Ernest L. Fallen

The Effects of β1-Blockade on Oxidative Metabolism and the Metabolic Cost of Ventricular Work in Patients With Left Ventricular Dysfunction A Double-Blind, Placebo-Controlled, Positron-Emission Tomography Study

Background—The mechanism for the beneficial effect of β-blocker therapy in patients with left ventricular (LV) dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using positron-emission tomography (PET), are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MVo2). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency. Methods and Results—The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work-metabolic index in patients with LV dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; LV ejection fraction <40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in analysis because of withdrawal from the study, incomplete follow-up, or nonanal...

Spectral analysis of heart rate variability following human heart transplantation: evidence for functional reinnervation

To determine the status of innervation in long-term human donor allografts, the power spectrum of heart rate variability was analysed in 9 post-transplant patients and 7 healthy control subjects. The mean post-transplant follow-up was 17.8 months (range: 2-37 months). Continuous ECG signals were recorded throughout a 15-min rest period. An R-R interval tachogram was generated and an autoregressive model using linear predictive coding, was applied to the heart rate variability data. In 8 transplant patients the frequency oscillations were irregular, broad based and widely dispersed from 0 to 1 Hz. The patterns resembled white noise and were consistent with dissociation of the donor allograft from the recipients central nervous system. In contrast, one patient displayed a heart rate variability spectrum indistinguishable from that of control subjects. This pattern contained two distinct spectral bands; one corresponding to the patients respiratory rate at 0.2 Hz and a low frequency Mayer wave at 0.1 Hz. Atropine abolished the respiratory (vagal) peak. Except for this patients post-transplant time (33 months compared to the group mean of 17.6 months), there were no clinical characteristics which distinguished this patient from the others. While the mean heart rate for the remaining 8 allografts was significantly higher than controls (95.3 vs 64.5 bt/min; P less than 0.001) the standard deviation of heart rate variability for the 8 patients was significantly narrower than controls (0.7 vs 4.86; P less than 0.01). The variance of heart rate for the patient with the normal power spectrum was fourfold greater than the mean SD of the other transplant patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Vagal Nerve Electrostimulation on the Power Spectrum of Heart Rate Variability in Man

The power spectrum of heart rate variability contains low frequency (LF = 0.08–0.12 Hz) and high frequency (HF = 0.18–0.30 Hz) components said to represent neurocardiac rhythms. To verify whether such a relationship exists we report a unique study where the heart rate autospectrum was determined in a 28‐year‐old epileptic male patient with an implanted vagal electrical stimulator. The stimulator was activated at 20 Hz, 300 psec pulse, and 1.25 V. Continuous ECG and respiratory waveform records were obtained over 45 minutes every 8 hours (7–8 AM; 3–4 PM; 11–12 PM) With the stimulator ON, then 24 hours OFF and then 24 hours ON again. The overall LF:HF peak ratio increased from 0.64 to 1.99 (P < 0.001) after the stimulator was turned OFF. There was a dramatic increase in the LF peak power (> 60%) and a corresponding decrease in the HF peak power (> 65%) when the stimulator was turned OFF. These values were reversed when the stimulator was turned ON again. In the early morning and late evening hours, there was a significant rightward shift in the LF peak power frequency (average 0.057 to 0.075 Hz) whenever the stimulator was ON. Otherwise, there were no significant circadian variations in any of the autospectral components. The results demonstrate an unequivocal relationship between selective vagal nerve electro stimulation and alterations in the heart rate autospectrum.

