Michael W. Dae

RELATIVE IMPORTANCE OF ACTIVATION SEQUENCE COMPARED TO ATRIOVENTRICULAR SYNCHRONY IN LEFT VENTRICULAR FUNCTION

This study evaluated the relative hemodynamic importance of a normal left ventricular (LV) activation sequence compared to atrioventricular (AV) synchrony with respect to systolic and diastolic function. Twelve patients with intact AV conduction and AV sequential pacemakers underwent radionuclide studies at rest and Doppler echocardiographic studies at rest and during submaximal exercise, comparing atrial demand pacing (AAI) to sequential AV sensing pacing (DDD) and ventricular demand pacing (VVI). Studies at rest were performed at a constant heart rate between pacing modes, and the exercise study was performed at a constant heart rate and work load. Cardiac output was higher during AAI than during both DDD and VVI (6.2 +/- 1 vs 5.6 +/- 1 and 5.3 +/- 1 liters/min, p less than 0.05). LV ejection fraction was likewise higher during AAI (55 +/- 12 vs 49 +/- 11 vs 51 +/- 13, p less than 0.05). VVI with or without AV synchrony was associated with a paradoxical septal motion pattern, resulting in a 25% impairment of regional septal ejection fraction. In addition, LV contraction duration was more homogenous during AAI. Peak filling rate during AAI and VVI was higher than during DDD (2.86 +/- 1 and 2.95 +/- 1 vs 2.25 +/- 1 end-diastolic volume/s; p less than 0.05). During VVI, the time to peak filling was significantly shorter than during both AAI and DDD (165 +/- 34 vs 239 +/- 99 and 224 +/- 99 ms; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction

OBJECTIVES The purpose of this study was to evaluate the safety and feasibility of endovascular cooling during primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND In experimental models of AMI, mild systemic hypothermia has been shown to reduce metabolic demand and limit infarct size. METHODS In a multi-center study, 42 patients with AMI (<6 h from symptom onset) were randomized to primary PCI with or without endovascular cooling (target core temperature 33 degrees C). Cooling was maintained for 3 h after reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to reduce the shivering threshold. The primary end point was major adverse cardiac events at 30 days. Infarct size at 30 days was measured using (99m)Tc-sestamibi SPECT imaging. RESULTS Endovascular cooling was performed successfully in 20 patients (95%). All achieved a core temperature below 34 degrees C (mean target temperature 33.2 +/- 0.9 degrees C). The mean temperature at reperfusion was 34.7 +/- 0.9 degrees C. Cooling was well tolerated, with no hemodynamic instability or increase in arrhythmia. Nine patients experienced mild episodic shivering. Major adverse cardiac events occurred in 0% vs. 10% (p = NS) of treated versus control patients. The median infarct size was non-significantly smaller in patients who received cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). CONCLUSIONS Endovascular cooling can be performed safely as an adjunct to primary PCI for AMI. Further clinical trials are required to determine whether induction of mild systemic hypothermia with endovascular cooling will limit infarct size in patients undergoing reperfusion therapy.

Effects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology

OBJECTIVES The purpose of this study was to better understand the effects of long-term right ventricular pacing on left ventricular perfusion, innervation, function and histology. BACKGROUND Long-term right ventricular apical pacing is associated with increased congestive heart failure and mortality compared with atrial pacing. The exact mechanism for these changes is unknown. In this study, left ventricular perfusion, sympathetic innervation, function and histologic appearance after long-term pacing were studied in dogs in an attempt to see whether basic changes might be present that might ultimately be associated with the adverse clinical outcome. METHODS A total of 24 dogs were studied. Sixteen underwent radiofrequency ablation of the atrioventricular (AV) junction to produce complete AV block. Seven of these underwent long-term pacing from the right ventricular apex (ventricular paced group), and nine had atrial and right ventricular apical pacing with AV synchrony (dual-chamber paced group). A control group of eight dogs had sham ablations with normal AV conduction. These dogs had atrial pacing only. Regional perfusion and sympathetic innervation were studied in all dogs by imaging with thallium-201 and [I123]metaiodobenzylguanidine, respectively. The degree of innervation was also determined by assay of tissue norepinephrine levels. Left ventricular function was assessed by radionuclide ventriculography. Cardiac histology was studied with both light and electron microscopy. RESULTS Mismatching of perfusion and innervation in the ventricular paced group was noted, with perfusion abnormalities of both the septum and free wall. Regional [I123]metaiodobenzylguanidine distribution was homogeneous. Tissue norepinephrine levels were elevated in both the ventricular and dual-chamber paced groups compared with the control group. No light or electron microscopic findings were noted in any groups. In the dual-chamber paced group, diastolic dysfunction was noted, with normal systolic function. CONCLUSIONS Ventricular pacing resulted in regional changes in tissue perfusion and heterogeneity between perfusion and sympathetic innervation. Both ventricular and dual-chamber pacing were associated with an increase in tissue catecholamine activity. The abnormal activation of the ventricles via right ventricular apical pacing may result in multiple abnormalities of cardiac function, which may ultimately affect clinical outcome.

