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Persisting alternation in mechanical response of the ventricle, pulsus alternans, develops when the heart is driven above certain rates. This critical rate varies, but tends to occur between rates of 200 and 300 beats/min. The ventricle can be driven slightly faster (10–20 beats/min) by direct than by indirect drive, through atrial electrodes, without showing pulsus alternans. There is a rate "threshold" for persisting alternation which represents the rate limits of compensation. Alternation appears at lower rates but the contractile process can gradually accelerate and alternation disappears even in denervated hearts and after adrenalectomy. Slower progressive accelerations delay onset of pulsus alternans and compensation occurs more quickly than when stepwise rate changes are made. Fast drives above the threshold for pulsus alternans can produce some additional acceleration of the contraction-relaxation process: if the rate is reduced to a level which previously produced a persisting alternation, pulsus alternans does not occur for a number of seconds. The resemblances of these phenomena to "treppe" and "postextrasystolic potentiation" and implications relative to catecholamine release and action are discussed.

To the Editor: —Dr. Harold E. B. Pardee (The Prognosis of Auricular Fibrillation,The Journal, June 19, 1915, p. 2057) uses the following phrase in his concluding sentence: "the irregularity, per se, adds little or nothing to the gravity of the prognosis." According to Lewis, the irregularity of the pulse of auricular fibrillation is the most common of the seven different varieties of arrhythmic pulse, and, of course, one of the gravest. That the irregularity, per se, has nothing to do with the prognosis is well exemplified in the following case: A man, aged 58, has had this type of irregular pulse since he was 33. He has no valve lesion, dilatation or other muscle disease or weakness; he has had no dyspnea or decompensation. There is no history of infectious disease, such as rheumatism, which might damage the conductivity and integrity of his heart muscle. Three times he was

Pulsus alternans involving the right side of the heart was studied in 5 patients. Four of 5 patients had mitral stenosis with severe pulmonary hypertension and the other had postpartum myocardial disease with clinical signs indicating both left and right heart failure. It was concluded that pulsus alternans in the pulmonary circulation was elicited in close connection with severe right ventricular strain or failure.Premature beat of ventricular origin was one of the most important trigger mechanism initiating pulsus alternans. Contrary to the previous opinion in the literature pulsus alternans following premature beats could persist for a rather long time, at least in the presence of pulmonary hyperten-sion. Pulsus alternans was induced in a patient by exercise as the pulmonary hypertension was exaggerated.Alternation of the right ventricular diastolic and right atrial pressures was found in 2 patients in addition to that of the right ventricular systolic pressure. However, it could not be considered that the atrial or right ventri-cular diastolic alternation played an important role in the genesis of pulsus alternans in the pulmonary circulation.

Eleven patients with arteriographically confirmed coronary artery disease and normal arterial oxygen saturation were studied. The angina threshold was determined first by successive elevation of heart rate at increments of 10 and 5 beats/min by right atrial pacing while the patients were breathing air via a close-fitting mask. The mask was then connected to an oxygen tank without the patient's knowledge. After 5 min of oxygen breathing, the heart rate was again raised to the previously determined threshold level. In nine of 11 patients angina did not recur. The absence of angina was associated with improvement in myocardial lactate extraction from -17 ± 15 to +18 ± 10% ( P < 0.025), in S-T abnormalities in six of seven patients, and in pulsus alternans in three of five patients. The pacing rate was then raised at increments of 5 beats/min until angina recurred. With oxygen breathing, angina developed at higher pacing rates (129 ± 7 beats/min with air and 137 ± 6 beats/min with oxygen, on the average; P < 0.005), at higher rate-pressure product (18.0 ± 0.8 and 19.5 ± 0.9 x 10 3 mm Hg/min, respectively; P < 0.01), and at higher left ventricular oxygen consumption (21.3 ± 1.1 and 24.6 ± 1.1 ml/min, respectively; P < 0.005). The results indicate that oxygen breathing permits the heart to do more work before coronary insufficiency develops.