Redistribution of Myocardial Blood Flow With Topical Nitroglycerin in Patients With Coronary Artery Disease

BACKGROUNDnUnlike nonselective coronary vasodilators, nitroglycerin (GTN) is said to exert its primary vasodilatory effect on epicardial conductance vessels. Thus, in experimental models of coronary occlusion GTN appears to preferentially direct blood flow to poststenotic zones of ischemia. This phenomenon has, to date, not been tested in humans. Using positron emission tomography we examined the effect of transdermal GTN on global and regional myocardial perfusion in patients with angiographically proven coronary artery disease.nnnMETHODS AND RESULTSnMyocardial perfusion with [13N]ammonia was estimated from dynamic time-activity curves at baseline and 3 hours following application of either a 0.4 mg/h GTN skin patch (n = 10) or a placebo patch (n = 10) in a double-blind parallel design. From resliced cross-sectional images, regional flow, expressed as [13N]ammonia retention, was estimated from 216 myocardial sectors. Ischemia was defined as a significant reduction (> 2 SDs from average counts/pixel in maximally perfused zones) in [13N]ammonia retention within 10 contiguous myocardial sectors coupled with an increase or no change in counts derived from [18F]fluorodeoxyglucose. There was no change in global myocardial blood flow as expressed by [13N]ammonia retention following either placebo (0.61 +/- 0.14 to 0.62 +/- 0.12 min-1) or GTN (0.75 +/- 0.22 to 0.74 +/- 0.19 min-1). Conversely, there was a significant increase in the proportion of blood flow to the ischemic zones with GTN (73.9 +/- 12.6% to 94.9 +/- 17.8%; P < .05). No change in the distribution of blood flow to either ischemic or nonischemic zones was observed with placebo. A slight but insignificant decrease in [13N]ammonia retention in nonischemic zones was observed with GTN (1.01 +/- 0.31 to 0.93 +/- 0.26 min-1).nnnCONCLUSIONSnThis study suggests that under resting conditions topical GTN alters myocardial perfusion by preferentially increasing flow to areas of reduced perfusion with little or no change in global myocardial perfusion in patients whose angina is responsive to GTN.

Diurnal variations of neurocardiac rhythms in acute myocardial infarction

To determine the diurnal pattern of cardiac autonomic tone in acute myocardial infarction (AMI), this study examined the power spectrum of heart rate (HR) variability in 24 patients during a single 24-hour segment within 4 days of AMI. Patients were nonrandomly allocated to a group (n = 14) without autonomic drugs and to a group (n = 10) already receiving beta blockers at the time of AMI. With use of autoregressive modeling, the power spectrum of HR variability was computed from continuous 1-hour electrocardiographic segments recorded at equally spaced intervals; 7 to 8 A.M., 3 to 4 P.M., and 11 to 12 P.M. All patients were supine, awake and pain free during recordings. There were no differences in HR, HR variance or the low-frequency peak power (0.06 to 0.1 Hz) from one temporal sequence to another. For the patients not taking beta blockers, the high-frequency peak power (0.2 to 0.36 Hz) or vagal component increased significantly from 3 P.M. to 11 P.M. (28 +/- 11 to 45 +/- 20 beats/min2.Hz-1, p less than 0.01). There was a significant decrease in the low- to high-frequency peak power and area ratios from 3 P.M. to 11 P.M. All power spectral parameters in the patients taking beta blockers remained unchanged over 24 hours. There was significantly heightened vagal modulation of sinus node activity in those receiving beta blockers, especially at 7 A.M. and 3 P.M. The data suggest that under steady-state wakeful conditions in the early recovery phase after an AMI, vagal tone is more pronounced during the late evening hours with a possible shift to relative sympathetic dominance during early morning and midafternoon hours.(ABSTRACT TRUNCATED AT 250 WORDS)

The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies.

Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut–brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1u2008±u20085.9 years), a 5u2008mm stainless‐steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15u2008mA, 200u2008μs) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1u2008Hz). Two series of stimuli were applied using each stimulation frequency. Two‐dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1u2008Hz and 1.0u2008Hz (P1/N2: 7.6u2008±u20081.2 vs 1.4u2008±u20080.3*u2008μV, N2/P2: 17.2u2008±u20081.7 vs 4.6u2008±u20080.4*u2008μV, P2/N3: 6.9u2008±u20080.7 vs 4.2u2008±u20080.5*u2008μV; *u2008=u2008Pu2008<u20080.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (Pu2008<u20080.0005), with a similar trend for the P3 peak (Pu2008<u20080.06), with increasing stimulus frequency from 0.1–1.0u2008Hz. Topographic brain maps localized the maximal early peaks (N1,P1,N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centro‐parietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.

