Integrated microscopy techniques for comprehensive pathology evaluation of an implantable left atrial pressure sensor.

The safety and efficacy of an implantable left atrial pressure (LAP) monitoring system is being evaluated in a clinical trial setting. Because the number of available specimens from the clinical trial for histopathology analysis is limited, it is beneficial to maximize the usage of each available specimen by relying on integrated microscopy techniques. The aim of this study is to demonstrate how a comprehensive pathology analysis of a single specimen may be reliably achieved using integrated microscopy techniques. Integrated microscopy techniques consisting of high-resolution gross digital photography followed by micro-computed tomography (micro-CT) scanning, low-vacuum scanning electron microscopy (LVSEM), and microground histology with special stains were applied to the same specimen. Integrated microscopy techniques were applied to eight human specimens. Micro-CT evaluation was beneficial for pinpointing the location and position of the device within the tissue, and for identifying any areas of interest or structural flaws that required additional examination. Usage of LVSEM was reliable in analyzing surface topography and cell type without destroying the integrity of the specimen. Following LVSEM, the specimen remained suitable for embedding in plastic and sectioning for light microscopy, using the positional data gathered from the micro-CT to intersect areas of interest in the slide. Finally, hematoxylin and eosin (H&E) and methylene blue staining was deployed on the slides with high-resolution results. The integration of multiple techniques on a single specimen maximized the usage of the limited number of available specimens from the clinical trial setting. Additionally, this integrated microscopic evaluation approach was found to have the added benefit of providing greater assurance of the derived conclusions because it was possible to cross-validate the results from multiple tests on the same specimen.

Radiofrequency ablation for common atrial flutter using an 8-mm tip catheter and up to 150 W.

The formation of bi-directional block in atrial flutter can be adversely affected by problems with the delivery of effective energy related to isthmus anatomy and contact. Higher energies can produce larger and more effective lesions. The optimum setting for power delivery using temperature controlled ablation has not been established, with the maximum reported being 100 W. This is a retrospective review of the first 50 new cases assessing the efficacy and safety of using temperature controlled (60-65 degrees C) flutter ablation with an 8mm tip electrode catheter and up to 150 W. All cases had either typical flutter alone (34%) or predominant flutter as the indication, no combined procedures were included. Acute procedural success was 94% and long-term success of 88%. Median number of ablations required was 11 (interquartile range 10-19), median procedure time 120 min (IQR 102-164), fluoroscopy time 22 min (IQR 17-36), radiation dose 17 Gy cm(2) (IQR 10-27), median number of lines 1 (IQR 1-2). Six patients achieved 150 W, but 42 achieved >100 W (median watts 142 W, IQR 104-147). Patients (12%) experienced an uncomplicated pop during the procedure. None experienced a significant complication. There were three late relapses. The setting of 150 W maximum delivered energy in temperature regulated ablation allowed higher energies (>100 W) to be delivered in most patients. This resulted in acute and long-term success rates that compare well with the literature but is associated with a 12% rate of pop. Subsequent to this series our 54th patient sustained a pop due to high energy ablation that resulted in perforation and tamponade, from which there was survival.

Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope.

The importance of cardiac output (CO) to blood pressure level during vasovagal syncope is unknown. We measured thermodilution CO, mean blood pressure (MBP), and leg muscle mean sympathetic nerve activity (MSNA) each minute during 60 degrees head-up tilt in 26 patients with recurrent syncope. Eight patients tolerated tilt (TT) for 45 min (mean age 60 +/- 5 yr) and 15 patients developed syncope during tilt (TS) (mean age 58 +/- 4 yr, mean tilt time 15.4 +/- 2 min). In TT patients, CO decreased during the first minute of tilt (from 3.2 +/- 0.2 to 2.5 +/- 0.3 l x min(-1) x m(-2), P = 0.001) and thereafter remained stable between 2.5 +/- 0.3 (P = 0.001) and 2.4 +/- 0.2 l x min(-1) x m(-2) (P = 0.004) at 5 and 45 min, respectively. In TS patients, CO decreased during the first minute (from 3.3 +/- 0.2 to 2.7 +/- 0.1 l x min(-1) x m(-2), P = 0.02) and was stable until 7 min before syncope, falling to 2.0 +/- 0.2 at syncope (P = 0.001). Regression slopes for CO versus time during tilt were -0.01 min(-1) in TT versus -0.1 l x min(-1) x m(-2) x min(-1) in TS (P = 0.001). However, MBP was more closely correlated to total peripheral resistance (R = 0.56, P = 0.001) and MSNA (R = 0.58, P = 0.001) than CO (R = 0.32, P = 0.001). In vasovagal reactions, a progressive decline in CO may contribute to hypotension some minutes before syncope occurs.