Summary In six out of eight instances mechanical ventricular alternans was accompanied by minute alternation in cycle length. Similar changes in cycle length were observed in the transient pulsus alternans which follows a premature contraction. The strong beats are followed by shortened cycles and the weak beats by longer cycles, the differences being usually about 0.01 to 0.03 second in duration. In four subjects in whom pulsus alternans was accentuated in the erect posture, both the mechanical and temporal types of alternation changed in a concordant direction, both tending to disappear in the recumbent position. The changes in cycle length are considered in most instances to be the consequence rather than the cause of alternation in strength of the contractions. The mechanism is believed to involve two asynchronous effects of a single strong or weak beat: (1) An immediate effect on the first succeeding cycle by alternation in direct mechanical distortion and stimulation of the pacemaker; (2) Delayed pressoreceptor reflex action which, because of the latent period, does not become manifest until the second cycle. In very rapid heart rates, slight alternations in cycle length may contribute to the development or severity of mechanical alternation.

In dogs anesthetized with pentobarbital, ventricular arrhythmias induced by ouabain were consistently reverted to sinus rhythm by acute lowering of the serum calcium. In ouabain-in-toxicated dogs, the depressed and shortened S-T segment was elevated and lengthened by induced hypocalcemia. Potassium administered concomitantly with ouabain exerted a protective effect against ouabain intoxication. Lowering of the serum calcium in animals showing moderately advanced potassium effects in their ECG precipitated acute, fatal potassium poisoning. Ouabain was capable of reversing the tachycardia and pulsus alternans due to hypocalcemia in the face of persistent hypocalcemic tetany.

Ventricular alternans was present in three cardiac patients only in the erect or semierect position and disappeared with recumbency. The phenomenon which was regularly reproduced in the standing posture was prevented or minimized by exercise, digitalis, infusions of blood and norepinephrine and by application of external vascular support. Ventricular alternation in the supine patient was noted only after phlebotomy, or venous pooling combined with Valsalva maneuvers. The observations suggest that in the mechanism of this type of pulsus alternans there is an important peripheral hemodynamic factor which exerts its effect by changes in diastolic length of an injured ventricular muscle.

Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

Pulsus alternans is characterized by a regular rhythm with alternation of strong and weak contractions. It is a phenomenon generally ascribed to severe myocardial dysfunction and occurs most commonly in patients with heart failure secondary to increased resistance to left ventricular ejection. It has also been described in coronary artery disease and in idiopathic dilated cardiomyopathy. Although pulsus alternans has more often been described in advanced myocardial disease, it has also been described in acute, transient ischemia.1 Right ventricular (RV) alternans has been described previously, but usually in patients with congestive heart failure or severe RV dysfunction, or both.2,3 The present report describes RV pulsus alternans that occurred acutely during balloon pulmonary valvotomy.

Concomitant pulsus and U-wave alternans were first described by Eyer in 1974. 1 We report herein a patient who had marked pulsus and U-wave alternans after head trauma.

echocardiogram from a 34-year-old man with coro- nary arterial disease. Rapid right ventricular pacing instituted at a rate of 160 impulses per minute re- sults in markedly diminished anterior motion of the mitral valve for the first three beats. The sixth beat of the tachycardia initiates an eight-cycle period of mechanical alternans. Alternation of motion of the septum, anterior mitral valve, and posterior left ventricular wall can be identified. Concordant peak aortic blood velocity and right ventricular pressure alternans is observed with greater blood flow and pressure preceded by enhanced posterior motion of both the left septum and posterior left ventricular wall. In addition, stronger beats were succeeded by larger anterior excursion of the anterior mitral valve and augmented opening of the mitral valve. Weaker beats were associated with opposite changes in an

Application of a small dose of glyceryl trinitrate paste (0.25 in) resulted in severe left ventricular dysfunction with the appearance of pulsus alternans in a patient with alcoholic cardiomyopathy. The echocardiogram showed a reduction in the amplitude and velocity of motion of the left ventricular posterior wall on alternate beats. Leg elevation promptly reversed the pulsus alternans, and the echocardiographic abnormality. Glyceryl trinitrate paste should be used with caution and under close supervision in patients with liver dysfunction.

