Reversal of Tachycardiomyopathy Due to Left Atrial Tachycardia by Ivabradine

Reversal of Tachycardiomyopathy . Ivabradine has been shown to be effective in reducing sinus rate. Here we report of a case where ivabradine reduced the rate of a focal atrial tachycardia relieving patient's symptoms and reversing tachycardiomyopathy. (J Cardiovasc Electrophysiol, Vol. 22, pp. 340‐342, March 2011)     

Inappropriate sinus tachycardia: focus on ivabradine

Inappropriate sinus tachycardia (IST) is an incompletely understood condition, characterised by an elevation in heart rate (HR) accompanied by wide ranging symptoms in the absence of an underlying physiological stimulus. The condition often takes a chronic course with significant adverse effects on quality of life. Currently, there is no effective treatment for IST. Beta‐blockers, generally considered the cornerstone of treatment, are often ineffective and poorly tolerated. Ivabradine is a novel sinus node I_f ‘funny current’ inhibitor, which reduces the HR. It has been approved for the treatment of beta‐blocker refractory chronic systolic heart failure and chronic stable angina but more recently has shown promise in the treatment of IST. This review provides an overview of IST prevalence and mechanisms followed by an examination of the evidence for the role and efficacy of ivabradine in the treatment of IST.     

Effects of ivabradine on the pulmonary vein electrical activity and modulation of pacemaker currents and calcium homeostasis

Effects of Ivabradine on Pulmonary Veins . Introduction: Ivabradine is a novel heart rate decreasing agent with selective and specific antagonist effects on the pacemaker current (I_f). The aim of this study was to investigate the pharmacological effects of ivabradine on the pulmonary vein (PV) cardiomyocytes. Methods and Results: Whole‐cell patch‐clamp techniques and the indo‐1 fluorimetric ratio technique were used to investigate the characteristics of the I_f and intracellular calcium (Ca ²⁺_i ) in single isolated rabbit PV cardiomyocytes with pacemaker activity before and after an ivabradine administration (0.3, 3, 10, and 30 μM). Ivabradine (0.3, 3, 10, and 30 μM) concentration dependently decreased the spontaneous activity by 6 ± 3%, 32 ± 6%, 49 ± 5%, and 85 ± 4%, and decreased the I_f by 35 ± 8%, 47 ± 9%, 62 ± 5%, and 65 ± 7%, respectively, in PV cardiomyocytes. The decreased extent of the PV beating rate or I_f by the different concentrations of ivabradine correlated well with the baseline PV beating rates. The IC₅₀ of the spontaneous activity and I_f induced by ivabradine were 9.5 and 3.5 μM, respectively. Moreover, ivabradine (30 μM, but not 3 μM) decreased the Ca ²⁺_i transient in the PV cardiomyocytes and ivabradine (30 μM) decreased the L‐type calcium current in the PV cardiomyocytes. Conclusion: Ivabradine decreased the I_fs and Ca ²⁺_i transient in the PV cardiomyocytes, which may contribute to its inhibitory effects on the PV spontaneous activity. (J Cardiovasc Electrophysiol, Vol. 23, pp. 200‐206, February 2012)     

The heart rate-lowering agent ivabradine inhibits the pacemaker current I(f) in human atrial myocytes

Introduction: It has been speculated that pacemaker current (I _f ) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I _f inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I _f in atrial myocytes.
Methods and Results:  Using patch-clamp technique, we studied effects of ivabradine on I _f present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I _f inhibition with an IC₅₀ at steady state of 2.9 μM. Time constant of block development (Tau_on) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 μM) was not modified in the presence of cAMP (10 μM) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected.
Conclusions:  Ivabradine inhibits I _f current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I _f recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f -channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed.     

Heart rate reduction in heart failure: ivabradine or beta blockers?

Ivabradine, a selective I f current inhibitor, decreasing the heart rate in those with sinus rhythm, has been added to the most recent European guidelines on heart failure. It is indicated in addition to beta blockers in patients with decreased left ventricular ejection fraction and sinus rate of over 70 beats per minute. Several well-designed studies including the BEAUTIFUL and the SHIFT trials demonstrated clear benefits of ivabradine in symptomatic patients, both with angina and with heart failure, with left ventricular systolic dysfunction. The main objective of this review is to provide a comprehensive summary of data on ivabradine, and to discuss the potential role of this new agent in the spectrum of modern therapeutics for heart failure.     