Effects of omapatrilat on systemic arterial function in patients with chronic heart failure.

The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction < or = 40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 +/- 4.5 vs 2.8 +/- 5.0 mm Hg, p < 0.05) and mean arterial (13.9 +/- 3.0 vs 0.3 +/- 3.3 mm Hg, p < 0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was improved with a dose-related decrease in augmentation index (-13.8 +/- 1.7% vs +6.1 +/- 2.1%, p < 0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the high-dose groups compared with the control group (+266 +/- 43% vs - 14 +/- 92%, p < 0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 +/- 11 vs -2 +/- 7 pmol/L, p < 0.01) in high-dose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure.

The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure.

OBJECTIVES: We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure. BACKGROUND: The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented. METHODS: Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF)< or =40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks. RESULTS: There was an improvement in functional status, as reported by the patient (p<0.001) and physician (p<0.001) at 12 weeks. Dose-dependent improvements in LVEF (p<0.001) and LV end-systolic wall stress (sigma) (p<0.05) were seen, together with a reduction in systolic blood pressure (p<0.05). There was evidence of a natriuretic effect (p<0.001), and total blood volume decreased (p<0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p<0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p<0.001) and epinephrine (p<0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated. CONCLUSIONS: The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.

Baroreceptor denervation presenting as part of a vagal mononeuropathy.

A 48-year-old woman presented with a history of progressive cough, dysphonia, dysphagia, and postural symptoms. Subsequent neurological investigations were consistent with a bilateral vagal mononeuropathy, and neurosarcoidosis was diagnosed after scalene node biopsy. Autonomic investigations including microneurography, neurohormones, and heart rate variability demonstrated arterial and cardiopulmonary baroreflex failure. In addition, parasympathetic control of heart rate was absent and consistent with a bilateral, nonselective lesion in the proximal vagus.

Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group.

OBJECTIVE: To determine the relations of plasma levels of brain natriuretic peptide (BNP), atrial natriuretic factor (ANF), N-terminal ANF (N-ANF), cyclic guanosine monophosphate (cGMP; the cardiac peptide second messenger), and plasma catecholamines to left ventricular function and to prognosis in patients admitted with acute myocardial infarction. DESIGN: Plasma hormones and ventricular function (radionuclide ventriculography) were measured 1-4 days after myocardial infarction in 220 patients admitted to a single coronary care unit. Radionuclide scanning was repeated 3-5 months after infarction. Clinical events were recorded over a mean period of 14 months. RESULTS: Both early and late left ventricular ejection fraction (LVEF) were most closely related to plasma BNP (r = -0.60, n = 220, p < 0.001; and r = -0.53, n = 192, p < 0.001, respectively), followed by ANF, N-ANF, cGMP, and the plasma catecholamines. Early plasma BNP concentrations less than twofold the upper limit of normal (20 pmol/l) had 100% negative predictive value for LVEF < 40% at 3-5 months after infarction. In multivariate analysis incorporating all the neurohormonal factors, only BNP remained independently predictive of LVEF < 40% (p < 0.005). Survival analysis by median levels of candidate predictors identified BNP as the most powerful discriminator for death (p < 0.0001). No early deaths (within 4 months) occurred in patients with plasma BNP concentrations below the group median (27 pmol/l), and over follow up only three of 26 deaths occurred in this subgroup. Of all episodes of left ventricular failure, 85% occurred in patients with plasma BNP above the median (p < 0.001). In multivariate analyses, BNP alone gave additional predictive information beyond sex, age, clinical history, LVEF, and plasma noradrenaline for both subsequent onset of LVF and death. CONCLUSIONS: Plasma BNP measured within 1-4 days of acute myocardial infarction is a powerful independent predictor of left ventricular function, heart failure, or death over the subsequent 14 months, and superior to ANF, N-ANF, cGMP, and plasma catecholamines.

Autonomic control of vasovagal syncope.

