Bradycardia and the Role of β-Blockade in the Amelioration of Left Ventricular Dysfunction
Background—It is clear that β-blockers are effective for treatment of congestive heart failure, but their mechanism of action remains controversial. Hypothesized mechanisms include normalization of β-receptor function and myocardial protection from the effects of catecholamines, possibly by the institution of bradycardia. We hypothesized that β-blockade–induced bradycardia was an important mechanism by which these agents were effective for correction of LV dysfunction.
Methods and Results—In 2 groups of dogs with mitral regurgitation and LV dysfunction, β-blockers were instituted. In 1 group that received β-blockers and pacing (group β+P), a pacemaker prevented the natural bradycardia that β-blockers cause. In both groups, substantial LV dysfunction developed. Before β-blockade, the end-systolic stiffness constant decreased from 3.5±0.1 to 2.7±0.2 (P<0.01) at 3 months in group β+P. A similar reduction occurred in the group that eventually received only β-blockers (group βB). In group βB, end-systolic stiffness improved after 3 months of β-blockade from 2.9±0.2 to 3.5±0.4 and was not different from baseline. However, in group β+P, end-systolic stiffness failed to improve (2.7±0.2) after 3 months of mitral regurgitation, and was 2.9±0.2 at the end of the studies. The contractile function of cardiocytes isolated from the ventricles at the end of the studies confirmed these in vivo estimates of contractility.
Conclusions—We conclude that institution of bradycardia is a major mechanism by which β-blockers are effective for restoration of contractile function in a model of LV dysfunction.
Although β-adrenergic receptor blockade was once considered contraindicated in patients with congestive heart failure, it is now clear that this therapy may provide substantial benefit to many heart failure patients.1 2 After 3 to 6 months of β-blockade therapy, ejection fraction (EF) increases and prognosis improves.3 4 Although elevated catecholamines are acutely beneficial for restoration of cardiac compensation in heart failure, long-term activation of the adrenergic nervous system appears deleterious. Mechanisms by which persistently elevated catecholamines are thought to cause left ventricular (LV) dysfunction include β-receptor downregulation and dysfunction or direct myocardial damage caused by catecholamines.5 Conversely, β-blockade could confer benefits by restoring β-receptor function6 or protecting myocardium from the deleterious effects of catecholamines. Regarding the latter mechanism, high levels of circulating catecholamines found in pheochromocytoma or produced by infusion in experimental animals are known to cause myocardial injury, presumably by increasing sarcoplasmic calcium release.7 8 In support of the catecholamine toxicity concept, we recently demonstrated that β-blockers restore myocardial contractility in chronic experimental mitral regurgitation by allowing myofibrillar density, which is decreased in that entity to a normal level, thereby increasing the number of force-generating units in the myocardium.9 We postulated that β-blockade in this instance allowed damaged myocardium to heal, presumably by protecting it from the effects of persistently elevated catecholamines.
One way in which β-blockers could confer protection is by slowing heart rate. Persistent tachycardia in humans and experimental animals causes congestive heart failure.10 11 Thus, tachycardia is intrinsically deleterious. Although in most types of primary heart failure the compensatory heart rate increase is not so dramatic as that produced in pacing models or by persistent atrial arrhythmias, some studies of β-blockade in human heart failure demonstrate that the greatest efficacy occurs in those patients with the highest pretreatment heart rates.12
In the present study, we tested the hypothesis that slowing of heart rate was a key mechanism by which β-blockade ameliorates myocardial dysfunction in chronic experimental mitral regurgitation.