Pulsus alternans of the pulmonary artery is uncommon. It has been described in association with conditions of varied etiology, affecting either left or right ventricular function. A case of pulmonary artery pulsus alternans associated with pulmonary artery hypertension secondary to pulmonary embolism is described. This pattern should suggest the possibility of pulmonary embolism when seen at cardiac catheterization.

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In Reply .—I would agree with Dr Murphy that an S 3 gallop and pulsus alternans are more specific to the heart and heart failure than, perhaps, dyspnea or edema. However, a third heart sound may be a physiologic finding in a child; a normal variant in a pregnant woman; a finding compatible with significant mitral regurgitation even without heart failure; or a finding of left ventricular dysfunction, with or without heart failure. Although a pulsus alternans may be seen with advanced myopathic conditions accompanied by congestive heart failure, it can also be seen with aortic stenosis without heart failure, as well as be produced under high afterload-low preload conditions. Therefore, despite the "traditional teachings of physical diagnosis," an S 3 gallop and a pulsus alternans have never been, and thus, cannot remain "specific signs of heart failure."

With use of the Doppler ultrasonic flowmeter catheter, phasic instantaneous left ventricular blood flow velocity was measured by radiotelemetry in 28 subjects during pacemaker-evoked pulsus alternans. Blood velocity alternation was more manifest at faster pacing rates. Four patients demonstrated diastolic blood velocity alternans at the mitral valve. Discordant right heart pressure and left ventricular blood velocity alternation was recorded in three subjects. In one such patient, rate-related shifts of concordant and discordant left ventricular blood velocity alternans occurred. Intermediate or variant forms of alternation, comprising weak and strong beats in a ratio of 2:1, were noted in two subjects. This study provides the first comprehensive description of left ventricular blood velocity alternans in man. The observed phenomena may be related to an altered inotropic state or to beat to beat variations in end-diastolic fiber length.

To the Editor .—Dr Kessler's article in the October 1988 issue of theArchives 1 was useful in regard to heart failure secondary to diastolic dysfunction. One statement that I feel needs correction is"... that the signs and symptoms of heart failure are not specific, but rather are subjective, and may be manifestations of noncardiac disorders." Signs of heart failure, such as S 3 gallop and pulsus alternans, are objective findings felt to be pathognomonic of heart failure according to the traditional teachings of physical diagnosis. Although these signs may not be sensitive in patients with diastolic dysfunction, as pointed out by Dr Kessler, they remain specific signs of heart failure.

The syndrome of peri-partum cardiac failure (PPCF) has been studied in 224 women seen in three years in Zaria, in northern Nigeria. A very high proportion were rural Hausa patients. There was a seasonal peak in July, and the incidence was about one per cent of deliveries. The risk increased with both age and parity. Symptoms began most commonly in the second week after delivery, and admission was commonest in the fourth. Typical signs of cardiac failure were found, and pulsus alternans, atrio-ventricular valvular incompetence, transient systemic hypertension and splenomegaly were common. The chest radiograph showed marked cardiomegaly, and extrasystoles and inverted T waves were often present in the electrocardiogram (ECG). Hypoalbuminaemia was common. Digoxin and diuretics were rapidly effective, causing a mean weight loss of 29 per cent in 15 days, resolution of hypertension, and a fall in the cardio-thoracic ratio (CTR) from 61 to 53 per cent. During the first year after diagnosis, the CTR became normal in 82 per cent of patients, and the ECG in 60 per cent. PPCF recurred, again with the same seasonal variation, after 19 per cent of subsequent pregnancies. During follow up for two to five years, 22 per cent of the women became hypertensive, and 11 per cent died. The prognosis was worst in those with an arrhythmia, hypertension, sustained cardiomegaly or aged 30 or more. Asymtomatic post-partum hypertension (PPHT) was found in 61 per cent of normal Hausa women, with a seasonal peak in May, especially in those with hypertension during pregnancy or labour, and twin pregnancies. Peri-partum cardiac failure may be due to the combined pressure load of PPHT, the volume load from eating the customary sodium-rich kanwa, and the cardiovascular demands of heat, both climatic and traditionally self-imposed.