In the pathophysiological study of vasovagal syncope, the nature of the interaction between baroreceptor sensitivity (BS), sympathetic withdrawal, and parasympathetic activity has yet to be ascertained. Altered BS may predispose toward abnormal sympathetic and parasympathetic responses to orthostasis, causing hypotension that may progress to syncope if there is sympathetic withdrawal. To examine this hypothesis, we monitored blood pressure (BP), heart rate (HR), BS, forearm blood flow, and muscle nerve sympathetic activity (MNSA) continuously in 18 vasovagal patients during 60 degrees head-up tilt, syncope, and recovery. Results were compared with those of 17 patients who were able to tolerate tilt for 45 min. During early tilt, BP was maintained in both groups by an increase in HR and MNSA from baseline (P < 0.01), but BS decreased more in the syncopal group (P < 0.05). At the start of presyncope (mean 2.7 +/- 0.2 min before syncope and 15.2 +/- 12 min after tilt), when BP fell, HR and sympathetic activity remained increased from baseline (P < 0.01). Thereafter, BP and HR correlated directly with sympathetic activity and regressed in linear fashion until syncope (P < 0.001), whereas BS increased to baseline. At syncope, BP, HR, and sympathetic activity fell below baseline (P < 0.01, P < 0.05, and P < 0.01, respectively), but BS did not increase. During recovery, sympathetic activity increased to baseline and BS increased (P < 0.05), whereas HR and BP remained low (P < 0.01 and P < 0.05, respectively). The mechanism for the initiation of hypotension during presyncope remains unknown, but BS may contribute. Vasodilatation and bradycardia during presyncope appear to be more closely related to withdrawal of sympathetic activity than to increased parasympathetic cardiac activity.

Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction.

BACKGROUND: Newly discovered circulating peptides, N-terminal pro-brain natriuretic peptide (N-BNP) and adrenomedullin (ADM), were examined for prediction of cardiac function and prognosis and compared with previously reported markers in 121 patients with myocardial infarction. METHODS AND RESULTS: The association between radionuclide left ventricular ejection fraction (LVEF) and N-BNP at 2 to 4 days (r=-.63, P<.0001) and 3 to 5 months (r=-.58, P<.0001) after infarction was comparable to that for C-terminal BNP and far stronger than for ADM (r=-.26, P<.01), N-terminal atrial natriuretic peptide (N-ANP), C-terminal ANP, cGMP, or plasma catecholamine concentrations. For prediction of death over 24 months of follow-up, an early postinfarction N-BNP level > or = 160 pmol/L had sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 72%, 39%, and 97%, respectively, and was superior to any other neurohormone measured and to LVEF. Only 1 of 21 deaths occurred in a patient with an N-BNP level below the group median (Kaplan-Meier survival analysis, P<.00001). For prediction of heart failure (left ventricular failure), plasma N-BNP > or = 145 pmol/L had sensitivity (85%) and negative predictive value (91%) comparable to the other cardiac peptides and was superior to ADM, plasma catecholamines, and LVEF. By multivariate analysis, N-BNP but not ADM provided predictive information for death and left ventricular failure independent of patient age, sex, LVEF, levels of other hormones, and previous history of heart failure, myocardial infarction, hypertension, or diabetes. CONCLUSIONS: Plasma N-BNP measured 2 to 4 days after myocardial infarction independently predicted left ventricular function and 2-year survival. Stratification of patients into low- and high-risk groups can be facilitated by plasma N-BNP or BNP measurements, and one of these could reasonably be included in the routine clinical workup of patients after myocardial infarction.

Neurohormonal response to head-up tilt and its role in vasovagal syncope.

In a controlled study, 26 patients with a history of recurrent syncope were found to have increased arginine vasopressin, corticotrophin, and atrial natriuretic factor levels after 5 minutes of 60 degrees head-up tilt, long before they became hypotensive. The exaggerated neurohormonal response in these patients may indicate a greater sensitivity to central hypovolemia which may predispose to vasovagal syncope, mediated by the vasodilatory effects of atrial natriuretic factor or the sensitization of mechanoreceptors by arginine vasopressin.

Autonomic control of asystolic vasovagal syncope.

A 30 year old woman with a lifelong history of severe, recurrent, vasovagal syncope became asystolic for 30 seconds after 37 minutes of 60 degrees head-up tilt. During early tilt, sympathetic activity, heart rate, left ventricular contractility, and cardiac output increased. Mean blood pressure was initially maintained. Presyncope was associated with maximal contractility and bradycardia despite sustained sympathetic activity. Subsequently, asystole occurred associated with complete withdrawal of muscle nerve sympathetic activity. In asystolic vasovagal reactions, presyncope may be triggered by increased left ventricular contractility and is associated with increased levels of parasympathetic and sympathetic activity. Asystole and peripheral vasodilatation may be caused by sudden and complete withdrawal of the increased sympathetic activity.