Beneficial effect of ivabradine in dilated cardiomyopathy from Becker muscular dystrophy

Objectives

The I(f) blocker ivabradine reduces heart rate and improves systolic function without causing arterial hypotension. Ivabradine has not been reported to improve cardiac involvement in Becker muscular dystrophy (BMD).

Case report

In a 22-year-old Vietnamese male with BMD, cardiac involvement became apparent at age 19?years with reduced systolic function, which was treated with ramipril. At the age of 20?years, he developed sinus tachycardia, leg edema, coughing, and arterial hypotension. Dilated cardiomyopathy was diagnosed and ramipril was successfully replaced by candesartan, ivabradine, and furosemide. An attempt to discontinue ivabradine and increase candesartan was followed by recurrence of sinus tachycardia and reduction of blood pressure. Under ivabradine, candesartan, and spironolactone, which replaced furosemide, he achieved heart rates between 60 and 80?beats/min and systolic blood pressure values between 85 and 105?mmHg without heart failure.

Conclusion

Ivabradine normalizes sinus tachycardia and resolves heart failure in patients with dilated cardiomyopathy from BMD. In addition to normalization of the heart rate and remodeling of the left ventricle, ivabradine seems to also have a positive inotropic effect in dilated cardiomyopathy of BMD patients.     

伊伐布雷定在心血管疾病应用中的研究进展

伊伐布雷定是目前唯一的特异性If电流通道阻滞剂,通过抑制窦房结P细胞动作电位4期If电流而达到减慢心率的作用.伊伐布雷定在减慢心率的同时不影响左心室收缩功能;治疗剂量范围内不影响PR间期、QRS间期及QTc;也不影响支气管平滑肌、糖脂代谢、血压.多项研究表明伊伐布雷定能明确改善冠心病、慢性心力衰竭等心血管疾病患者的临床症状及预后,且对窦性心动过速亦有疗效.     

A Case of Atrial Tachycardia Treated with Ivabradine as Bridge to Ablation

Ivabradine is indicated in cardiac failure and ischemia to reduce sinus rate by inhibition of the pacemaker I(f) current in sinoatrial node. We report a case of an 18‐year‐old woman with left atrial tachyarrhythmia resistant to several antiarrhythmic drugs and to electric cardioversion who responded only to ivabradine, which significantly reduced heart rate without abolishing the arrhythmia itself. An ectopic focus in the ostium of left pulmonary veins was found and the patient was successfully ablated. We suggest that ivabradine might be therefore useful in the treatment of supraventricular tachyarrhythmias due to an enhanced automaticity.     

Effect of ivabradine on left ventricular diastolic function of patients with heart failure with preserved ejection fraction -IVA-PEF study-

BackgroundHigh resting heart rate (HR) is a known marker of cardiovascular outcomes for heart failure (HF) patients. Ivabradine is a new class of HR lowering drug and a specific inhibitor of the I_f current in the sinoatrial node. Ivabradine substantially and significantly reduces major risks associated with HF when added to guideline-based treatment for left ventricular (LV) ejection fraction ≤35% and HR ≥70 bpm in sinus rhythm. On the other hand, HF with preserved ejection fraction (HFpEF) currently accounts for roughly half of all HF cases and usually presents as LV diastolic dysfunction. However, the association between HR reduction and LV diastolic function for HFpEF patients remains uncertain.Methods/designThis investigation into the effect of IVAbradine on left ventricular diastolic function of patients with heart failure with Preserved Ejection Fraction (IVA-PEF) is a multicenter, prospective, uncontrolled, open-label, single assignment, and an interventional single-arm study to investigate the effect of ivabradine on LV diastolic function of HFpEF patients. The key inclusion criterion is HFpEF with resting HR ≥75bpm in sinus rhythm. After completed informed consent forms are obtained, patients will be given 5 mg/day of ivabradine during the study. LV diastolic function is assessed in terms of mitral inflow E and mitral e’ annular velocities (E/e’). The primary endpoint will be defined as a change in E/e′ between baseline and 3 months after the start of administration of ivabradine.ConclusionThe findings of our trial may provide a new perspective on ivabradine for the treatment of HFpEF.     