At all times, care of the animals used in the present studies met or exceeded guidelines set forth by the American Physiological Society and the American Association for Accreditation of Laboratory Animal Care. Two groups of dogs with experimental mitral regurgitation were studied (Figure 1⇓). In each group, all dogs were studied at baseline (“normal”) and then again after 3 months of chronic mitral regurgitation. In 1 group of dogs with mitral regurgitation, β-blockade was instituted after 3 months and gradually increased over the ensuing 3 months. In the other group of dogs with mitral regurgitation, β-blockade was also instituted as above, but a pacemaker was inserted to maintain heart rate at pre–β-blockade level, to thereby prevent β-blockade–induced bradycardia. In a third group of normal dogs (without mitral regurgitation), ventricular function was studied at baseline and after 3 months of pacing at the average rate for the dogs that received mitral regurgitation pacing (130 bpm).
At each investigation, hemodynamics and indexes of LV contractility were evaluated. At baseline and all experimental observations, acute β-blockade was induced by infusion of esmolol to remove confounding effects of normal adrenergic reflexes for cardiac compensation.13 In dogs that received chronic β-blockade, addition of esmolol had no effect because β-blockade had already been instituted. However, constant use of esmolol throughout all experiments maintained consistency of experimental conditions for each experimental observation period. Contractile function of myocytes isolated from the ventricles at termination of the experiments was used to corroborate our estimates of in vivo contractility.
In Vivo Estimation of Contractility
Contractility is defined as the ability of the myocardium to generate force independent of preload. Although no estimation of contractility is ideal, end-systolic stiffness (K) has correlated well with an independent gold standard, that of the contractility of cardiocytes isolated from ventricles in which this in vivo determination had been made.9 14 15 K is dimensionless and thus is unaffected by heart size.16 It is relatively preload insensitive and incorporates afterload into its expression.16 Slope of the end-systolic pressure-volume (ESPVR) or stress-volume (ESSVR) relationship has been used more traditionally to assess in vivo contractility. However, it is limited by dependence on cardiac size (if the heart increases in volume, ESPVR will decrease regardless of contractility).16 17 18 Additionally ESPVR may become disparate from maximum elastance (Emax) in mitral regurgitation.19 However, previous studies have indicated that correction of the slope of the end-ejection stress-volume relationship (EESVR) for the mass present at the time of the contractility estimate has related well to isolated cardiocyte function.14 Thus, in the present study, K and mass-corrected EESVR (EESVRmc) were used to assess contractility at different periods of investigation. Data for developing this relationship were derived from simultaneously obtained angiograms and high-fidelity manometers. Angiographic volume and LV pressure were varied by use of an inferior vena cava balloon, as done previously.13 20 21 In turn, loading alterations caused by balloon deflation created the changes in volume, pressure, and stress needed to construct indexes of contractility.
Protocol for In Vivo Assessment of Hemodynamics and Contractility
Fasting dogs were brought to an experimental cardiac catheterization laboratory. Anesthesia was induced in the dogs by intravenous infusion of fentanyl and droperidol and was maintained by periodic reinjection of fentanyl and droperidol together with inhalation of nitrous oxide and oxygen in a 3:1 gas mixture. A large balloon catheter was inserted into the jugular vein and advanced to the inferior vena cava for eventual use in the regulation of LV pressure and volume. A Swan-Ganz catheter was passed through the same vein into the pulmonary artery to obtain pulmonary capillary wedge and pulmonary artery pressures and to record thermodilution cardiac outputs. A 5F pigtail catheter was introduced into the right carotid artery and advanced to the LV. The catheter was connected to a previously mercury-calibrated strain gauge and was used to record pressure and for contrast injection during ventriculography. A high-fidelity manometer-tipped Millar catheter was advanced from the same carotid artery to the LV, in which it was matched to the mercury-calibrated, fluid-filled catheter. β-blockade was produced as noted below. In the pacing group, the pacer was deactivated, which allowed hemodynamic assessment to be made at relatively similar heart rates at each observation. After pressures were recorded and thermodilution cardiac outputs obtained, a left ventriculogram was performed in the right anterior oblique position with non-onic contrast (iohexol). Twenty cm3 of dye was injected at a rate of 7 cm3/s, and the cineangiogram was recorded during simultaneous recording of LV pressure. From this ventriculogram, LV mass and LV volumes, EF, and regurgitant fraction were calculated. Volumes and masses calculated in this fashion have correlated well with weighed actual masses in the past.20 21 After a 15-minute equilibration period, a “contractility ventriculogram” was performed. During this ventriculogram, the inferior vena caval balloon, which had previously been inflated, was deflated so that it produced a beat-by-beat increase in both pressure and volume, which provided the data to construct the indexes of contractility.