It is well known that heart-block may result from digitalis medication. That this event is not necessarily a cause for apprehension or for cessation of further administration of the drug is the burden of this paper. One notes cases of severe cardiac insufficiency in which digitalis has not been given adequately because of the fear of the production of heart-block. It is my opinion that this fear implies a misconception of digitalis therapy and that the error is rather prevalent. TOXIC EFFECTS OF DIGITALIS There are many symptoms and signs of the toxic action of digitalis. Among these are gastric symptoms, sinus arrhythmia, extrasystoles, "coupled rhythm," ventricular escape, pulsus alternans, auricular paroxysmal tachycardia, auricular fibrillation, ventricular paroxysmal tachycardia and ventricular fibrillation. Not all of these are present, of course, in a single individual. Robinson and Wilson 1 reported an important experimental study of the relation of the various effects of

It is a matter of common observation that in many conditions, notably cardiac arrhythmias, the sphygmomanometer will often detect the fact that in a given heart the beats may vary in strength, some strong beats pushing through to the artery at the wrist, though the pressure of the manometer cuff is sufficient to cut off all those that are weak or of average power. The arrhythmia of mitral stenosis when auricular fibrillation has set in is a good example. In the hypertension of chronic nephritis or of arteriosclerosis, the same phenomenon may be encountered. When the systolic pressure is being tested in a patient in whom an alternating pulse is present, a manometer pressure may be reached that cuts off every other beat—the weaker beat—thus halving the rate of the pulse at the wrist. Increasing the pressure on the brachial artery, by still further inflation of the cuff, of course

Volhard1in 1905 studied the characteristic sphygmographic features in cases of pulsus alternans and reported that by listening to the heart one could recognize a conspicuous alternation of the second heart sound in all the cardiac cycles and of the first heart sound in only three or four cycles after each extrasystole. This alternation of the sounds revealed itself through modifications in their intensity and pitch; the sounds in the cycle with a large pulse beat were more intense and of a higher pitch than those in the cycle with a small pulse beat. Although the initial fact was verified at the beginning of the present century, there are only a few cases reported in the medical literature in which alternation of the heart sounds was recognized on auscultation (Meyer and Levy2and Morris3). With the exception of Morris,3all other authors who have been interested

It is now an accepted fact that, in the absence of tachycardia, pulsus alternans in cardiac or cardiorenal disease indicates a grave prognosis. Lewis1says: Alternation of the pulse belongs to a small group of phenomena witnessed by those who attend the sick, which, treated as isolated signals, are in themselves emphatic and portentous. It ranks with subsultus tendinum, with optic neuritis, with the risus sardonicus, and other ill omened messengers. It is the faint cry of an anguished and fast failing muscle, which, when it comes, all should strain to hear, for it is not long repeated. A few months, a few years at most, and the end comes. A perusal of the litearture is apt to convey the impression that pulsus alternans is uncommon and that a tracing of the radial pulse is necessary for its detection. Vaquez 2 refers to it as "at once the rarest

A false positive diagnosis is made in approximately 25% of patients who are considered to have angina pectoris on an arteriosclerotic basis. The opportunity arose to examine 12 patients during spontaneous bouts of angina and attention was directed to the presence or transient development of pulsus alternans, abnormal precordial pulsations, paradoxical splitting of the second sound, atrial or ventricular diastolic gallops, an apical regurgitant murmur, and the response of the pain to carotid sinus pressure. At rest, 11 of the 12 patients had an atrial and six had a ventricular diastolic gallop. In ten out of 12 instances, abnormal physical findings became manifest and/or carotid sinus pressure was effective in relieving the angina. The observation of transient physical signs of left ventricular dysfunction may help resolve a difficult diagnostic problem.

