Treatment of Postural Orthostatic Tachycardia Syndrome and Inappropriate Sinus Tachycardia

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1 Treatment of Postural Orthostatic Tachycardia Syndrome and Inappropriate Sinus Tachycardia M. Yousuf Kanjwal, MD*, Daniel J. Kosinski, MD, and Blair P. Grubb, MD Address *Medical College of Ohio, Room 1192 (O), 3000 Arlington Avenue, Toledo, OH , USA. Current Cardiology Reports 2003, 5: Current Science Inc. ISSN Copyright 2003 by Current Science Inc. Postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia are two clinically different entities but with significant overlap of symptoms. Treatment by and large is medical; however, other modalities of treatment are being evaluated. Introduction Postural orthostatic tachycardia syndrome (POTS) is defined as a complex syndrome with clinical manifestations of orthostatic intolerance with symptoms of lightheadedness, fatigue, signs of edema, and acrocyanosis associated with orthostatic tachycardia within 10 minutes of upright posture and without significant orthostatic hypotension [1]. The increase in heart rate has to be either 30 beats/min or a rate that exceeds 120 beats/min. According to one estimate, at least half a million people in the United States suffer from POTS or some form of dysautonomia [2 ]. The conditions that must be excluded before diagnosing POTS are those leading to a state of deconditioning such as chronic debilitating disorders, prolonged bed rest, or medications that impair autonomic reflexes. Most investigators believe that POTS may represent the earliest and most easily measured finding of orthostatic intolerance [3 ]. The majority of patients may have only a modest decline of blood pressure, no decline at all, or even an increase in blood pressure when they assume an upright posture [4]. On the other hand, inappropriate sinus tachycardia is an ill-defined clinical syndrome with a relative or absolute increase of heart rate at rest, or an exaggerated heart rate response inappropriate to the degree of physical or emotional stress [5,6]. This inappropriate heart rate has to be in the absence of any cardiovascular or systemic disease. Postural Orthostatic Tachycardia Syndrome Postural orthostatic tachycardia syndrome is often manifested by a state of orthostatic intolerance, which is defined as provocation of symptoms upon standing, such as exercise intolerance, extreme fatigue, lightheadedness, lack of concentration, tremors, nausea, headache, near syncope, and occasionally syncope. These symptoms obviate upon assuming a supine posture; patients at times are mislabeled as having anxiety or panic disorder. Postural orthostatic tachycardia syndrome has been categorized into a primary form for which no cause has been found, and a secondary form, which is usually associated with a particular disease [4]. The primary form of POTS is further categorized into a partial dysautonomic form, which comprises 90% of cases, and a hyperadrenergic form, which comprises the remaining 10%. In the partial dysautonomic form there is a failure of the peripheral vasculature to increase resistance adequately in the face of orthostatic stress, producing a compensatory tachycardia. The partial dysautonomic form may have an underlying immune problem in some individuals; these patients seem to have a form of peripheral neuropathy. Some investigators have found serum autoantibodies to α acetylcholine receptors of the peripheral autonomic ganglia in some patients with this form of POTS [7]. Catecholamine levels in the upright position in these patients are normal. The hyperadrenergic form, on the other hand, has unique features, such as high levels of catecholamine on upright tilt [8], and exaggerated response to low-dose isoproterenol. Many patients may display orthostatic hypertension; some believe there may be a specific genetic abnormality [9 ]. Secondary POTS is associated with underlying disease, the most common being diabetes mellitus. Other conditions include amyloidosis, alcoholism, chemotherapy, heavy metal poisoning, Sjogren s syndrome, lupus, and type III Ehlers- Danlos syndrome [10 12]. It may be an initial presentation of pure autonomic failure or multiple system atrophy [13]. POTS may also be seen as a manifestation of paraneoplastic syndrome [14]. There may be cardiac autonomic denervation with preserved cardiac innervation [15 ]. There are few data available regarding the prognosis of POTS. Some studies have shown better prognosis in POTS associated with preceding viral syndrome; younger patients may fare better.