Scintigraphic assessment of regional cardiac adrenergic innervation.

To assess the feasibility of noninvasively imaging the regional distribution of myocardial sympathetic innervation, we evaluated the distribution of sympathetic nerve endings, using 123I metaiodobenzylguanidine (MIBG), and compared this with the distribution of myocardial perfusion, using 201Tl. Twenty dogs were studied: 11 after regional denervation, and nine as controls. Regional denervation was done by left stellate ganglion removal, right stellate ganglion removal, and application of phenol to the epicardial surface. Computer-processed functional maps displayed the relative distribution of MIBG and thallium in multiple projections in vivo and excised heart slices in all animals. In six animals, dual isotope emission computed tomograms were acquired in vivo. Tissue samples taken from innervated and denervated regions of the MIBG images were analyzed for norepinephrine content to validate image findings. Normal controls showed homogeneous and parallel distributions of MIBG and thallium in the major left ventricular mass. In the left stellectomized hearts, MIBG was reduced relative to thallium in the posterior left ventricle; whereas in right stellectomized hearts, reduced MIBG was in the anterior left ventricle. Phenol-painted hearts showed a broad area of decreased MIBG extending beyond the area of phenol application. In both stellectomized and phenol-painted hearts, thallium distribution remained homogeneous and normal. Norepinephrine content was greater in regions showing normal MIBG (550 +/- 223 ng/g) compared with regions showing reduced MIBG (39 +/- 44 ng/g) (p less than 0.001), confirming regional denervation. Combined MIBG-thallium functional maps display the regional distribution of sympathetic innervation. This new ability to noninvasively map the distribution of sympathetic nerves with simultaneous comparison to regional perfusion may provide important new insights into mechanisms, whereby an imbalance in sympathetic activity may relate to clinical disorders.

Acute Neurocardiogenic Injury After Subarachnoid Hemorrhage

Background— Left ventricular (LV) systolic dysfunction has been reported in humans with subarachnoid hemorrhage (SAH), and its underlying pathophysiology remains controversial. Possible mechanisms include myocardial ischemia versus excessive catecholamine release from sympathetic nerve terminals. Methods and Results— For 38 months, echocardiography and myocardial scintigraphy with technetium sestamibi (MIBI) and meta-[123I]iodobenzylguanidine (MIBG) were performed on 42 patients admitted with SAH to assess myocardial perfusion and sympathetic innervation, respectively. A blinded observer interpreted the scintigraphic images. Cardiac troponin I (cTI) was measured to quantify the degree of myocyte necrosis. Blinded observers calculated the LV ejection fraction and graded each LV segment as normal (score=1), hypokinetic (score=2), or akinetic (score=3). A wall-motion score was calculated by averaging the sum of the 16 segments. All subjects with interpretable scans (N=41) had normal MIBI uptake. Twelve subjects had either global (n=9) or regional (n=3) absence of MIBG uptake. In comparison with patients with normal MIBG uptake, those with evidence of functional denervation were more likely to have LV regional wall-motion abnormalities (92% versus 52%, P=0.030) and cTI levels >1 &mgr;g/L (58% versus 21%, P=0.029). Conclusions— LV systolic dysfunction in humans with SAH is associated with normal myocardial perfusion and abnormal sympathetic innervation. These findings may be explained by excessive release of norepinephrine from myocardial sympathetic nerves, which could damage both myocytes and nerve terminals.