Plasma cortisol, PRL, ACTH, AVP and corticotrophin releasing hormone responses to direct current cardioversion and electroconvulsive therapy.

OBJECTIVE: We aimed to evaluate and contrast the hypothalamo-pituitary-adrenal (HPA) response to direct current (DC) cardioversion and electroconvulsive therapy (ECT). SUBJECTS: Six male subjects (mean age 61.2 years, range 46-74) with chronic atrial fibrillation were selected for cardioversion. Six subjects with depression (one male, five female; mean age 43.2 years, range 31-59) were selected for ECT. Those taking glucocorticoid drugs, opiates or beta-adrenoceptor antagonists were excluded. MEASUREMENTS: Patients attended for serial blood sampling on the day of cardioversion or ECT, and for an equivalent time period on a control day at least one week before. Intravenous propofol was given to each subject for anaesthesia on the day of cardioversion or ECT. On both study and control days, blood samples were taken at -30, -15, 0 (just prior to cardioversion or ECT), +5, +10, +15, +30, +60, +90 and +120 minutes for assay of cortisol, PRL, ACTH, AVP and CRH. RESULTS: For cardioversion: plasma cortisol increased from 252.5 +/- 39.8 to a maximum of 721.3 +/- 50 nmol/l at 30 minutes (P < 0.0001 compared with control day). ACTH increased from 12.8 +/- 2.8 to a maximum of 64 +/- 14 pmol/l at 5 minutes (P < 0.0001 compared with control day). AVP increased from 6.6 +/- 3.3 to a maximum of 42.9 +/- 16 pmol/l at 5 minutes post-cardioversion (P < 0.005 compared with control day). PRL increased from 141 +/- 28 mlU/l to a maximum of 873 +/- 219 mlU/l at 10 minutes (P < 0.001 compared with control day). There was no significant difference in CRH responses between cardioversion and control days. There was no significant correlation between total electrical energy delivered and maximum ACTH and AVP responses (R = 0.54 and -0.13, respectively). For ECT: on the day of ECT plasma cortisol increased from 419.5 +/- 25.9 to a maximum of 614.7 +/- 26.9 nmol/l (P < 0.002 compared with control day). ACTH increased from 22.7 +/- 6.2 to a maximum of 77.8 +/- 19.1 pmol/l (P < 0.0003 compared with control day). PRL increased from 771 +/- 317 to a maximum of 3152 +/- 703 mlU/l (P < 0.001 compared with control day, and significantly greater than the peak response to cardioversion, P < 0.03). AVP increased from 13.0 +/- 10.8 to a maximum of 35.1 +/- 5.6 pmol/l (P < 0.02 compared with control day). There was no significant difference in CRH responses between ECT and control days. Peak cortisol and ACTH responses did not differ significantly between ECT and cardioversion. Baseline cortisol levels, however, were significantly higher in the depressed group compared with the cardioversion group, P < 0.02, but not ACTH or AVP. CONCLUSION: Significant hypothalamic-pituitary-adrenal activation and PRL release occur in response to both cardioversion and ECT. AVP may have an important role in mediating the acute ACTH response to electrical stimulation.

Hemodynamic comparison of dopexamine and nitroprusside at high and low doses in patients with coronary artery disease and impaired left ventricular function.

