Resting Heart Rate Does Not Reflect the Degree of Beta-Blockade in Subjects with Heart Failure on Chronic Beta-Blocker Therapy

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1 RESEARCH Resting Heart Rate Does Not Reflect the Degree of Beta-Blockade in Subjects with Heart Failure on Chronic Beta-Blocker Therapy Andrea Mignatti, Daniel B. Sims, Paolo C. Colombo, Luis I. Garcia, Rachel Bijou, Mario C. Deng & Ulrich P. Jorde Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA Keywords Beta Blockers; Heart Failure; Resting Heart Rate (HR). Correspondence Ulrich P. Jorde, M.D., Columbia University Medical Center, 622 West, 168th Street, PH 12-Stem, New York, NY Tel.: ; Fax: ; We investigated the relationship between resting heart rate (HR) and two measures of beta-1 receptor sensitivity/blockade: (1) the percentage of maximal predicted heart rate reached during exercise (%MPHR), and (2) the HR increase per unit of circulating norepinephrine (NE) or the chronotropic responsiveness index (CRI) in 28 patients with systolic CHF on chronic beta-blocker therapy. Our results show that resting HR is not associated with HR response during exercise nor with beta-1 receptor sensitivity to circulating NE. doi: /j x Introduction In healthy volunteers, beta-blockers dose-dependently reduce resting and exercise heart rate (HR), and the maximal reduction of exercise HR in normal subjects is approximately 20% [1 3]. Despite the availability of this bioassay, guideline recommendations for the use of beta-blockers in chronic heart failure (CHF) specify doses used in clinical trials rather than physiological endpoints achieved in individual patients, that is, resting or peak exercise HR or change in HR. With respect to resting HR, the rationale for these guidelines is provided by at least two clinical trials: in Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), metoprolol CR/XL significantly reduced mortality and hospitalizations, independent of resting baseline HR, achieved HR, and change in HR [4]. In Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA), the only apriorirandomized outcome study for different doses of beta-blocker in CHF ( mg carvedilol, b.i.d.), the benefit increased with dose, whereas resting HR was comparable in all dosing groups [5]. Regardless, beta-blockers are frequently not uptitrated to recommended doses. This may, in large part, be due to a continuing belief that further uptitration will not be achieved once resting HR is in a nontachycardic range, that is, bpm. Experimental evidence demonstrating the absence of an association of the achieved degree of beta-blockade and resting HR in CHF is lacking. The degree of betareceptor sensitivity/blockade in vivo can be assessed by reduction in the percentage of maximal predicted exercise heart rate (%MPHR) as well as by the chronotropic responsiveness index (CRI). Accordingly, we examined the association of resting heart rate with %MPHR and CRI in subjects with CHF on optimal medical therapy including chronic beta-blockade. Methods Study Population Twenty-eight consecutive subjects with systolic CHF on stable medical therapy including beta-blocker for at least 3 months referred for cardiopulmonary exercise tolerance testing (CPETT) were enrolled (Table 1). All patients were 42 Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd

