Tenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype.

Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR-CA). The prevalence of upper limb tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson-Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved. OBJECTIVE: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR-CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history. PARTICIPANTS: Consecutive patients with a diagnosis of ATTR-CA, HCM and AFD were evaluated. A control group of consecutive patients was recruited among subjects hospitalized for noncardiac reasons and no cardiac disease history. The presence of BBTR, CTS or prior surgery related to these conditions was ascertained. RESULTS: 342 patients were prospectively enrolled, including 168 ATTR-CA (141 ATTRwt, 27 ATTRm), 81 with HCM/AFD (N = 72 and 9, respectively) and 93 controls. CTS was present in 75% ATTR-CA patients, compared with 13% and 10% of HCM/AFD and controls (P = 0.0001 for both comparisons). Bilateral CTS was present in 60% of ATTR-CA patients, while it was rare (2%) in the other groups. BBTR was present in 44% of ATTR-CA patients, 8% of controls and 1% in HCM/AFD. CONCLUSIONS: CTS and BBTR are fivefold more prevalent in ATTR-CA patients compared with cardiac patients with other hypertrophic phenotypes. Positive predictive accuracy for ATTR-CA is highest when involvement is bilateral. Upper limb assessment of patients with HCM phenotypes is a simple and effective way to raise suspicion of ATTR-CA.

Correction to: A priori dietary patterns and blood pressure in the EPIC Florence cohort: a cross-sectional study.

In the original publication of the article have been published in an incorrect form. The correct form is given below.

A priori dietary patterns and blood pressure in the EPIC Florence cohort: a cross-sectional study.

PURPOSE: Several foods and nutrients have been independently associated with systolic (SBP) and diastolic (DBP) blood pressure values. This study aimed to evaluate the effects of combined dietary habits on SBP and DBP values in a large cohort of healthy adults, with a cross-sectional design. Adherence of participants to four a priori dietary patterns was considered: the Healthy Eating Index 2010 (HEI-2010); the Dietary Approaches to Stop Hypertension (DASH); the Greek Mediterranean Diet Score (MDS); and the Italian Mediterranean Index (IMI). METHODS: Overall, 13,597 volunteers (35-64 years) were enrolled in 1993-1998 in the EPIC-Florence cohort. Information on dietary habits, anthropometry, smoking status, education, physical activity habits, previous diagnosis of hypertension and SBP and DBP measurements were collected at baseline. Multivariate regression models were performed on 10,163 individuals (7551 women) after excluding subjects with prevalent hypertension. RESULTS: IMI, DASH and HEI-2010 were significantly and inversely associated with SBP and DBP values in the total population. The strongest association emerged between IMI and SBP (ß - 1.80 excellent adherence vs low adherence, 95% CI - 2.99; - 0.61, p trend 0.001) and DBP (ß - 1.12, 95% CI - 1.869; - 0.39, p trend 0.001) values. In sub-group analyses, an inverse association also emerged between IMI and SBP and DBP values among females and between DASH and DBP among males. MDS was not associated with SBP or DBP. CONCLUSION: Overall, this study, carried out in a large cohort of healthy adults from Tuscany (Central Italy), showed inverse significant associations between specific a priori dietary patterns, identifying general models of health-conscious diet, and blood pressure values.

Physical activity and blood pressure in 10,000 Mediterranean adults: The EPIC-Florence cohort.

BACKGROUND AND AIMS: The relevant role of physical activity (PA) in cardiovascular risk prevention is widely agreed. We aimed to evaluate, in a large Mediterranean population, the influence of PA on systolic (SBP) and diastolic blood pressure (DBP), taking into account individual characteristics and lifestyle habits. METHODS AND RESULTS: In the Florence section of the European Prospective Investigation into Cancer and Nutrition 10,163 individuals, 35-64 years, without a previous diagnosis of hypertension were recruited. Information on occupational and leisure-time PA and blood pressure were collected at recruitment, together with data on lifestyle, dietary habits and anthropometry. Multivariate regression models were applied to evaluate the effect of total, occupational and leisure-time PA on SBP and DBP. Mean values of SBP and DBP in the study subjects were 124.4 (SD 15.6) and 79.7 mmHg (SD 9.4), respectively. Overall, a total PA index and an index including cycling, fitness and occupational PA (Cambridge index) were inversely associated with DBP (beta -0.87, p-value 0.02 actives vs inactives, p for trend 0.02 and beta -0.84, p value 0.003 actives vs inactives, p for trend 0.002, respectively), while SBP was associated only with the latter index (beta -1.14, p-value 0.01 actives vs inactives, p for trend 0.006). An inverse association emerged between manual/heavy manual occupation and DBP (p 0.02, ref sedentary/standing occupation) and between increasing cycling activity and SBP (p for trend 0.04). CONCLUSIONS: In this large cohort of Mediterranean adults without a diagnosis of hypertension we confirm the role of overall PA in modulating SBP and DBP values. Cycling and manual occupations were associated with lower DBP values.

