Faculty Peer Reviewed
Mr. M is a 63-year-old man with a history of coronary artery disease and systolic CHF (ejection fraction 32%) on lisinopril, metoprolol, and spironolactone who presents to Primary Care Clinic complaining of persistent dyspnea with exertion, two-pillow orthopnea, and severely limited exercise tolerance. His vital signs on presentation are T 98.0º F, BP 122/76, HR 84 bpm. What are his therapeutic options?
A Race Against Time: Tachycardia in the Failing Heart
Congestive heart failure (CHF) is a clinical syndrome that results from any disruption in the ability of the heart to maintain sufficient cardiac output to supply the body’s metabolic demand. It is manifested by the well-known symptoms of exertional dyspnea, decreased exercise tolerance, and fluid retention. The yearly incidence of CHF continues to increase as more patients who have myocardial infarctions survive but subsequently develop ischemic cardiomyopathy.
As the failing heart struggles to maintain cardiac output, it undergoes a series of structural changes in attempt to maximize stroke volume. These changes, from initial hypertrophy, to progressive dilation, and finally to fibrosis and failure, have been well described. Once the heart can no longer increase stroke volume by increasing either preload or intrinsic contractility, it attempts to recover cardiac output by increasing heart rate. While this compensation is able to rescue cardiac output temporarily, it rapidly leads to cardiomyocyte apoptosis, collagen deposition, and fibrosis (reviewed in ). Indeed, rapid atrial pacing in an otherwise healthy heart has been known for almost 50 years to produce symptomatic CHF. This is thought to be due to a combination of diminished coronary blood flow, an increase in pro-apoptotic factors such as tumor necrosis factor-alpha, and decoupling of cardiac myocyte excitation and contraction secondary to a reduction in inward rectifier potassium current.
The pharmacologic agents that have been shown to improve mortality in systolic CHF (renin-angiotensin system inhibitors [5-7], aldosterone antagonists , and beta blockers [9-11]) do so by preventing pathologic ventricular remodeling.[12,13] Less well studied, however, is the development of tachycardia as a compensatory mechanism in CHF. The relatively minor emphasis on heart rate is surprising, given that an elevated heart rate is a well-established risk factor for cardiovascular mortality. Heart rate is additionally a source of interest, given the measurable benefit of beta blockers in patients with CHF beyond that which can be achieved with angiotensin-converting enzyme (ACE) inhibitors and diuretics.[9-11] In fact, some of the earliest studies demonstrating a mortality benefit from timolol in CHF  suggested that the majority of risk reduction might be due to its negative chronotropic effects. Recent meta-analyses of randomized, placebo-controlled trials of beta blockers in CHF have supported this hypothesis by demonstrating that the mortality benefit of beta blockers correlates not with medication dosage but with heart rate reduction.[17,18] Thus, control of heart rate may be the unique method by which beta blockers slow pathologic left ventricular remodeling in a manner that is independent of the effect of ACE inhibitors.
Addition of beta blockers to a CHF regimen has not eliminated the detrimental impact of increased heart rate on the progression of CHF. In a recent 10-year observational study of patients with CHF, every increment of 10 beats per minute (bpm) above baseline was associated with a sequential increase in cardiovascular death; notably, this correlation persisted in the presence of beta blockade. This association between elevated heart rate and cardiovascular morbidity applies even to patients who have had implantable cardioverter-defibrillator (ICD) placement for diminished left ventricular ejection fraction, as demonstrated by studies in which patients with elevated resting heart rates despite ICD placement and optimized beta blocker therapy were at markedly increased risk of death or hospitalization for symptomatic CHF. Thus, it appears that a certain aspect of heart rate variability that is unaffected by beta blockade may be a significant contributor to CHF-associated morbidity and mortality.
The New Player: I(f) in CHF
When investigating the origins of cardiovascular autoregulation, one must give due credit to the English physician William Harvey. Harvey’s seminal text, “De Motu Cordis,” also known as “On the Motion of the Heart and Blood,” describes a series of experiments by which he determined that the heart was not a passive conduit for blood, as had been suggested by the Greek philosopher and physician Galen of Pergamon, but rather the critical driving force maintaining systemic circulation. Harvey eloquently stated, “It must therefore be concluded that the blood in the animal body moves around in a circle continuously and that the action or function of the heart is to accomplish this by pumping. This is only reason for the motion and beat of the heart.” In the course of these experiments, Harvey noted that a pigeon heart, when removed from its body, continued to beat autonomously. This was the first indication that the heart contained an intrinsic clock for initiating and maintaining contractions: a “pace maker.”
The mechanism by which the sinoatrial (SA) and atrioventricular nodes drive the regular contraction of cardiac myocytes was elucidated in 1979 with the characterization of the so-called “funny current,” or I(f): a slow, mixed sodium-potassium depolarizing current that is activated by hyperpolarization, enhanced by sympathetic stimulation, and present only in myocytes with intrinsic pacemaker function. The depolarizing mixed current is carried through the I(f) channel, which contains four subunits, each with six transmembrane domains containing cation-selective voltage sensors, as well as binding sites for cyclic nucleotides on their intracellular faces. These cyclic nucleotide binding sites are the location of sympathetic stimulation. Sympathetic input increases I(f) amplitude by binding to adrenergic receptors on the surface of SA nodal cells; the resultant elevation in intracellular cyclic adenosine monophosphate (AMP) binds and activates I(f) channels. Equivalently, beta blockers slow heart rate by blocking sympathetic-mediated increases in I(f) amplitude.