This book is a guide to the operation of a coronary care unit based on the practice and the experiences of the authors. The format is excellent. It opens with a description of the natural history of patients with acute myocardial infarction and closes by emphasizing the necessity for an intermediate coronary care unit. In between these two chapters, the major problem areas in management of patients with myocardial infarction are considered. Although the authors make a laudable plea for avoiding the use of new terms that contribute little or nothing to a better understanding of fundamental mechanisms (page 148), they descend to terms such as "coronoid," "coronette" and "mitral madness." The example chosen to illustrate pulsus alternans, is not the classic form. Throughout the book there is unnecessary repetition which detracts from this otherwise concise volume. The book is intended as a guide for those just starting a new

The question of the possibility of producing alternation of the pulse by very vigorous and prolonged exertion was the incentive to a study of the pulse of twenty men who ran the annual Boston Marathon of 25 miles from Ashland to Boston, April 19, 1916. Myocardial exhaustion resulting from damage such as that produced by arteriosclerosis or syphilis has been shown to be an important cause of alternation of the pulse. The greater the strain on such a heart, the more marked is likely to be the alternation. The strain necessary to sustain a high blood pressure is especially likely to bring out alternation. Extreme and prolonged tachycardia, as in auricular flutter or paroxysmal tachycardia, may result in pulsus alternans. But it has never been shown, so far as I am aware, that alternation has been found in the pulse of a normal individual after severe exertion. Von Tabora 1

To the Editor: —Several contributions to the literature of pulsus alternans with respect to its determination by the sphygmomanometer have recently been made in this country and abroad without due recognition of Hoffmann and Rehberg, who described the method in 1906 and 1909, respectively, the former in the Munchener medizinische Wochenschrift (liii, 1977), and the latter in the Zeitschrift fur klinische Medizin (lxviii, 247). Rehberg in his summary says: There are two methods of rendering manifest a latent pulsus alternans: ( a ) by artificially increasing the frequency; ( b ) by increasing the pressure proximally from the artery being investigated. This not only can increase the size of the pulse waves but may also render evident any retardation in the small pulse. (Als besondere Ergebnisse hebe ich hervor: 1. dass es 2 Methoden gibt, den latenten Pulsus Alternans zur Wahrnehmung zu bringen: ( a ) durch die (hier nicht angewendete) kunstliche Erhohung der

The signs and symptoms of left ventricular failure have been described frequently, and their clinical significance is well known. Certain symptoms, namely exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea and sometimes cough, and certain signs, namely gallop rhythm, pulsus alternans and increase of the pulmonary second sound, are generally recognized as early evidence of failure of the left side of the heart. Patients with dyspnea and orthopnea do not, as a rule, sleep well, but little space in the literature has been devoted to the insomnia resulting from these symptoms other than to mention that it occurs, for in most patients the insomnia is of secondary importance. Relief of pulmonary congestion by either digitalis or diuretics often causes a striking improvement in the patient's condition, and as the orthopnea disappears so does the accompanying insomnia. There are patients, however, with left ventricular failure and pulmonary vascular congestion in whom the principal

Recently Hamburger, Katz and Saphir1described two cases of electrical alternans without pulsus alternans —the first reported in this country. This electrocardiographic phenomenon (fig. 1) has been exceedingly rare, but now that the Chicago investigators have made cardiologists "alternans conscious," to use their expression, we believe that relatively many more cases will be reported. The two cases that are the subject of this report include one case of electrical alternans with demonstrable pulsus alternans and one case in which pulsus alternans was not demonstrated. Our first case was discovered Jan. 22, 1935. Careful search through our files then brought the additional case to light. Electrical alternans consists of a regular alternation at equal intervals, in contour or amplitude, or both, of successive phases of the electrocardiographic record. White2says that electrical alternans accompanying pulsus alternans is rare; the QRS or T waves may rarely alternate in amplitude although

The ease with which the grave constant type of alternation of the pulse can be detected by the auscultatory method of blood pressure estimation has caused us to investigate the value and error in this method of diagnosing the condition. The use of compression of the brachial artery in augmenting and revealing an alternation of the pulse was first described by Hoffmann 1 in 1906, and has since been mentioned by several writers. Of late Herrick 2 and McGill 3 have written of the use of auscultation over the brachial artery during its compression by the cuff of the sphygmomanometer in the diagnosis of alternation of the pulse. At a pressure just below the systolic reading, the pulse rate is halved if alternation is present. As has been pointed out by several writers, most recently by one of us, 4 the two important conditions which may produce a pulse which