Creation of Mitral Regurgitation
After assessment of baseline hemodynamics and contractility at the first observation period, mitral regurgitation was produced by use of urologic stone-grasping forceps, as previously described.9 13 14 15
Isolated Cardiocyte Function
Cardiocytes were isolated and function was measured (as previously described)13 14 15 by investigators blinded to the in vivo results. Briefly, after the in vivo evaluation of LV function at 6 months, the dogs were deeply anesthetized. Pericardium was excised and hearts rapidly removed and placed in a cold calcium-free buffer. A wedge of LV supplied by the circumflex artery was isolated, and the artery was cannulated and perfused with collagenase to allow disaggregation of viable cardiocytes. Then, the tissue was minced into 2-mm cubes and gently agitated for 5 minutes at 37°C while being gassed with 100% O2. Cardiocytes were harvested by drawing off the supernatant in which they were suspended for filtration through 210-μm nylon mesh. Laser diffraction was then used to analyze the extent and velocity of sarcomere shortening. Cardiocyte data from 8 previously unreported normal dogs served as control data.
After 3 months of chronic mitral regurgitation, β-blockade was instituted gradually, beginning with 12.5 mg/d of atenolol. The dosage of atenolol was advanced every 2 weeks until a total dose of 50 mg was administered. Dogs were then maintained on the 50-mg dose for 1 additional month. Because we previously demonstrated that adrenergic reflexes in the dog can maintain apparently normal contractile function even when innate contractile function is depressed,13 it was necessary to compare the in vivo indexes of contractile function during β-blockade in every case. Thus, acute β-blockade was instituted at baseline and at 3 months after mitral regurgitation by infusion of esmolol at a loading dose of 0.5 mg/kg followed by constant infusion of 0.3 mg · kg−1 · min−1 for in vivo study of contractility. At 6 months of mitral regurgitation, esmolol was also used to maintain consistency of experimental conditions even though the animals also received long-term atenolol.
Under general anesthesia, a small right-sided thoracotomy was performed. Pacing wires were implanted into the right atrium, and the pacemaker generator was connected to the leads and placed in a subcutaneous pouch on the back of each dog. After 3 months of mitral regurgitation, the pacer was activated at the heart rate recorded while the awake animal was resting quietly in a sling.
LV mass was calculated with the method of Rackley et al.22 We have found angiographic determination of LV mass by use of this method to be reliable for reproduction of actual masses obtained by weighing the LV at euthanization.21 LV wall stress was calculated with the method of Mirsky et al.23 K was determined by fitting the systolic stress and end-systolic wall thickness to the following curvilinear equation:
where y is stress and x=ln/(1/wall thickness).16
Dispersion from the mean is indicated as ±SEM. Comparisons made regarding various parameters over the course of the study represented multiple repeated comparisons; therefore, we tested for statistical significance by use of 2-way ANOVA followed by Newman-Keuls test to locate differences.
Severe mitral regurgitation existed for both groups. Average regurgitant fraction was >50% at all observation periods and was not different between groups. Change in LV mass normalized for body weight is shown in Figure 2⇓. LV mass increased significantly and not differently in both groups. Ambulatory heart rate at baseline was similar for both groups: 108±11 bpm in the eventually unpaced group versus 110±9 bpm in the eventually paced group. After 3 months of mitral regurgitation, heart rate had increased significantly (P<0.05) in both groups (139±10 versus 135±6 bpm). At 6 months, the group that received β-blockade had a significant decrease in heart rate (109±12 bpm) whereas, as expected, the paced group had no decrease in heart rate (139±9 bpm). Heart rate in the paced group was significantly greater than in the unpaced group. Pulmonary capillary wedge pressure is shown in Figure 3⇓. It was similar in both groups at baseline, increased in a similar manner after 3 months of mitral regurgitation, and decreased in both groups after β-blockade was instituted, regardless of whether pacing was instituted.