2 A. Mignatti et al. Resting Heart Rate and Beta-Blockade Table 1 Demographics and clinical characteristics Demographics and clinical characteristics Age (years) ± 12 Male sex 19 (67.8%) LVEF (%) 25.7 ± 8.1 Ischemic cardiomyopathy 10 (35.7%) Nonischemic cardiomyopathy 18 (64.3%) Hypertension 15 (53.5%) Diabetes 5 (17.8%) Sinus rhythm 28 (100%) Weight (kg) 82 ± 16.2 Height (cm) 173 ± 0.09 Baseline HR (bpm) 72.7 ± 12.5 Peak HR (bpm) 137 ± 23 Percentage of maximal predicated heart rate 78 ± 11 Exercise time (min) 9.7 ± 3.1 NE pre (pg/ml) 595 ± 343 NE post (pg/ml) 2859 ± 1506 Chronotropic responsiveness index ± 5.5 VO 2 (ml/kg/min) 16.7 ± 5.9 RER 1.09 ± 0.04 Beta-blocker dose Carvediol ( mg) 21 (75%) Toprol ( mg) 7 (25%) Mean daily carvedilol dose 35.8 mg Mean daily toprol dose 89.2 mg HR, heart rate; LVEF, left ventricular ejection fraction; NE, norepinephrine; VO 2, peak oxygen consumption; RER, respiratory exchange ratio. in sinus rhythm and were instructed to take their usual beta-blocker dose 2 h prior to CPETT. attained in the final 20 seconds of exercise when the respiratory exchange ratio was 1.0. Measurement of Norepinephrine Following an overnight fast including medications, an 18- or 20-gauge angiocatheter was inserted into a forearm vein without the use of a tourniquet. A total of 30 ml of venous blood was collected in EDTA vials: 15 ml after 30 min of supine rest, and an additional 15 ml at peak exercise. The samples were stored on ice until centrifugation and then frozen immediately at 80 C. Norepinephrine (NE) was measured using high-performance liquid chromatography. Calculation of the CRI The CRI was calculated using the following formula: (peak HR baseline HR)/log (peak NE baseline NE). Conversion of Metoprolol to Carvedilol Equivalents Twenty-one patients were on carvedilol (range mg), and 7 patients were on long-acting metoprolol (Toprol XL, range mg, metoprolol succinate extended release tablets; AstraZeneca Pharmaceuticals, LP, Sodertalje, Sweden). In order to standardize the betablocker dosage, we used a factor of to convert longacting metoprolol to carvedilol equivalents [6]. Cardiopulmonary Exercise Tolerance Testing (CPETT) Resting HR was obtained after 30 min of rest in a quiet, temperature-controlled room. Peak oxygen consumption (peak VO 2 [ml/kg/min]) was then assessed during graded treadmill exercise. Expired gases were collected throughout exercise, and VO 2 was recorded on a breathby-breath basis using a Medgraphics metabolic cart (Medgraphics Medical Graphics Corporation, St. Paul, MN, USA). The instruments were calibrated before every test and were corrected for humidity, room temperature, and barometric pressure, according to the manufacturer s protocol. The work rate increased continuously as a ramp function by augmenting the speed and grade of the treadmill according to the Naughton protocol. The patients exercised to a symptom-limited maximum. HR and electrocardiogram were recorded continuously during exercise, and blood pressure was measured at rest, every 2 min during exercise, and upon completion of exercise. Peak VO 2 was defined as the highest value of oxygen uptake Statistical Analysis All analyses were performed using SPSS 15.0 software (SPSS Inc., Chicago, IL, USA). Data are expressed as means ±SD for continuous variables, and as frequency distributions for categorical variables. The Student t-test was used to compare group means; Pearson coefficient was used for correlations. Results Correlation between CRI and %MPHR The CRI and %MPHR were highly correlated (R = 0.743, P < 0.001). (Fig. 1) Correlation Between Resting HR, CRI, and %MPHR Resting HR was 72.7 ± 12.5 bpm, CRI was 17.9 ± 5.5, and %MPHR was 78 ± Resting HR did not correlate Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd 43

3 Resting Heart Rate and Beta-Blockade A. Mignatti et al. Figure 1 Correlation between chronotropic responsiveness index and percentage of maximal predicted heart rate (HR). (R = 0.743, P < 0.001). with CRI (R = 0.209, P = 0.285) (Fig. 2) or %MPHR (R = 0.255, P = 0.182) (Fig. 3.) CRI in Patients with %MPHR <80% The mean CRI in patients with %MPHR <80% (a commonly employed cutoff to define chronotropic incompetence) was 13.7 ± 3.2, and the mean CRI in patients with %MPHR >80% was 21.5 ± 4.4 (P < 0.05). (Fig. 4) Correlation between Beta-Blocker Dose, CRI, and %MPHR Beta-blocker dose did not correlate with CRI (R = 0.347, P = 0.290) and nor with %MPHR (R = 0.207, P = 0.290). Correlation Between CRI and Exercise Tolerance The CRI correlated positively with peak VO 2.(R = 0.518, P < 0.005) (Fig. 5). Discussion We examined the relationship of resting HR and the two measures of beta-1 receptor sensitivity/blockade in patients with systolic CHF on chronic beta-blocker therapy. Our principal findings are as follows: First, the two chosen measures of in vivo beta-receptor sensitivity/blockade, CRI and %MPHR, are well correlated in patients with advanced CHF on chronic beta-blockade. Second, resting HR is not associated with either measure and thus should not be used to tailor beta-blocker therapy in this population. Third, CRI and peak VO 2 are well-correlated. The inverse association of resting HR and long-term cardiovascular risk has been demonstrated by a series of epidemiological studies [7 9]. Beta-blockers lower resting HR, and their use is associated with substantial reductions in morbidity and mortality in CHF [10]. In this context, it is of note that resting HR is often simply a measure of clinical compensation and may also be lowered by acute decongestion as well as non-beta-blocker interventions that reduce mortality in CHF such as angiotensin converting enzyme (ACE) inhibitors [11] or cardiac 44 Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd

4 A. Mignatti et al. Resting Heart Rate and Beta-Blockade Figure 2 Correlation between resting heart rate (HR) and chronotropic responsiveness index (R = 0.209,P = 0.285). bpm, beats per minute. resynchronization therapy (CRT) [12]. In fact, it is unknown whether a low resting HR observed in subjects with CHF during chronic therapy is (proportionally) due to beta-1 receptor blockade or simply a result of less overall neurohormonal activation. To our knowledge, we are the first to examine the relationship of resting and exercise HRs on the one hand, and beta-1 receptor responsiveness to circulating NE on the other hand in subjects with advanced CHF on chronic beta-blockade. In our study, %MPHR and CRI, the two measures of beta-1 receptor blockade, were closely correlated. However, we did not observe any association between resting HR and either measure of beta-receptor responsiveness. We also did not observe a correlation between beta-blocker dose and either measure of betareceptor sensitivity in this population. The latter observation underscores prior observations that the chronotropic response to exercise is impaired in patients with CHF, irrespective of beta-blockade [13 15]. Our findings on the close relationship of the CRI and peak VO 2 are concordant with the results of Samejima et al. [16], who studied the relationship between impaired chronotropic response and exercise tolerance in patients with CHF not receiving chronic beta-blocker therapy. Samejima hypothesized that an impaired response to increased NE is one of the mechanisms responsible for low exercise tolerance in CHF patients: our results suggest that this is also true after chronic betablockade. Our study is, in principal, limited by its retrospective and cross-sectional nature. Specifically, we do not provide longitudinal follow-up of HR and CRI throughout beta-blocker initiation. It is further of note that although CRI has been demonstrated to reflect beta-receptor sensitivity [14 16], prospective studies examining its role as a measure of beta-blockade in CHF are lacking. Last, given the fact that we are a transplant referral center, our subjects are somewhat younger than the average heart failure patient. In summary, the two chosen measures of in vivo betareceptor sensitivity/blockade, the CRI and %MPHR, are well correlated in patients with advanced CHF. Resting HR is not associated with either measure. Our data support current guideline recommendation to uptitrate beta-blockers to doses used in clinical trials rather than to physiological endpoints that might reflect the degree of beta-blockade in subjects without CHF. Importantly, the interpretation of our data is limited to resting HR Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd 45

5 Resting Heart Rate and Beta-Blockade A. Mignatti et al. Figure 3 Correlation between resting heart rate (HR) and percentage of maximal predicted heart rate. (R = 0.255,P = 0.182). bpm, beats per minute. and does not address whether longitudinal assessment of %MPHR during beta-blocker uptitration might be a useful tool to assess beta-blockade in vivo in patients with CHF [17]. Conflict of Interest The authors declare no conflict of interest. References 1. Billeh R. Randomized, double-blind comparison of acute beta1-blockade with 50 mg metoprolol tartrate vs 25 mg carvedilol in normal subjects. Congest Heart Fail 2006;12: Lipworth BJ, Irvine NA, McDevitt DG. A dose-ranging study to evaluate the beta 1-adrenoceptor selectivity of bisoprolol. Eur J Clin Pharmacol 1991;40: de Mey C. Dose-effect and pharmacokineticpharmacodynamic relationships of the beta 1-adrenergic receptor blocking properties of various doses of carvedilol in healthy humans. Clin Pharmacol Ther 1994;55: Gullestad L. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). JAmCollCardiol 2005;45: Bristow MR. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996;94: Vittorio TJ. Differential effects of carvedilol and metoprolol succinate on plasma norepinephrine release and peak exercise heart rate in subjects with chronic heart failure. J Cardiovasc Pharmacol Ther 2008;13: Bevilacqua M. Role of the Frank-Starling mechanism in maintaining cardiac output during increasing levels of treadmill exercise in beta-blocked normal men. Am J Cardiol 1989;63: Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J 1997;18: Kannel WB. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 1987;113: Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd

6 A. Mignatti et al. Resting Heart Rate and Beta-Blockade Figure 4 Chronotropic responsiveness index in subjects with percentage of maximal predicted heart rate above or below 80%. (P < 0.05). %MPHR, percentage of maximal predicted heart rate. 10. Hjalmarson A. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). MERIT-HF Study Group. JAMA, 2000;283: Topic N, Kramer B, Massie B. Acute and long-term effects of captopril on exercise cardiac performance and exercise capacity in congestive heart failure. Am Heart J 1982; 104(5 Pt 2): Fantoni C. Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure. JAmCollCardiol 2005;46: Castro P. Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure. Eur J Heart Fail 2005;7: Colucci WS. Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization. Circulation 1989;80: Jorde UP. Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: time to pace? Eur J Heart Fail 2008;10: Samejima H. Relationship between impaired chronotropic response, cardiac output during exercise, and exercise tolerance in patients with chronic heart failure. Jpn Heart J 2003;44: Gali JK, Pina IL, Chiong JR, Lenihan DJ, Wagoner LE, Dunlap SH, Dupree CA, Van Bakel AB, Glotzer JM, Patterson JH, et al. Changes in resting and maximal exercise heart rate during dosing of beta blocker therapy in patients with systolic heart failure. J Card Fail 2008;14:S76 S77. Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd 47

7 Resting Heart Rate and Beta-Blockade A. Mignatti et al. Figure 5 Correlation between chronotropic responsiveness index and peak oxygen consumption. (R = 0.518, P < 0.005). Peak V0 2, peak oxygen consumption. 48 Cardiovascular Therapeutics 27 (2009) c 2009 Blackwell Publishing Ltd