https://www.infekt.ch/content/uploads/2013/11/jc_juli11_horvath.pdf

Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial

Objective. —To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure. Data Sources and Study Selection. —Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat, regardless of sample size. Trials were identified based on literature review and correspondence with investigators and pharmaceutical firms. Data Extraction. —Using standard tables, data were extracted by one author and confirmed where necessary by the other author or the principal investigator of the trial. Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm. Data Synthesis. —The data for each outcome were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method. Overall, there was a statistically significant reduction in total mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.67 to 0.88;P Conclusions. —Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients. (JAMA. 1995;273:1450-1456)

https://jamanetwork.com/journals/jama/articlepdf/388358/jama_273_18_040.pdf

Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure

Background We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure. Methods and Results Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, ...

Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects With Chronic Heart Failure

The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 +/- 68 pg/ml (mean +/- SE) compared with 211 +/- 21 pg/ml in 15 subjects without heart failure (p less than .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 +/- 9 vs 5 +/- 1 ng/min; p less than .002) and renal (202 +/- 45 vs 66 +/- 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 +/- 38 pg/ml compared with 71 +/- 12 pg/ml in control subjects (p less than .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications.

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

Given the importance of the autonomic nervous system to cardiovascular health, it is not surprising that there is and has been great interest in measurements of human sympathetic and vagus nerve traffic as tools that might inform physiological and pathophysiological mechanisms. Pagani and coworkers1 advanced the provocative notion that the instantaneous balance between sympathetic and vagal nerve activities can be captured by a single number, obtained by dividing RR-interval spectral power centered at ≈0.1 Hz by spectral power centered at higher, primarily respiratory frequencies. This ratio, or sympathovagal balance, has been embraced with great enthusiasm2 because it offers new possibilities for understanding dynamic, critically important autonomic interrelations in humans by the use of totally noninvasive, unobtrusive means.3

The broad bases for this mathematical treatment are as follows: (1) 0.1-Hz RR intervals are importantly mediated by fluctuations of sympathetic nerve activity; (2) higher-frequency RR-interval rhythms are mediated almost exclusively by fluctuations of vagal-cardiac nerve activity; and (3) physiological interventions tend to provoke reciprocal changes of sympathetic and vagal neural outflows. Sympathovagal balance, the ratio of these periodicities, is taken to reflect the balance between the opposing neural mechanisms. This review examines the physiological foundations of sympathovagal balance.

The ECG is recorded with the subject in a steady state (when rhythms are stationary) for a period sufficiently long to define events occurring over frequencies of interest. RR-interval spectral power is calculated from this series of intervals with an autoregressive algorithm, which yields center frequencies and absolute power of component fluctuations, based on a model whose order (the number of parameters) is selected automatically to minimize Akaike’s information criterion statistic.4 (The statistical uncertainty and consequences of the automatic selection of the autoregressive model have not been defined fully; however, it is clear that the model order importantly determines both …

Sympathovagal Balance A Critical Appraisal

Plasma noradrenaline measurements are a fallible guide to sympathetic nervous tone, being dependent on noradrenaline plasma clearance. We have developed radiotracer techniques, based on measurement of the rate of spillover of noradrenaline to plasma, to simultaneously estimate total, and organ-specific, sympathetic nervous activity in humans. In 27 unmedicated subjects without renal or liver disease, or cardiac failure, regional noradrenaline spillover rates were as follows: lungs 138 +/- 36 ng/min (mean +/- SE) (33% of total noradrenaline spillover), kidneys 77 +/- 10 ng/min (22% of total), skeletal muscle 64 +/- 11 ng/min (20%), hepatomesenteric 29 +/- 9 ng/min (9%), skin 18 +/- 4 ng/min (5%), and heart 11 +/- 4 ng/min (3%). Organ-specific noradrenaline spillover measurements are well suited to the elucidation of sympathetic nervous system pathophysiology in human diseases. Since the sympathetic nervous system outflow to individual organs is not activated or suppressed uniformly in different disease states, biochemical measures of "overall sympathetic nervous activity" are insufficiently specific for this purpose.

Contribution of individual organs to total noradrenaline release in humans.

Recently developed radiotracer methods for measuring the overall rate of release of noradrenaline to plasma, for the body as a whole, can be used to estimate 'total sympathetic nervous system activity' in humans. These techniques find application in clinical studies of sympathetic nervous physiology and pharmacology. The inherent weakness of any biochemical test of global sympathetic tone such as this lies in the fact that sympathetic nervous system responses typically show regional differentiation. Biochemical indices of overall sympathetic activity are insufficiently discriminating to delineate patterns of sympathetic nervous response, representing instead an algebraic sum of all regional increases or decreases in sympathetic tone. Modification of the whole-body radiotracer methodology enables organ-specific sympathetic nervous system activity to be estimated, from measurements of regional release of noradrenaline to plasma. This should facilitate investigation of possible sympathetic pathophysiology in disease states. Illustrative of potential application of the method are preliminary findings of increased renal sympathetic nervous tone in young patients with essential hypertension, and of selective activation of sympathetic nerves to the kidney by diuretics.

Plasma noradrenaline kinetics in humans

The overall rate of release of noradrenaline to plasma was increased in 31 patients with essential hypertension; the median value was 32% (526 pmol/min) higher than in 22 subjects with normal blood pressure. To ascertain the pattern of sympathetic nervous system activation underlying this abnormality, regional sympathetic nervous activity was estimated, from radiotracer-derived estimates of organ-specific noradrenaline release to plasma, in the kidneys, heart and hepatomesenteric circulation. Renal sympathetic nervous tone was preferentially increased in essential hypertension, especially in young patients with hypersecretion of renin. Cardiac noradrenaline release (and possibly cardiac sympathetic tone) was also higher in hypertensive patients; the difficulty in interpretation here arises because left ventricular mass is also increased in essential hypertension. Approximately half of the surfeit in total noradrenaline release to plasma noted in hypertensive patients was accounted for by the increased cardio-renal noradrenaline release. The balance comes from undetermined sites, but not from the splanchnic circulation, in which sympathetic nervous activity was not increased.

Estimation of 'total' renal, cardiac and splanchnic sympathetic nervous tone in essential hypertension from measurements of noradrenaline release.

The effects of the new, orally administered converting-enzyme inhibitor, enalapril (MK-421), were studied in 12 ambulatory patients with severe cardiac failure who were also receiving digoxin and diuretic agents. The study was double-blind, parallel, placebo-controlled and randomized. The clinical characteristics and pretreatment exercise performance were similar in the two groups of patients. All vasodilator drugs had been withdrawn two weeks before the start of the trial. At 12 weeks, the patients receiving enalapril showed a significant improvement in the functional class of the disease, exercise time (P less than 0.01), and maximum workload achieved, and experienced relief of symptoms. Blood pressure fell in patients receiving active treatment suggesting a reduction of afterload. Left ventricular ejection fraction was unchanged in enalapril-treated patients, but fell in patients on placebo (P less than 0.001). Enalapril was well tolerated without apparent adverse effects. It was effective when used with digoxin and diuretic agents in the treatment of severe cardiac failure, and its efficacy was maintained throughout 12 weeks of therapy.

Johns J

Papers

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

Contribution of individual organs to total noradrenaline release in humans.

Plasma noradrenaline kinetics in humans

Estimation of 'total' renal, cardiac and splanchnic sympathetic nervous tone in essential hypertension from measurements of noradrenaline release.

Enalapril for severe congestive heart failure. A double-blind study.