However, cardiac performance and contractility behaved disparately in the 2 groups of dogs that had mitral regurgitation. EF was similar at baseline in the group of dogs designated to undergo mitral regurgitation (0.52±0.02 mitral regurgitation in the β-blockade group versus 0.48±0.04 mitral regurgitation in the group that received β-blockade and pacing). Institution of the favorable loading conditions of mitral regurgitation increased EF identically to 0.64±0.02 in both groups. At the end of the study, EF was unchanged in the group that received mitral regurgitation and β-blockade (0.65±0.02) but decreased significantly to 0.49±0.02 in the group that received mitral regurgitation, β-blockade, and pacing (P<0.01). Indexes of contractility are shown in Figure 4⇓. Slope of the EESVRmc (Figure 4A⇓) was similar at baseline and fell significantly in both groups after 3 months of mitral regurgitation. However, EESVRmc improved in the β-blocked group but did not improve in the group that was β-blocked and paced. K (Figures 4B⇓ and 4C⇓) behaved similarly; however, it tended to improve (not significantly in the paced group). Heart rates at which the indexes of contractility were recorded are shown in Figure 5⇓. As noted above, all heart rates were recorded during esmolol infusion and with the pacer deactivated in the pacemaker group. Although at 6 months heart rate was slightly deceased in both groups compared with at 3 months, no difference existed between groups.
Sarcomere-shortening velocity of cardiocytes isolated from the ventricles of the respective groups behaved in a manner similar to that in the in vivo tests of contractility (Figure 6⇓). Shortening velocity was depressed in a separate group of similar dogs killed after 3 months of mitral regurgitation (reported earlier9 ). Sarcomere-shortening velocity of β-blocked dogs with mitral regurgitation from the present study was normal. Sarcomere-shortening velocity improved slightly but significantly in the β-blocked and paced group compared with our previously studied 3-month mitral regurgitation group but was significantly depressed compared with the unpaced group.
In Figure 7⇓, functional data for 4 normal dogs paced to 130 bpm is shown at baseline and after 3 months of pacing. EF (Figure 7A⇓) fell insignificantly. EESVRmc (Figure 7B⇓) fell insignificantly, whereas K (Figure 7C⇓) rose insignificantly.
Although the theory once met with skepticism, it has become clear that use of β-blockade in congestive heart failure due to systolic dysfunction can improve symptoms, increase EF, and probably improve longevity.1 2 3 4 12 24 25 26 Mechanisms proposed for the effectiveness of β-blockade in heart failure have included (1) improved β-receptor function,6 (2) protection of the myocardium from the effects of prolonged exposure to high levels of circulating catecholamines,9 and (3) that bradycardia that usually accompanies β-blockade might be beneficial for improvement of myocardial energetics.27 Clearly, some β-blockers in heart failure cause β-receptor upregulation and improve β-receptor function.6 However, because the β-receptors are chronically blocked by the therapy itself, β-receptor upregulation is probably most important in response to acute increases in catecholamines, such as might occur during exercise. On the other hand, recent studies in our laboratory demonstrated that β-blockade reversed cardiomyopathy of chronic experimental mitral regurgitation by restoring myofibrillar density and contractile function to cardiocytes comprising the ventricle.9 Improved myocyte contractile function occurred in tandem with improved in vivo ventricular function. The finding of enhanced cardiocyte contractile function was important because it occurred in the absence of β-stimulation. Thus, even if β-receptor function were improved by chronic β-blockade, this mechanism was probably not active in the in vitro improvement that we observed nor was it likely to be operative in restoration of contractile element density.
