitations.
The acute nature of this hemodynamic study restricted the ability to examine the long-term consequences of change in diastolic function that resulted from septal ablation. Infarct-related remodeling occurs after ablation (32). As the result of the absence of a clinical indication for repeat catheterization, further characterization of diastolic function with invasive means in subsequent follow-up was not attempted. We did not pursue chronic studies by using echocardiography because the current noninvasive methods of examining diastolic function in patients with HCM are of limited accuracy (33). In addition, we did not believe it was ethical to perform invasive cardiac catheterization on these patients in follow-up. Thus, this investigation was limited to the acute setting.
Second, because of the inherent difficulties in the echocardiographic quantification of dynamic mitral regurgitation because of obstructive HCM, such measures of mitral regurgitation were not undertaken. Third, variations in septal infarct size could contribute to the observed heterogeneity in the effects of septal ablation and quantitative measures of infarct size were not systematically performed. Finally, the present investigation examined diastolic function only in resting conditions and the effects of ablation on exercise-induced diastolic dysfunction remain unknown.
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Conclusions
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By using high-fidelity invasive measurements, we have shown a variable effect of septal ablation on diastolic function in patients with HCM. There are several competing factors that determine the final effect on LAP, including the relief of contraction load, effect on ventricular relaxation, residual degree of mitral regurgitation, as well as the primary consequence of the myocardial infarction. These findings shed insight into the pathophysiological consequences of relief of LVOT obstruction in patients with HCM.
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Footnotes
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Michael A. Kutcher, MD, FACC, served as Guest Editor for this paper.
* Reprint requests and correspondence: Dr. Rick A. Nishimura, 200 1st Street SW, Rochester, Minnesota 55906 (Email: rick.nishimura{at}mayo.edu).
Manuscript received March 27, 2008;
revised manuscript received July 8, 2008,
accepted July 11, 2008.
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Abstract
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