Therefore, one might wonder whether beta blockade in systolic CHF is merely counteracting pathologic catecholamine release driving inappropriate increases in heart rate in an attempt to rescue cardiac output. While increased serum catecholamines are a hallmark feature of heart failure, there is evidence for decreased myocardial tissue catecholamine concentrations. This suggests that the pathologic tachycardia seen in CHF is not mediated entirely by sympathetic input, and may therefore not be maximally responsive to beta blockade.
What additional mechanisms may account for the increased heart rates seen in some patients with CHF? One possible explanation came from gene analysis of ventricular samples from human patients with and without CHF. This analysis showed that two out of the four genes that encode the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (of which the funny current is one), are significantly upregulated in patients with systolic CHF. In patch clamping of the same failing ventricular myocytes, I(f) was shown to activate at a less negative potential and to be of larger inward amplitude. Thus, upregulation and hypersensitization of I(f) channels may be a pathologic adaptation resulting in elevated resting heart rates in patients with CHF. An elevated heart rate secondary to upregulation of I(f) channel expression would likely be unresponsive to beta blockade.
The hypothesis that intrinsic I(f) activity contributes to pathological heart rate elevations seen in CHF became testable with market approval of ivabradine, an orally bioavailable I(f) channel-specific inhibitor that lowers heart rate without affecting myocardial contractility. It was initially pioneered as an anti-anginal drug, based on studies in which atherosclerotic mice treated with ivabradine showed reduced atherosclerotic plaque size, improved endothelial vasodilatory responses to hypoxia, and decreased systemic signs of oxidative stress. Subsequently, ivabradine was shown in a randomized, placebo-controlled trial to improve exercise tolerance and time to ischemia in patients with stable chronic angina undergoing exercise stress testing, and in 2005 it was approved for use in Europe for this purpose. A 2009 European Heart Journal study showed efficacy of ivabradine in patients with chronic stable angina beyond that which could be achieved with beta blockers. Based on these data, a randomized, double-blinded prospective study (BEAUTIFUL) was initiated to evaluate ivabradine as secondary prevention in patients with coronary artery disease and a left ventricular ejection fraction of less than 40%. With a patient enrollment of 11 000, this study stands as the largest set of clinical data investigating this drug. While the results did not show a reduction by ivabradine in a primary endpoint composed of hospital admission for worsening HF, death from cardiovascular causes, or acute MI, a subgroup analysis showed that ivabradine reduced hospital admission for MI or need for subsequent coronary revascularization in a predetermined subgroup of patients with a resting heart rate of greater than 70 bpm, and called for further research into this subset.
These data suggested that ivabradine might be beneficial in patients with left ventricular dysfunction and elevated resting heart rates. However, due to concerns that a drug that lowers resting heart rate might induce end-organ damage in patients struggling to maintain cardiac output, the role of ivabradine in CHF was initially studied in animal models. In rats with ischemic CHF induced by coronary artery ligation, a ninety-day treatment of ivabradine resulted in decreased ventricular collagen accumulation; notably, ivabradine-treated rats maintained cardiac output by increasing stroke volume, and they supported this increased myocardial work by increasing left ventricular capillary density. A subsequent study showed that ivabradine treatment in rats with ischemic cardiomyopathy specifically decreased protein expression of angiotensin-converting enzyme and angiotensin I, and reduced subsequent ventricular interstitial fibrosis, suggesting a role for ivabradine in preventing tachycardia-induced structural progression of CHF. Not all animal studies showed a positive role for ivabradine, however. In rats with pressure-overload CHF generated by banding of the ascending aorta (a model for diastolic CHF), heart rate reduction by ivabradine resulted in elevated left ventricular filling pressure, hypertrophy, fibrosis, serum brain natriuretic peptide elevation, and more frequent pleural and peritoneal effusions. Based on this, ivabradine was not proposed as a potential therapy for patients with diastolic dysfunction.
In human patients, initial testing showed that ivabradine could reduce heart rate without dropping left ventricular ejection fraction. In an initial observational study, 10 patients with class III CHF and an average ejection fraction of 21% were given intravenous ivabradine 0.1 mg/kg over 90 minutes. After 4 hours, ivabradine reduced heart rate by 25% but maintained cardiac output by increasing stroke volume.
Would ivabradine improve mortality in patients with chronic, stable CHF on optimal medical therapy? Stay tuned…
Santosh Vardhana is a 4th year medical student at NYU Langone Medical Center
Peer reviewed by Robert Donnino, MD, Section Editor-Cardiology, Clinical Correlations
Image courtesy of Wikimedia Commons
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