The present studies add to the previous work by demonstrating that in this model, bradycardia is important to the salutary effects of β-blockade on contractility. Prevention of bradycardia with a pacemaker largely negated beneficial β-blockade effects both in vivo and in vitro, although some improvement occurred in vitro despite pacing. In clinical studies of β-blockade in heart failure, institution of β-blockade has always resulted in a decrease in heart rate. Whether this decrease in heart rate has been related to the positive outcome of β-blockade has been unclear. The present study suggests that achievement of bradycardia is important to a beneficial outcome and is consistent with a recent report by Packer et al.12 In that study, patients whose resting heart rate was >82 bpm had the largest benefit and enhanced survival when the β-blocker carvedilol was instituted. Eichhorn et al28 did not find a significant relationship between resting pretreatment heart rate and improvement in systolic function. However, in that study, the actual values for heart rate were unpublished. If little variation in heart rate existed at baseline, correlation between this variable and outcome might be hard to prove.
Data from the present study pose the obvious question, “By what mechanism does bradycardia restore contractile element number,9 which leads to the beneficial myocardial effects during β-blockade?” Although the present studies were not designed to answer that question, we speculate that reduction in heart rate might improve myocardial energetics by improving the relationship between myocardial blood flow and oxygen consumption. This could occur as a result of either decreased oxygen consumption or increased capillary density.29 Or, bradycardia might lead to improved myocardial calcium handling, which could reduce calcium overload, and, in turn, would protect the myocardium from the deleterious effects of calcium overload. Alternatively, bradycardia might improve myocardial metabolism by restoring depleted high-energy phosphates.30 A final possibility is that by slowing heart rate we helped move the ventricle to the point on its force-frequency curve at which force development was improved.31
Our experiments in pacing in normal dogs also deserve comment. We did not find any consistent decrease in performance at 130 bpm, although a downward trend occurred. Furthermore, fast heart rates are known to cause heart failure. These findings suggest that tachycardia is a key element in some forms of heart failure and that even modest tachycardia may be deleterious. Whether a threshold heart rate exists for induction of failure is unclear.
Note that in both β-blockade groups, left atrial hypertension improved even with pacing. These results suggest a beneficial hemodynamic effect of β-blockade independent of its effects on contractility. We speculate that this benefit could stem from the effects of β-blockade in the reduction of activation of the renin-angiotensin system, thus leading to diuresis.
The present studies rest on our ability to measure contractility, which, as noted previously, is problematic. However, we think that our independent corroboration with in vitro studies supports our methods and helps confirm our results.
Because heart rate can affect contractility, it was important to make our measurements at similar heart rates. Although heart rate was slightly less in the β-blocked and unpaced group, this difference was small.
Finally, our experiments were performed under light anesthesia. Although we believe that our anesthetic combination has little effect on contractility, it is still artificial compared with waking conditions.
In summary, the present studies confirm our previous work, which demonstrated a beneficial effect of β-blockade for restoration of contractile function to isolated cardiocytes and to the left ventricle in experimental mitral regurgitation. The present studies further demonstrate that ≥1 of the important mechanisms of action of β-blockade in contractile failure is to reduce heart rate, because prevention of β-blockade–induced bradycardia ablated the beneficial effects of therapy.
The present research was supported in part by grant R01 (HL 38185) from the NIH, NHLBI, Bethesda, Md.
- Received May 26, 1999.
- Revision received September 2, 1999.
- Accepted September 15, 1999.
- Copyright © 2000 by American Heart Association
Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-β-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation. 1995;92:212–218.
Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995;25:1225–1231.
Eichhorn EJ, Bedotto JB, Malloy CR, Hatfield BA, Deitchman D, Brown M, Willard JE, Grayburn PA. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure: improvements in hemodynamic, contractile, and diastolic performance with bucindolol. Circulation. 1990;82:473–483.
Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992;85:790–804.
Heilbrunn SM, Shah P, Bristow MR, Valantine HA, Ginsburg R, Fowler MB. Increased β-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation. 1989;79:483–490.