Pure vasodilator drugs are currently the preferred agents for treatment of acute and chronic heart failure of all grades of severity. In contrast, the role of drugs that combine vasodilation with inotropic action remains highly controversial despite their several advantageous physiological actions and long therapeutic history in heart failure. We hypothesize that this uncertainty might be due first to subtle unfavorable hemodynamic effects not detectable by the relatively crude hemodynamic methods by which these agents are usually analyzed, particularly with regard to the quantification of afterload, and secondly to the narrow therapeutic range of these drugs, such that the dose administered is critical. We tested this hypothesis by comparing several refined hemodynamic measurements of dopexamine, an inotropic vasodilator, with a pure arteriovenous dilator (sodium nitroprusside, SNP) on left ventricular (LV) systolic and diastolic function, large arterial behavior, and coupling of the left ventricle to the arterial system at two dose levels in 35 patients with ischemic heart disease. The study protocol was a fixed order of 15-min infusions of saline, dopexamine 1 microg/kg/min, and dopexamine 3 + ++microg/kg/min, or saline, SNP 1 microg/kg/min, and SNP 3 microg/kg/min. Detailed hemodynamic observations were made at the end of each 15-min infusion period. Both drugs produced equivalent arterial vasodilation, as measured by the decrease in systemic vascular resistance index (SVRI), but dopexamine resulted in a significantly greater increase in cardiac index (CI). Myocardial contractility, assessed by several load-independent indexes, increased with dopexamine, as anticipated with an inotropic drug, but did not alter with SNP. Arterial compliance, a measure of the distensibility of large conduit arteries, was increased by SNP but not by dopexamine. Arterial wave reflection was increased by dopexamine, especially at high doses, but reduced by SNP. Increased arterial compliance and reduced wave reflection reduce LV afterload. SNP reduced preload, whereas dopexamine had no effect on this aspect of ventricular function. Vasodilator drugs and those which combine vasodilator and inotropy increase cardiac output (CO) and reduce SVR. Therapy with inotropic vasodilators has no effect on preload and does not reduce the dynamic components of ventricular afterload, although it does reduce its static components. These effects are dose dependent; there is less perturbation of afterload at lower doses. In contrast, vasodilator therapy reduces preload and both static and dynamic parts of afterload.

Neurohormonal changes after acute myocardial infarction. Relationships with haemodynamic indices and effects of ACE inhibition.

To determine the neurohormonal response to angiotensin-converting enzyme (ACE) inhibition after acute myocardial infarction, 36 patients presenting within 6 h of the onset of chest pain were studied in a single regional cardiology service. In this double-blind study, 13 patients were randomized to receive captopril, 12 patients received enalapril, and 11 patients received placebo, for 12 months. In patients receiving placebo, acute myocardial infarction was associated with activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, and stimulation of plasma brain natriuretic peptide and atrial natriuretic peptide levels. ACE inhibition did not significantly alter circulating levels of norepinephrine, brain natriuretic peptide or atrial natriuretic peptide. Compared with placebo, enalapril induced a steep decline in plasma ACE activity, and plasma angiotensin II levels were reduced by both ACE inhibitors. Using grouped data, circulating levels of brain natriuretic peptide at the zero sampling time were significantly higher than atrial natriuretic peptide values. Brain natriuretic peptide levels at 72 h were significantly correlated with the radionuclide left ventricular ejection fraction measured 5 days and 3 months after infarction. Similar associations were observed for atrial natriuretic peptide and norepinephrine. We confirm activation of the renin-angiotensin-aldosterone and sympathetic nervous systems after acute myocardial infarction. The atrial natriuretic peptide and brain natriuretic peptide and sympathetic nervous system responses to acute myocardial infarction were not significantly modified by ACE inhibition. Brain natriuretic peptide and atrial natriuretic peptide levels were significantly correlated with the left ventricular ejection fraction measured 5 days and again 3 months after myocardial infarction, and may prove a useful prognostic index.

Blockade of the renin-angiotensin system.

HISTORICAL OVERVIEW: Milestones in understanding the renin-angiotensin system (RAS) until the development of angiotensin II antagonists are described briefly. Sites at which the RAS might be blocked are outlined. PEPTIDE ANALOGUE ANTAGONISTS OF ANGIOTENSIN II RECEPTORS: Saralasin-like compounds were used in numerous experimental and clinical situations and clarified the role of the RAS. Some of these situations are described (e.g. hypertension and cardiac failure) particularly in regard to the control of arterial pressure and aldosterone secretion by the RAS. Saralasin and its analogues allowed visualization, for the first time, of complete angiotensin II/effector (especially blood pressure) dose-response curves. ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: The clinical usefulness of ACE inhibitors in hypertension, cardiac failure, diabetes mellitus and after acute myocardial infarction is emphasized. In particular, ACE inhibitors have actions beyond blockade of angiotensin II formation, necessitating cautious interpretation of data from their use. RENIN INHIBITORS: Experience with renin inhibitors in documenting and confirming the role of the RAS is outlined. NON-PEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS: Characteristics of losartan-like compounds are discussed in brief, and the results of their limited use in clinical medicine are outlined. CONCLUSION: Blocking agents have led to great advances in knowledge of the RAS and its physiological and pathophysiological functions. ACE inhibitors are used regularly in a number of clinical disorders and, in theory, have therapeutic potential beyond alternative antihypertensive drugs in the prevention of cardiovascular complications in essential hypertension. The place of renin inhibitors and angiotensin II receptor antagonists in clinical practice, however, remains to be determined.