Buspirone and meperidine synergistically reduce the shivering threshold

Mild hypothermia (i.e., 34°C) may prove therapeutic for patients with stroke, but it usually provokes shivering. We tested the hypothesis that the combination of buspirone (a serotonin 1A partial agonist) and meperidine synergistically reduces the shivering threshold (triggering tympanic membrane temperature) to at least 34°C while producing little sedation or respiratory depression. Eight volunteers each participated on four randomly-assigned days: 1) large-dose oral buspirone (60 mg); 2) large-dose IV meperidine (target plasma concentration of 0.8 &mgr;g/mL); 3) the combination of buspirone (30 mg) and meperidine (0.4 &mgr;g/mL); and 4) a control day without drugs. Core hypothermia was induced by infusion of lactated Ringer’s solution at 4°C. The control shivering threshold was 35.7°C ± 0.2°C. The threshold was 35.0°C ± 0.8°C during large-dose buspirone and 33.4°C ± 0.3°C during large-dose meperidine. The threshold during the combination of the two drugs was 33.4°C ± 0.7°C. There was minimal sedation on the buspirone and combination days and mild sedation on the large-dose meperidine day. End-tidal Pco2 increased ≈10 mm Hg with meperidine alone. Buspirone alone slightly reduced the shivering threshold. The combination of small-dose buspirone and small-dose meperidine acted synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity.

Iodine-123 metaiodobenzylguanidine scintigraphic assessment of the transplanted human heart: Evidence for late reinnervation

OBJECTIVES This study attempted to determine whether cardiac sympathetic reinnervation occurs late after orthotopic heart transplantation. BACKGROUND Metaiodobenzylguanidine (MIBG) is taken up by myocardial sympathetic nerves. Iodine-123 (I-123) MIBG cardiac uptake reflects intact myocardial sympathetic innervation of the heart. Cardiac transplant recipients do not demonstrate I-123 MIBG cardiac uptake when studied < 6 months from transplantation. However, physiologic and biochemical studies suggest that sympathetic reinnervation of the heart can occur > 1 year after transplantation. METHODS We performed serial cardiac I-123 MIBG imaging in 23 cardiac transplant recipients early (< or = 1 year) and late (> 1 year) after operation. In 16 subjects transmyocardial norepinephrine release was measured late after transplantation. RESULTS No subject had visible I-123 MIBG uptake on imaging < 1 year after transplantation. However, 11 (48%) of 23 subjects developed visible cardiac I-123 MIBG uptake 1 to 2 years after transplantation. Only 3 (25%) of 12 subjects with a pretransplantation diagnosis of idiopathic cardiomyopathy demonstrated I-123 MIBG uptake compared with 8 (73%) of 11 with a pretransplantation diagnosis of ischemic or rheumatic heart disease (p = 0.04). All 10 subjects with a net myocardial release of norepinephrine had cardiac I-123 MIBG uptake; all 6 subjects without a net release of norepinephrine had no cardiac I-123 MIBG uptake. CONCLUSIONS Sympathetic reinnervation of the transplanted human heart can occur > 1 year after operation, as assessed by I-123 MIBG imaging and the transmyocardial release of norepinephrine. Reinnervation is less likely to occur in patients with a pretransplantation diagnosis of idiopathic cardiomyopathy than in those with other etiologies of congestive heart failure.

Quantitation of mitral regurgitation by Doppler echocardiography.

The evaluation and care of patients with mitral regurgitation would be facilitated by an easy, reproducible and noninvasive method that could quantitate the hemodynamic burden. In this study, we describe a new Doppler echocardiographic method that measures the regurgitant fraction and we compare it with angiographic and scintigraphic methods. A total of 27 patients with mitral regurgitation were evaluated by echocardiography and either cardiac catheterization or scintigraphy. With two-dimensional echocardiography, diastolic and systolic volumes were measured to derive the left ventricular stroke volume (LVSV). The forward stroke volume (FSV) was obtained from the product of M mode-derived aortic valve area and ascending aortic flow velocity integral assessed by continuous-wave Doppler. Regurgitant fraction was calculated as follows: (LVSV - FSV)/LVSV. Comparisons showed that regurgitant fraction calculated by Doppler echocardiography correlated with regurgitant fraction determined by both cardiac catheterization (r = .82) and by scintigraphy (r = .89). There was, however, an important interobserver variability within each method: 10%, 13%, and 11% for Doppler echocardiography, angiography, and scintigraphy, respectively. In conclusion, Doppler echocardiography can be used to quantitate mitral regurgitation. Serial noninvasive determinations of regurgitant fraction may be useful in the evaluation of therapy and in the follow-up of patients with mitral insufficiency.

Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction.

To evaluate the feasibility of detecting denervated myocardium in the infarcted canine heart, the distribution of sympathetic nerve endings using I-123 metaiodobenzylguanidine (MIBG) was compared with the distribution of perfusion using thallium-201, with the aid of color-coded computer functional map in 16 dogs. Twelve dogs underwent myocardial infarction by injection of vinyl latex into the left anterior descending coronary artery (transmural myocardial infarction, n = 6), or ligation of the left anterior descending coronary artery (nontransmural myocardial infarction, n = 6). Four dogs served as sham-operated controls. Image patterns were compared with tissue norepinephrine content and with histofluorescence microscopic findings in biopsy specimens. Hearts with transmural infarction showed zones of absent MIBG and thallium, indicating scar. Adjacent and distal regions showed reduced MIBG but normal thallium uptake, indicating viable but denervated myocardium. Denervation distal to infarction was confirmed by reduced norepinephrine content and absence of nerve fluorescence. Nontransmural myocardial infarction showed zones of wall thinning with decreased thallium uptake and a greater reduction or absence of MIBG localized to the region of the infarct, with minimal extension of denervation beyond the infarct. Norepinephrine content was significantly reduced in the infarct zone, and nerve fluorescence was absent. These findings suggest that 1) MIBG imaging can detect viable and perfused but denervated myocardium after infarction; and 2) as opposed to the distal denervation produced by transmural infarction, nontransmural infarction may lead to regional ischemic damage of sympathetic nerves, but may spare subepicardial nerve trunks that course through the region of infarction to provide a source of innervation to distal areas of myocardium.

Hypothermia during reperfusion limits ‘no-reflow’ injury in a rabbit model of acute myocardial infarction

OBJECTIVE Reflow following coronary artery occlusion is an important predictor of clinical outcome. This study tests the effects of regional hypothermia, initiated late during ischemia and maintained for 2 h of reperfusion, on the no-reflow phenomenon. METHODS Anesthetized, open-chest New Zealand White rabbits received 30 min of coronary artery occlusion and 3 h reperfusion. Regional myocardial hypothermia (H, n=14), starting 10 min before reperfusion and continuing for 2 h of reperfusion, was compared with normothermia (N, n=14). Regional myocardial blood flow (microspheres) was measured during occlusion and at the end of reperfusion. The anatomic zone of no-reflow (thioflavin S in vivo injection) and infarct size were measured in the ischemic risk region at the end of the study. RESULTS Myocardial temperature in H rabbits was decreased by 5.0+/-0.4 degrees C from baseline (37.1+/-0.2 degrees C) and remained about 32 degrees C during the cooling phase, returning to 36.0+/-0.3 degrees C at 3 h. N hearts remained within 0.2 degrees C of baseline (37.3+/-0.1 degrees C) throughout. Both groups were equally ischemic during occlusion, but at the end of reperfusion reflow to the previously ischemic zone was significantly higher in H, 77+/-5% of normal blood flow versus 36+/-4% in N (P=0.0001). The zone of anatomic no-reflow was significantly smaller in H, 11+/-3% of the ischemic risk zone versus 37+/-3% in N (P=0.0001), and was proportionally smaller when represented as a percent of the necrotic zone 36+/-6% compared with 75+/-5% in N. Infarct size, expressed as a percent of the ischemic risk zone was significantly smaller in H vs. N hearts (27+/-4 and 51+/-5%, P=0.0000). CONCLUSION This study shows that hypothermic therapy initiated late during ischemia and continuing for several hours of reperfusion significantly improves reflow and reduces macroscopic zones of no-reflow and necrosis in this model. The improvement in reflow was greater than would be expected in the H group compared with N, based on the extent of necrosis. As reflow is a predictor of outcome, this intervention may have clinical implications.