Tsutsui H, Spinale FG, Nagatsu M, Schmid PG, Ishihara K, DeFreyte G, Cooper G IV, Carabello BA. Effects of chronic β-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest. 1994;93:2639–2648.
Spinale F, ed. Pathophysiology of Tachycardia-Induced Heart Failure. Armonk, NY: Futura; 1996:1–231.
Nagatsu M, Zile MR, Tsutsui H, Schmid PG, DeFreyte G, Cooper G IV, Carabello BA. Native beta-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function. Circulation. 1994;89:818–826.
Urabe Y, Mann DL, Kent RL, Nakano K, Tomanek RJ, Carabello BA, Cooper G IV. Cellular and ventricular contractile dysfunction in experimental canine mitral regurgitation. Circ Res. 1992;70:131–147.
Ishihara K, Zile MR, Kanazawa S, Tsutsui H, Urabe Y, DeFreyte G, Carabello BA. Left ventricular mechanics and myocyte function after correction of experimental chronic mitral regurgitation by combined mitral valve replacement and preservation of the native mitral valve apparatus. Circulation. 1992;86(suppl II):II-16–II-25.
Nakano K, Sugawara M, Ishihara K, Kanazawa S, Corin WJ, Denslow S, Biederman RWW, Carabello BA. Myocardial stiffness derived from end-systolic wall stress and the logarithm of reciprocal of wall thickness: contractility index independent of ventricular size. Circulation. 1990;82:1352–1361.
Belcher P, Boerboom LE, Olinger GN. Standardization of end-systolic pressure-volume relation in the dog. Am J Physiol. 1985;249:H547–H553.
Brickner ME, Starling MR. Dissociation of end systole from end ejection in patients with long-term mitral regurgitation. Circulation. 1990;81:1277–1286.
Nakano K, Swindle MM, Spinale F, Ishihara K, Kanazawa S, Smith A, Biederman RWW, Clamp L, Hamada Y, Zile MR, Carabello BA. Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload. J Clin Invest. 1991;87:2077–2086.
Corin WJ, Swindle MM, Spann JF Jr, Nakano K, Frankis M, Biederman RW, Smith A, Taylor A, Carabello BA. Mechanism of decreased forward stroke volume in children and swine with ventricular septal defect and failure to thrive. J Clin Invest. 1988;82:544–551.
Rackley CE, Dodge HT, Coble YD Jr, Hay RE. A method for determining left ventricular mass in man. Circulation. 1964;29:666–671.
Mirsky I, Tajimi T, Peterson KL. The development of the entire end-systolic pressure-volume and ejection fraction-afterload relations: a new concept of systolic myocardial stiffness. Circulation. 1987;76:343–356.
Woodley SL, Gilbert EM, Anderson JL, O’Connell JB, Deitchman D, Yanowitz FG, Mealey PC, Volkman K, Renlund DG, Menlove R, Bristow MR. β-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation. 1991;84:2426–2441.
Moe GW, Grima EA, Seth R, Jeejeebhoy K, Howard RJ, Armstrong PW. Diverse metabolic response of cardiac versus skeletal muscle in experimental heart failure. Can J Cardiol. 1992;8:104B. Abstract.
Hudlicka O. Growth of capillaries in skeletal and cardiac muscle. Circ Res. 1982;50:451–461.
Zhang J, Toher C, Erhard M, Zhang Y, Ugurbil K, Bache RJ, Lange T, Homans DC. Relationships between myocardial bioenergetic and left ventricular function in hearts with volume-overload hypertrophy. Circulation. 1997;96:334–343.
Mulieri LA, Leavitt BJ, Ittleman FP, Martin BJ, Haeberle JR, Alpert NR. Forskolin reverses the force-frequency defect in left ventricular subepicardium (EPI) but not in papillary myocardium (PAP) in human mitral regurgitation heart failure. Circulation. 1993;88(suppl I):I-406. Abstract.