2 Postural Orthostatic Tachycardia Syndrome Kanjwal et al. 403 The diagnostic evaluation of POTS should begin with patient history and physical examination. Other conditions that produce orthostatic intolerance should be excluded. In addition, some patients take medications that are known to either cause or exacerbate symptoms. The most common condition that needs to be differentiated from POTS is inappropriate sinus tachycardia. There is such an overlap of symptoms between the two conditions that some people think they might represent different points on the spectrum of the same disease process [16]. The major difference between the two conditions is that patients with POTS seem to display a greater degree of postural change in heart rate, and resting heart rate rarely exceeds 100 beats/min, as opposed to inappropriate sinus tachycardia, in which resting heart rates over 100 beats/min are more common. Symptoms of inappropriate sinus tachycardia range from intermittent palpitations to multisystem complaints [5,17]. It is an uncommon form of arrhythmia with a preponderance in women, and an association with healthcare professions is well recognized. The underlying mechanism is not well understood; however, it has been postulated that enhanced intrinsic automaticity, enhanced sympathetic tone, increased sympathetic receptor sensitivity, and blunted parasympathetic tone may play a role in the pathogenesis. Some have suggested sympathovagal imbalance as the cause [6]. Other conditions that need to be differentiated from both these conditions is somatization disorders, deconditioning, and autonomic causes of true orthostatic hypotension. Symptoms of POTS should also be differentiated from other forms of autonomic orthostatic hypotension. Patients with the latter condition have evidence of a state of generalized autonomic failure involving the cardiovagal, sudomotor, urinary, adrenergic, and gastrointestinal systems. Currently work is underway to better define the relationship between POTS and chronic fatigue syndrome (CFS) [18]. It has been shown that orthostatic tachycardia in CFS is qualitatively and quantitatively indistinguishable from orthostatic tachycardia associated with POTS. Heart rate variability has been found to be decreased in patients with CFS and POTS [3,19]. Patients undergoing radiofrequency ablation may have symptomatic inappropriate sinus tachycardia in the postablation period [20]. The exact etiology of this condition is not known; however, it is thought to be due to some disregulation of the autonomic system. Management Treatment of patients with both POTS and inappropriate sinus tachycardia can be challenging. Secondary causes such as prolonged immobilization and diabetes mellitus need to be excluded and addressed. Many medications can cause or exacerbate the symptoms mimicking POTS; potential illicit drug use must also be considered. A detailed conversation with the patient and family should be held to discuss the possible causes and management of this condition, which at times can be quite challenging. Often patients and their families are frustrated and distraught, and have little understanding of the nature of their illness or what to expect from it. It is important for the physician to establish reasonable goals for treatment, and provide goals and expected outcomes. Compliance may be an important issue, as most of the patients are young and of reproductive age. The importance of nonpharmacologic maneuvers cannot be ignored. This includes avoiding dehydration, extreme heat, and alcohol consumption. Patients should increase their fluid and salt intake, and should consume at least 2 to 2.5 L/d of fluid and 150 to 250 meq/d of sodium. We also encourage patients to sleep with their head elevated to 45 (this can be easily accomplished by placing a brick under each bedpost at the head of the bed). This strategy conditions them to orthostatic stress. We also encourage younger patients to keep salt crackers or pretzels handy in the car, along with water, when driving long distances. We encourage patients to participate in aerobic exercises. This can initially be achieved by slowly working out for 20 minutes at least three times per week [21 ]. Some patients who are deconditioned find swimming a good exercise in the beginning. Resistance training of the lower extremities is also advised; elastic support hose with 30 mm Hg pressure may also be helpful. We strongly advise patients to try to undergo tilt training; this can be done by standing for a variable amount of time at home and gradually increasing the time of standing. In the medical management of patients with POTS one has to consider that one drug may work for one patient and not for another, and sometimes many drugs may not work for one patient. One cannot predict a patient s response; hence, it is important