The present investigation was undertaken to determine whether interference with the coronary circulation has any effect on the tolerance of an animal to the digitalis bodies. 1 There has long been a certain hesitation to administer digitalis to patients with heart failure associated with disorders of rhythm similar to those arising from excessive digitalization. Because of the striking similarity between the cardiac disturbances resulting from diphtheria and those from large doses of digitalis, McCullough 2 recommended that the drug be withheld in this disease. The existence of such disorders as premature beats, coupling, various degrees of heart block and pulsus alternans has been taken by some as a contraindication to the use of digitalis, or, at least, as an indication for especial caution in its administration. It has seemed logical to assume that the occurrence of these abnormal phenomena implied a predisposition in the heart to their development through the digitalis bodies

Hemodynamic changes occurring with spontaneous atrioventricular dissociation, left ventricular pulsus alternans, a rise in systemic arterial pressure, and the injection of angiographic con...

It is generally recognized that electrocardiography adds little to the clinical diagnosis of pulsus alternans. While the electrocardiogram may show evidence of slight or widespread coronary and myocardial involvement, paradoxically it rarely demonstrates alternation of the ventricular complexes as one, a priori, might expect. The two cases of electrical alternans without pulsus alternans we are about to describe—the first to be reported in this country—are in sharp contrast to the usual type of alternans, which is confined to the pulse, heart sounds or apex beat, without evidence of electrocardiographic alternation. The electrocardiographic finding of electrical alternans, judging from the literature and our own experience, is an exceedingly rare phenomenon. Our first case, observed in March 1933, constitutes the only one we have seen in a series of approximately 10,000 electrocardiograms covering a period of about thirteen years. However, since the appearance of the first case, three additional cases of electrical

Alternation in the electrocardiogram is only occasionally seen in patients with pulsus alternans. Furthermore, it may occur without alternation in the peripheral pulse. 1 In children alternation in the electrocardiogram has rarely been reported. In 1917, Windle 2 recorded alternation in a boy 13 years of age following treatment with digitalis. In a series of 16 patients Kalter and Grishman 3 reported alternation in 3 children under 13 years of age, the youngest being 5 years old. In these 3 children only alternation of the QRS complex was reported. Unfortunately, none of the tracings were reproduced in their paper. Nadrai 4 mentioned alternation in the electrocardiogram (his fig. 24) in a child 9 months old with situs inversus and truncus arteriosus communis. The child died soon afterward. As far as we know, this is the earliest age at which alternation has been observed. Alternation in the electrocardiogram, especially in patients

In cardiac myocytes, the elementary Ca cycling events are Ca sparks, spatially discrete Ca release events due to random and collective openings of ryanodine receptor (RyR) channels clustered in close proximity to L-type Ca channels (LCCs), forming what are known as Ca release units (CRUs). A typical cardiac myocyte includes about 10,000 to 20,000 CRUs. It is well known that heart failure (HF) remodeling induces changes in whole cell currents and Ca cycling proteins that promote Ca alternans, manifested clinically as pulsus alternans. In addition to electrical remodeling, HF also induces structural remodeling of t-tubules that alters the spatial distribution of CRUs in a myocyte, creating orphaned RyRs that are not associated with LCCs. An interesting question is whether such modifications in the spatial organization of LCCs have independent effects on Ca alternans, even if the whole cell LCC current remains unchanged. Here we address this question by studying the role of the spatial organization of LCCs in the genesis of Ca alternans in a 3D computer model of a ventricular myocyte containing a diffusively coupled network of 20,000 (100x20x10) CRUs. We show Ca alternans is strongly promoted by increasing nonuniformity in LCC distribution among CRUs (simulating T-tubule disruption/dysregulation), independent of changes in the whole cell Ca current. This observation may provide a mechanistic link between T-tubule disruption and Ca alternans observed in failing myocytes. More generally, our results indicate that subcellular details of ion channel distribution can have profound effects on global cellular function not captured by whole cell current measurements.