Can Nitrogen-13 Ammonia Kinetic Modeling Define Myocardial Viability Independent of Fluorine-18 Fluorodeoxyglucose?

OBJECTIVESnThe hypothesis of this study was that evaluation of myocardial flow and metabolism using nitrogen-13 (N-13) ammonia kinetic modeling with dynamic positron emission tomographic (PET) imaging could identify regions of myocardial scar and viable myocardium as defined by fluorine-18 fluorodeoxyglucose (F-18 FDG) PET.nnnBACKGROUNDnUptake of most perfusion tracers depends on both perfusion and metabolic retention in tissue. This characteristic has limited their ability to differentiate myocardial scar from viable tissue. The kinetic modeling of N-13 ammonia permits quantification of blood flow and separation of the metabolic component of its uptake, which may permit differentiation of scar from viable tissue.nnnMETHODSnSixteen patients, > 3 months after myocardial infarction, underwent dynamic N-13 ammonia and F-18 FDG PET imaging. Regions of reduced and normal perfusion were defined on static N-13 ammonia images. Patients were classified into two groups (group I [ischemic viable], n = 6; group II [scar], n = 10) on the basis of percent of maximal F-18 FDG uptake in hypoperfused segments. Nitrogen-13 ammonia kinetic modeling was applied to dynamic PET data, and rate constants were determined. Flow was defined by K1; volume of distribution (VD = K1/k2) of N-13 ammonia was used as an indirect indication of metabolic retention.nnnRESULTSnFluorine-18 FDG uptake was reduced in patients with scar compared with normal patients with ischemic viable zones (ischemic viable 93 +/- 27% [mean +/- SD]; scar 37 +/- 16%, p < or = 0.01). Using N-13 ammonia kinetic modeling, flow and VD were reduced in the hypoperfused regions of patients with scar (ischemic viable flow: 0.65 +/- 0.20 ml/min per g, scar: 0.36 +/- 0.16 ml/min per g, p < or = 0.01; VD: 3.9 +/- 1.3 and 2.0 +/- 1.07 ml/g, respectively, p < or = 0.01). For detection of viable myocardium in these patients, the sensitivity and specificity were 100% and 80% for N-13 ammonia PET flow > 0.45 ml/min per g; 100% and 70% for VD > 2.0 ml/g; and 100% and 90% for both flow > 0.45 ml/min per g and VD > 2.0 ml/g, respectively. The positive and negative predictive values for the latter approach were 86% and 100%, respectively.nnnCONCLUSIONSnIn this cohort, patients having regions with flow < or = 0.45 ml/min per g or VD < or = 2.0 ml/g had scar. Viable myocardium had both flow > 0.45 ml/min per g and VD > 2.0 ml/g. Nitrogen-13 ammonia kinetic modeling permits determination of blood flow and metabolic integrity in patients with previous myocardial infarction and can help differentiate between scar and ischemic but viable myocardium.

Afferent vagal modulation: Clinical studies of visceral sensory input

UNLABELLEDnThe frequency composition of a continuous time series of R-R intervals may be viewed as the phasic output of a central processing system intimately dependent on sensory input from a variety of afferent sources. While different measures of heart rate variability permit a glimpse into the autonomic efferent limb of this complex system, direct access of afferent fibers in humans has remained elusive. Using a specially designed esophageal catheter/manometer probe, we have been able to gain access to vagal afferent fibers in the distal esophagus. Our studies on the effect of vagal afferent electrostimulation on both cerebral evoked potentials (EvP) and the power spectrum of heart rate variability have yielded the following observations: 1. Stimulation of esophageal vagal afferents dramatically and reproducibly increases the high frequency (HF) vagal power and reduces the low frequency (LF) power of the heart rate autospectrum. 2. This effect is constant across stimulation frequencies from 0.1 to 1.0 Hz and across stimulation intensities from 2.5 to 20 mA. 3. Regardless of the stimulation parameters, there are only minimal changes in heart rate (2-6 bpm) and no change in respiratory frequency. 4. There is a linear correlation between electrical stimulation intensity and the amplitude of cerebral evoked potentials, whereas there is a non-linear relationship with all short-term power spectral indices. 5. While cerebral evoked potentials are only elicited at stimulation intensities above perception threshold, there is already a significant shift to increased vagal efferent modulation well below perception threshold.nnnCONCLUSIONnThese studies support the concept that power spectral indices of heart rate variability represent phasic output responses to tonic afferent viscerosensory signals in humans. These studies also demonstrate the feasibility of accessing vagal afferents in humans.