to keep trying different medications. This can be frustrating for the patient and challenging for the treating physician. In addition, most of these medications are being used off-label, as they are not approved by the US Food and Drug Administration for this purpose. Some of these medications, along with their dosages and relevant side effects, are listed in Table 1. The management of patients is somewhat different in each form of POTS. In the partial dysautonomic form fludrocortisone, a mineralocorticoid can be used. It acts on the distal tubule causing reabsorption of sodium in exchange of potassium and hydrogen. This leads to retention of water, thereby expanding volume, but at times at the cost of hypokalemia. Potassium levels should be checked within 1 week to 10 days after administration and appropriately managed. This drug not only expands volume, but also appears to sensitize peripheral α adrenergic receptors to the patient s own catecholamine [13]. We recommend 0.1 mg orally per day to start, not to

3 404 Antiarrhythmic Drugs Table 1. Treatment options Therapy Method or dose Common problems Head-up tilt of bed 45 head-up tilt of bed (often requires footboard) Hypotension, sliding off bed, leg cramps Elastic support hose Requires at least mm Hg ankle counterpressure, works best if waist high Uncomfortable, hot, difficult to get on Diet Fluid intake of L/d Na+ intake of meq/d Supine hypertension, peripheral edema Exercise Aerobic exercise (mild) may aid venous return; water exercise is particularly helpful May lower blood pressure if done too vigorously Fludrocortisone Begin at mg/d; may work up to doses not exceeding 1.0 mg/d Hypokalemia, hypomagnesemia, peripheral edema, weight gain, congestive heart failure Methylphenidate 5 10 mg po tid given with meals; give last dose before 6 pm Agitation, tremor, insomnia, supine hypertension Midodrine mg every 2 4 hours; may use up to 40 mg/d Nausea, supine hypertension Clonidine mg po bid or patches placed once per week Dry mouth, bradycardia, hypotension Yohimbine 8 mg po bid to tid Diarrhea, anxiety, nervousness Ephedrine sulfate mg po tid Tachycardia, tremor, supine hypertension Fluoxetine mg po qd (requires 4 6 weeks of therapy) Nausea, anorexia, diarrhea Venlafaxine 75 mg extended release form po qd or bid Nausea, anorexia, hypertension Erythropoietin 8000 IU sq once per week Requires injections, burning at site, increased hematocrit, CVA Pindolol mg po bid to tid Hypotension, congestive heart failure, bradycardia Desmopressin An analog of vasopressin used as a nasal spray or pill Hyponatremia at 0.2 mg po qhs Octreotide 25 µg sq bid; may titrate to µg tid Nausea, abdominal pain, muscle cramps, hypertension bid twice daily; CVA cerebrovascular accident; po by mouth; qd every day; qhs every hour of sleep; sq subcutaneous; tid three times daily. (Adapted from Grubb et al. [3 ].) exceed 0.4 mg/d. Vasopressin, another volume-expanding agent, in a dose of 0.1 to 0.2 mg, can be given at bed time. This agent also prevents nocturnal polyuria [22]. Side effects include hyponatremia and headaches. Failure of vascular resistance to increase is an important factor in POTS, and theoretically peripheral vasoconstrictors would be helpful. Midodrine, a peripheral α-1 receptor agonist, is also helpful not only in orthostasis but also in tachycardia [23]. It is a prodrug and gets metabolized to an active form, desglymidodrine, which causes actual vasoconstriction. It is absorbed rapidly; peak action occurs within 20 to 40 minutes, and its half-life is 30 minutes. The usual dose is 2.5 to 10 mg three to four times daily. Many studies have shown it to be useful in orthostatic hypotension. The side effects include nausea and cutis anserine (skin goosebumps and tingling in the scalp); another important side effect is supine hypertension. Methylphenidate is another α-blocker that can be used as an alternative to midodrine. The advantage of this drug is its long half-life [24]. Side effects vary from headache and insomnia to dependence. Central α-2 stimulation inhibits sympathetic activity [25]. Any antagonist to these receptors would increase sympathetic outflow. Yohimbine is one such agent that is an α-2 receptor antagonist. By increasing the sympathetic outflow it causes increase in plasma epinephrine levels and blood pressure. Yohimbine is given in a dose of 8 to 10 mg orally two to three times per day. Nervousness, anxiety, and diarrhea are common side effects. Erythropoietin, a polypeptide that is mainly produced by the kidney, has been shown to be beneficial [26,27]. It not only increases erythrocyte mass, but also has a peripheral vasoconstrictive effect. The limitation of this therapy is that it is expensive, has to be given subcutaneously every week, and requires hematocrit monitoring. Hematocrit levels should not be allowed to rise