Potential New Indication for Ivabradine: Treatment of a Patient with Congenital Junctional Ectopic Tachycardia

Ivabradine is a new antiarrhythmic agent with direct inhibition of the pacemaker (If) current. It has been used extensively to decrease sinus rate in the treatment of cardiac failure, and also in a single case of atrial ectopic tachycardia in a child. Here we report the case of a 3‐year‐old girl with congenital junctional ectopic tachycardia (JET), resistant to conventional antiarrhythmic medications, who was successfully treated with ivabradine. We suggest that ivabradine can be an effective treatment for junctional automatic tachycardias and can be considered as a new line of therapy for this incessant form of tachycardia.     

Antianginal Efficacy of Ivabradine/Metoprolol Combination in Patients With Stable Angina

Medical treatment is the main clinical strategy for controlling patients with chronic stable angina and improving their quality of life (QoL). Ivabradine treatment on top of metoprolol decreases angina symptoms and improves QoL in patients with stable angina and coronary artery disease (CAD). This is a post hoc analysis (636 CAD patients given ivabradine/metoprolol free combination) of a prospective, noninterventional study that included 2403 patients with CAD and stable angina. Data were recorded at baseline at 1 and 4 months after inclusion. Patient QoL was assessed using the EQ‐5D questionnaire. From baseline to study completion; ivabradine administration on top of metoprolol decreased heart rate (HR) from 80.8 ± 9.6 to 64.2 ± 6.2 bpm (P < 0.001). Mean number of angina attacks decreased from 2.0 ± 2.0/wk to 0.2 ± 0.6/wk (P < 0.001), whereas nitroglycerin consumption decreased from 1.4 ± 1.9 times/wk to 0.1 ± 0.4 times/wk (P < 0.001). The percentage of patients in Canadian Cardiovascular Society angina class III to IV decreased from 15.4% to 1.9% (P < 0.001). The improvement of symptoms and angina class led to a significant 14.7‐point increase in EQ‐5D questionnaire score (P < 0.001). Patients with increased HR showed greater improvement (P = 0.001). Adherence to treatment during the entire trial was high (98%). Ivabradine combined with metoprolol significantly decreased angina symptoms and use of nitroglycerin in patients with stable angina and CAD, leading to improved QoL. The benefits observed with this combination explain the high rate of adherence to treatment.     

Ivabradine in the treatment of non-paroxysmal junctional tachycardia with interference atrioventricular dissociation: A case report

Ivabradine reduces the heart rate by selectively inhibiting the I_f current of the sinoatrial node, mainly for the treatment of chronic heart failure with decreased left ventricular systolic function and inappropriate sinus tachycardia, but the inhibitory effect on the atrioventricular node is rarely reported. The patient was admitted to hospital mainly because of intermittent chest pain for 7 years, which worsened for 10 days. Admission electrocardiogram (ECG) considered sinus tachycardia, with QS wave and T wave inversion in II, III, aVF, V₃R-V₅R, V₄–V₉ leads, and non-paroxysmal junctional tachycardia (NPJT) with interference atrioventricular dissociation. After treatment with ivabradine the ECG returned to normal conduction sequence. NPJT with interference atrioventricular dissociation is a fairly rare electrocardiographic phenomenon. This case reports for the first time that ivabradine is used in the treatment of NPJT with interference atrioventricular dissociation. It is speculated that ivabradine has a potential inhibitory effect on the atrioventricular node.     

Differential effects of ivabradine and ryanodine on pacemaker activity in canine sinus node and purkinje fibers

Effects of Ivabradine and Ryanodine on Cardiac Pacemakers . Introduction: It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly I_f) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca²⁺ release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity. Methods and Results: Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1–3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca²⁺ release or I_f, respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl₂. In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol‐accelerated automaticity. In PF depolarized with BaCl₂, ivabradine decreased BaCl₂‐induced automatic rate while ryanodine had no effect. Conclusion: In canine SN, I_f contributes to both basal automaticity and β‐adrenergic‐induced rate acceleration while the ryanodine‐inhibited Ca clock appears more involved in β‐adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on I_f. Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN‐like responses to inhibition of membrane and Ca clocks. (J Cardiovasc Electrophysiol, Vol. 23, pp. 650–655, June 2012)     

Effect of ivabradine vs atenolol on heart rate and effort tolerance in patients with mild to moderate mitral stenosis and normal sinus rhythm