Clinical Utility of Heart Rate Variability

With the advent of signal processing technology and the application of time series analysis, non-invasive access to autonomic neural activity is both feasible and clinically meaningful. Contained within continuous ECG recordings are hidden interbeat oscillations that re_ect the state of autonomic control of sinoatrial node activity [1–3]. It is now recognized that in certain clinical disorders there is impairment of autonomic regulation, which may take the form of either heightened neural sympathetic tone [4,5] or reduced total power in cycle length variability [6]. There are several methodologic approaches to the study of heart rate variability (HRV) [7,8]. This review focuses on two comparatively simple non-invasive techniques; namely, time domain and frequency domain analysis of HRV from variable length ECG recordings. The simplest method is time domain analysis, of which there are two types: One is a time domain approach in which descriptive statistics applied to the 24-hour ECG record yields the overall variance or power contained in the interbeat signal [9]. Among these parameters are the standard deviation of all successive sinusconducted RR intervals (SDNN) or portions thereof (e.g., standard deviation of the averages of RR intervals in 5-minute segments or SDANN). The other time domain approach re_ects mainly parasympathetic in_uence by examining successive differences in RR intervals [9]. These include the root mean square standard deviation of successive intervals (rMSSD) or the proportion of successive interbeat intervals that vary more than 50 msec (pNN50). The advantages of time domain methods are their simplicity, reproducibility and proven prognostic power [10,11]. The disadvantages include nonstationarity of the ambulatory signal, the need for an adequate sampling frequency and the dif~culty in comparing physiologic states [7]. Frequency domain indices are best derived from steady state short data recordings ranging from 2.5 to 5 minutes in length [7,12]. Although these short data sets comprise less than 5 percent of the total 24-hour signal power and include mostly linear components of the system, they nonetheless yield a spectrum within which useful physiologic information can be derived. These include respiratory driven vagal efferent modulation of sinoatrial node activity expressed by the highfrequency power (HF) and a sympathetic component (low-frequency band or LF), especially under conditions that activate sympathetic neural activity [13,14]. A Word about Clinical Utility

Coronary artery disease, inflammation and the ghost of John Hunter

In her uproarious novel, According to Queeney, Beryl Bainbridge has the infamous lexicographer Samuel Johnson refer to John Hunter’s penchant for experimenting on rare anatomic specimens as that “medical man who, curious as to what constitutes life, is forever anatomizing them into death” (Bainbridge, 2001). In point of fact, Hunter’s so-called grotesque experiments on interspecies transplantation was nothing less than a serious effort to describe inx8f ammation as an obligatory reaction to all manner of tissue injury (Qvist, 1981). He recognized three types of inx8f ammation: suppurative, ulcerative and adhesive; each a different process based on the nature of the insult. Without benex8e t of elemental microbiology, let alone histology, Hunter astutely prophesied that tissue injury initiates a complex sequence of cellular reactions (inx8f ammation) whose purpose is to contain and heal while battling the offensive injury. In Hunter’s time (1728–1793), infection and mortal combat were the major provocateurs. Today, the common scourge is atherosclerosis. While countless theories of its pathogenesis have been proposed over the last eight decades, it has taken more than two centuries to vindicate Hunter’s original concepts of tissue injury and inx8f ammation as a plausible mechanism for the initiation, propagation and complications of the atheromatous plaque. Heretofore, the popular conception of an atheroma was a localized lifeless mass of lipid debris within the intima of an artery devoid of endothelial reactivity. For many decades the scientix8e c dispute on