more than 50%. We do involve the services of a hematologist in the management of these patients. We usually recommend 8000 IU subcutaneously once per week. This may produce local irritation. Another extreme side effect is cerebrovascular accident. Postviral POTS patients have autoantibodies to acetylcholine receptors, and this concept has prompted investigators to evaluate pyridostigmine, an acetylcholinesterase inhibitor, as a potential therapy. Patients with the hyperadrenergic form of POTS have high catecholamine levels; therefore, β-blockers are useful agents. It has been shown that this class of drugs may actually worsen the partial dysautonomic form. Labetalol has both α- and β-blocker action, and has been shown to be effective. Central sympatholytic agents such as clonidine and α methyl dopa are helpful in certain groups of patients. Clonidine has been extensively used and is also very effective in this group of patients [28]; the patch form is more effective for compliance reasons. Clonidine stabilizes both heart rate and blood pressure. The dose can be titrated, and at certain occasions we have used oral clonidine in addition to the patch. There

4 Postural Orthostatic Tachycardia Syndrome Kanjwal et al. 405 is some limited experience with α methyl dopa and phenobarbital [4,10]. Several studies have shown a disturbance of central serotonin production and regulation in patients with POTS and other syndromes of autonomic dysfunction [29]. The selective serotonin reuptake inhibitors (SSRIs) have a role in the treatment of select patients of POTS. We have found venlafaxine to be more effective than other SSRIs; however, any other agent in this class may be effective. This could perhaps be due to its effect on both norepinephrine as well as serotonin. The usual dose is 75 mg extended release orally once or twice daily. The side effects include nausea, anorexia, and hypertension. Patients with POTS may respond to a combination of therapies, and some investigators have shown that lowdose combination therapy may be more effective and well tolerated than high-dose monotherapy. Physicians treating these patients should be well aware that they can have other associated disorders of autonomic system aside from the problems of dysautonomia and heart rate. These include disorders of thermoregulation, bowel and bladder control, and sexual function. This may require involvement of other specialties in the care of these patients. Some of these patients may worsen over years, and the post-viral group may show improvement over the subsequent 2 to 5 years. Some of the aspects of these disorders may not be voluntarily presented by the patient, including psychologic, marital, occupational, legal, and financial problems. The importance of these problems cannot be underscored and must be addressed appropriately. Inappropriate Sinus Tachycardia Inappropriate sinus tachycardia, also called nonparoxysmal tachycardia or permanent sinus tachycardia, is basically an atria tachycardia with a P-wave morphology similar to sinus rhythm. The diagnostic criteria are 1) heart rate over 100 beats/min at rest and with minimal exertion associated with symptoms; 2) P-wave morphology similar to sinus rhythm or positive in leads I, II, and av f ; 3) exclusion of physiologic sinus tachycardia; and 4) exclusion of atrial tachycardia or sinus node reentry [30]. The potential mechanism described could be some form of autonomic dysfunction, abnormal automaticity of the sinus node or atrial tachycardia coming from the sinus node region. Some authors have concluded that there is an abnormal autonomic control of the sinus node, and others have found a decrease in heart rate variability. Low et al. [1] found ultrastructural abnormality of sinus node in three patients with inappropriate sinus tachycardia. Morillo et al. [6] found abnormally elevated intrinsic sinus rates after autonomic blockade with propranolol and atropine. Others have shown increased response to catecholamines. Inappropriate sinus tachycardia can occur the first time a patient undergoes atrioventricular node modification [21 ]. It has been reported in 10% of cases. Most of the time it is self limiting; occasionally medical or ablative therapy is needed, and there may be some form of sympathovagal imbalance. There is a significant overlap between the symptoms of POTS and inappropriate sinus tachycardia, and as such can be debilitating. The diagnosis is usually one of exclusion. Most of the patients have a normal heart; however, there is some association with mitral valve prolapse. Electrocardiogram and Holter monitoring may help in diagnosis and symptom correlation. Electrophysiologic study may be needed to rule out sinus node reentry or atrial tachycardia. Treatment is initially pharmacologic, but is usually ineffective. No randomized trials are