BackgroundPatients with mitral stenosis become symptomatic at a higher heart rate. We studied the comparative efficacy of heart rate control with ivabradine or atenolol and its effect on effort tolerance in patients with mild-moderate mitral stenosis in normal sinus rhythm.Methods and ResultsFifty patients with mild-moderate mitral stenosis in sinus rhythm were randomized to receive ivabradine or atenolol for 4 weeks each in an open-label, randomized, crossover design trial. A 24-hour Holter and treadmill test was performed at baseline and after each active treatment period. In the first treatment period, 23 patients were allocated to ivabradine (22 analyzed), and 27 were allocated to atenolol (26 analyzed). In the second period, all 48 patients were analyzed. Ivabradine increased the mean total exercise time to 500.7 seconds (SD 99.7) from a baseline of 410.3 seconds (SD 115.4), and atenolol increased it to 463.7 seconds (SD 113.1). The point estimate (absolute difference between ivabradine and atenolol) was 35.27 seconds (95% CI 15.24–55.20; P = .0009). The point estimate for decrease in the maximum exercise heart rate and mean heart rate were 7.64/min (95% CI 0.37–15.9; P = .04) and 5.61/min (95% CI 2.51–8.71; P = .0007), respectively.ConclusionsIvabradine is more effective than atenolol for effort related symptoms in patients with mild-moderate mitral stenosis and normal sinus rhythm.     

Ivabradine--the first selective and specific I(f) inhibitor, novel preparation for treatment of stable angina

Results of large epidemiological studies allowed to establish that heart rate (HR) is an independent risk factor, elevating rates of total, cardiovascular and sudden mortality. Ivabradine bounds specifically with f channels of sinus node cells providing HR lowering. In experiments with the use of the method of registration of transmembrane currents in cells of sinoatrial node it was revealed that Ivabradine blocks f-channels in a dose-dependent manner. Due to specific action on sinus node and selective suppression of I(f)-currents ivabradine causes dose dependent decrease of HR both at rest and maximal physical exercise without changes of mean blood pressure. It was shown in 3 large clinical studies that Ivabradine together with favorable tolerability profile possesses pronounced antianginal and anti-ischemic efficacy which is at least the same as efficacy of currently available drugs for the treatment of angina beta-adrenoblockers and calcium antagonists. Firstly this confirms clinical significance of concept of specific and selective inhibition of I(f) ionic current in the treatment of patients with ischemic heart disease and stable angina. Secondly this allows to consider the preparation as alternative to available antianginal drugs in case of the presence of contraindications to them or development of side effects at the background of standard therapy.     

High‐Density Mapping of the Sinus Node in Humans: Role of Preferential Pathways and the Effect of Remodeling

Sinus Node Mapping . Introduction: The area of the functional sinus node complex exceeds that of the anatomical sinus node; however, reasons for this discrepancy are unknown. We aimed to characterize the functional sinus node complex in health and disease with high‐density simultaneous mapping. Methods and Results: Sinus node activity was characterized in 15 reference patients after ablation for supraventricular tachycardia. A further 16 patients were studied following ablation of chronic atrial flutter to determine effects of atrial remodeling. High‐density simultaneous mapping of the sinus node complex was performed using a multi‐electrode array. In reference patients, distance from superior vena cava‐right atrial (SVC‐RA) junction to earliest activation (EA) was 4 ± 4 mm and sinus break‐out (SBO) 9 ± 6 mm. Preferential pathways of conduction were observed between EA and SBO. For patients with flutter, these distances were greater (EA: 15 ± 12 mm, P = 0.003; SBO: 23 ± 11 mm, P < 0.001). Conduction time along preferential pathways was 15 ± 5 ms for reference patients and 23 ± 8 ms for patients with flutter (P = 0.005). Following pacing, distance from SVC–RA junction to EA and SBO lengthened to 13 ± 8 mm (P = 0.006) and 16 ± 10 mm (P = 0.02), respectively, in reference patients, and 19 ± 12 mm (P = 0.045), 28 ± 9 mm (P = 0.02) in patients with flutter. This resulted in caudal shifts in EA and SBO of 10 ± 9 mm and 7 ± 8 mm in reference patients but diminished shifts in patients with flutter; 4 ± 7 mm and 4 ± 6 mm. Conclusion: The functional sinus node complex demonstrates dynamic changes in activation. There are preferential pathways of conduction from sinus node to atrial myocardium. The remodeled atria demonstrate longer conduction times along preferential pathways and a restricted functional sinus node complex. (J Cardiovasc Electrophysiol, Vol. 21, pp. 532‐539, May 2010)     

A phase 3 trial of mometasone furoate sinus implants for chronic sinusitis with recurrent nasal polyps

Background

Topical intranasal corticosteroid sprays (INCSs) are standard treatment for nasal polyps (NPs), but their efficacy is reduced by poor patient compliance and impaired access of drug to the sinus mucosa. A corticosteroid‐eluting sinus implant was designed to address these limitations in patients with recurrent polyposis after sinus surgery by delivering 1350 μg of mometasone furoate (MF) directly to the ethmoid sinus mucosa over approximately 90 days.