available. Pharmacologic treatment is initially with β-blockers. The efficacy and response can be judged by response to exercise or to isoproterenol infusion. Calcium channel blockers may be an alternative and effective in a subgroup of patients with inappropriate tachycardia and a normal response to isoproterenol. Propafenone and amiodarone have also been used in select patients, but with significant side effects with the latter drug. Some of the nonpharmacologic treatment modalities have emerged in recent years for patients refractory to medical therapy, including surgical excision of the sinus node [31], selective occlusion of the sinus node artery [32], and radiofrequency ablation. Selective modification of the sinus node is possible. Although acute success can be achieved, there is high recurrence of symptoms. Complete ablation of sinoatrial node with junctional rhythm and pacemaker implantation may have better long-term success. There is a considerable symptom overlap between inappropriate sinus tachycardia and POTS. Shen et al. [2 ] took a group of patients who had inappropriate sinus tachycardia with features of POTS and performed sinus node modification. Seven patients underwent radiofrequency modification. All patients were refractory to medical therapy. There was a significant reduction in the heart rate in five (71%) of seven patients; however, the long-term clinical response was disappointing. Symptoms of palpitations, orthostatic intolerance, and other complaints persisted. Therefore, the authors cautioned about selecting patients for radiofrequency modification of the sinus node. The symptoms of orthostasis may persist even after complete ablation of the sinoatrial node or even atrioventricular node ablation. Patients who even received DDD pacing continued to have extracardiac symptoms. Lee et al. [20] reported successful radiofrequency modification of the sinus node in 12 of 16 patients with inappropriate sinus tachycardia; however, sustained improvement was only obtained in 36% of patients during a mean follow-up period of 8 ± 5 months. Shen et al. [2 ] concluded that radiofrequency ablation is not recommended in patients with inappropriate sinus tachycardia associated with features of POTS and the precise role of sinus node modification in patients of inappropriate sinus

5 406 Antiarrhythmic Drugs tachycardia in absence of autonomic dysfunction remains to be determined. Conclusions Postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia have symptoms and signs that overlap, and sometimes are associated with each other. Secondary causes need to be excluded. Initial management with nonpharmacologic maneuvers may alleviate symptoms; however, most of the patients need some kind of medical therapy. Radiofrequency modification of sinus node has not been successful in the long-term management of these patients. A multipronged strategy needs to be applied, and it is imperative for both patient and the treating physician to be patient and hopeful. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Low PA, Opfer-Gehrking TL, Textor SC, et al.: Postural tachycardia syndrome (POTS). Neurology 1995, 45(Suppl 5):S19 S Shen WK, Low PA, Jahangir A, et al.: Is sinus node modification appropriate for inappropriate sinus tachycardia with features of postural orthostatic tachycardia syndrome? PACE 2001, 242: This reference describes that clinical symptoms are not significantly improved after sinus node modification in patients with inappropriate sinus tachycardia and postural orthostatic tachycardia. Mean heart rate during 24-hour Holter monitoring reduced significantly, despite no change in the autonomic symptom score. 3. Grubb BP, Kosinski DJ, Kanjwal MY: Orthostatic hypotension: causes, classification and treatment. PACE 2003, 26: A detailed description of various causes of pathophysiology, and up to date management of orthostatic hypotension. 4. Jacob G, Biaggioni I: Idiopathic orthostatic intolerance and postural tachycardia syndromes. Am J Med Sci 1999, 317: Krahn AD, Yee R, Klein GJ, et al.: Inappropriate sinus tachycardia: evaluation and therapy. J Cardiovasc Electrophysiol 1995, 6: Morillo CA, Klein GJ, Thakur RK, et al.: Mechanism of inappropriate sinus tachycardia. Role of sympathovagal balance. Circulation 1994, 90: Schondorf R, Low P: Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993, 43: Polinsky RJ, Kopin EJ, Ebert MH, et al.: Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981, 31: Shannon JR, Flatten NL, Jordan J, et al.: Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 2000, 342: Excellent article testing the hypothesis that impaired functioning of norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. The authors conclude that genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance. 10. 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