Methods

A randomized, sham‐controlled, double‐blind trial was undertaken in 300 adults with refractory chronic rhinosinusitis with NPs (CRSwNP), who were candidates for repeat surgery. Eligible patients were randomized (2:1) and underwent in‐office bilateral placement of 2 implants or a sham procedure. All patients used the MF INCS 200 μg once daily. Co‐primary efficacy endpoints were the change from baseline in nasal obstruction/congestion score and bilateral polyp grade, as determined by an independent panel based on centralized, blinded videoendoscopy review.

Results

Patients treated with implants experienced significant reductions in both nasal obstruction/congestion score (p = 0.0074) and bilateral polyp grade (p = 0.0073) compared to controls. At day 90, implants were also associated with significant reductions in 4 of 5 prespecified secondary endpoints compared to control: proportion of patients still indicated for repeat sinus surgery (p = 0.0004), percent ethmoid sinus obstruction (p = 0.0007), nasal obstruction/congestion (p = 0.0248), and decreased sense of smell (p = 0.0470), but not facial pain/pressure (p = 0.9130). One patient experienced an implant‐related serious adverse event (epistaxis).

Conclusion

Significant improvements over a range of subjective and objective endpoints, including a reduction in the need for sinus surgery by 61%, suggest that MF sinus implants may play an important role in management of recurrent NP.     

Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: Meta‐analysis of randomized controlled trials

Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta‐analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical Trials.gov, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta‐blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction (MD = −9.57; 95% CI ‐11.15, −8.00), improved LVEF (MD = 3.89; 95% CI 2.61, 5.17), left ventricular reverse remodeling improvement (MD = −3.73; 95% CI ‐4.25, −3.21, LVESV; MD = −17.00, 95%CI ‐29.65, −4.35, LVEDD; MD = −1.43, 95%CI ‐2.78, −0.08, LVEDV; MD = −14.75, 95%CI ‐34.36, 4.87), increased exercise capacity (exercise duration; MD = 8.52; 95%CI 0.09, 16.94), and significant reduction on rehospitalization due to worsening HF (RR = 0.76, 95%CI 0.69, 0.84). However, Ivabradine has no significant effect on the quality of life (MD = 0.65; 95%CI ‐10.52, 11.82), and cardiovascular mortality (RR = 0.92; 95%CI 0.82, 1.03). Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group (RR = 4.76; 95%CI 3.03, 7.48; RR = 3.78; 95%CI 2.77, 5.15, respectively). Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.     

Exaggerated carotid sinus massage responses are related to severe coronary artery disease in patients being evaluated for chest pain

Background: Previous studies have reported that carotid sinus massage responses are associated with advancing age and carotid or coronary artery disease. Hypothesis: This study was undertaken to investigate the potential role of carotid sinus hypersensitivity as a marker for the presence of coronary artery disease, and especially left main stem disease, in patients who were referred for evaluation of chest pain. Methods: Toward this end, carotid sinus stimulation with simultaneous recordings of the electrocardiogram and aortic pressure was performed before coronary arteriography in 150 selected consecutive patients (mean age 59.4 ± 9 years) who were referred for evaluation of chest pain. Results: Coronary artery disease was present in 118 patients (78.7%); of these, 35 had single‐vessel disease, 35 had double‐vessel disease, 33 had triple‐vessel disease, and 15 had left main stem with or without such vessel disease. Carotid sinus hypersensitivity was found in 40 patients (26.6%). The incidence of hypersensitivity in patients with single‐, double‐, or triple‐vessel disease and left main stem disease was 8.5, 14.2, 57.5, and 73.3%, respectively. Stepwise multiple logistic regression analysis revealed that left main stem disease was significantly and independently related to the presence of carotid sinus hypersensitivity (p < 0.05). In addition, the presence of hypersensitivity had 73.3% sensitivity, 86.2% specificity, and 96.3% negative predictive value for the presence of left main stem disease. Conclusion: In patients being evaluated for suspected ischemic heart disease, carotid sinus massage responses are related to severe coronary disease. The absence of hypersensitivity may reflect absence of left main stem disease.