Clinical aspects and diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls.

OBJECTIVE: To evaluate the diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls compared to those with a syncope etiologically unexplained after initial evaluation. METHODS: It is an observational study, comparing 298 patients with unexplained fall with 989 patients with unexplained syncope. Each patient underwent supine and upright blood pressure measurement, tilt testing (TT) and carotid sinus massage (CSM). RESULTS: Patients with unexplained falls were older (75.3 ± 11.1 vs. 63.2 ± 19.2 years, p < 0.001), were more frequently hypertensive (66.1 vs. 47.2 %, p < 0.001) and more frequently prescribed antihypertensive drugs (62.4 vs. 48.7 %, p < 0.001) or benzodiazepines (15.7 vs. 10.6 %, p = 0.01), and in a greater proportion they experienced major traumatic injuries (77.5 vs. 29.6 %, p < 0.001) as a consequence of falls. The TT was less frequently positive in patients with unexplained falls (36 vs. 51.3 %, p < 0.001), whereas a Carotid Sinus Syndrome as suggested by CSM had a similar prevalence in the two groups (14.3 vs. 10.5 %, p = 0.074). Overall, either TT or CSM were positive in 61 % of patients with unexplained falls, and in 64 % of those with syncope (p = 0.346). After matching by age 298 patients with falls (75.3 ± 11.1 years) and 298 patients with unexplained syncope (75.4 ± 11.1 years), we found that the positivity prevalence of TT and CSM were similar in the two groups. CONCLUSIONS: The positivity prevalence of TT and CSM in patients with unexplained falls compared to patients with unexplained syncope is similar. Given its high diagnostic relevance, the neuroautonomic evaluation should be routinely performed in older patients with unexplained falls.

Effects of antihypertensive treatments on incidence of diabetes: a case-control study.

AIMS: Aim of this case-control study is the assessment of the relationship between antihypertensive treatment and incidence of diabetes in an unselected cohort of subjects participating in a screening program for diabetes. METHODS: A case-control study nested within a cohort of nondiabetic subjects with a mean follow-up of 27.7 ± 11.3 months was performed, comparing 40 cases of incident diabetes and 160 controls matched for age, sex, body mass index, fasting plasma glucose, 2-h post-load glycemia, smoking and alcohol abuse. RESULTS: When considering antihypertensive treatment at enrolment, a lower proportion of cases was exposed to ACE-inhibitors/angiotensin receptor blockers (ACE-i/ARB) in comparison with controls. A non-significant trend toward a higher exposure to diuretics, which were mainly represented by thiazide diuretics, was observed in cases. In a multivariate analysis, including both ACE-i/ARB and diuretics, a protective effect of ACEi/ARB, and an increased risk with diuretics were observed. Similar results were obtained in alternative models, after adjusting for systolic and diastolic blood pressure at enrolment, diagnosis of hypertension, concurrent treatment with ß-blockers or calcium-channel blockers, and number of antihypertensive medications. CONCLUSIONS: Diuretics seem to be associated with a higher incidence of diabetes, whereas treatment with ACEi/ARB could have a protective effect.

Supine hypertension: A state of the art.

Patients with cardiovascular autonomic failure (AF) may suffer from neurogenic supine hypertension (nSH), defined as systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, after 5 min of rest in the supine position, combined with neurogenic orthostatic hypotension (nOH) in approximately 50% of the cases. nSH may be the manifestation of central or peripheral autonomic lesions. Long-term risks are hypothesized with SH, including renal dysfunction, left ventricular hypertrophy, cerebrovascular disease and cognitive impairment. Yet, large longitudinal studies investigating long-term outcomes of nSH are lacking. In clinical practice, nSH should be investigated in patients with nOH. Office screening should be performed measuring supine BP immediately after lying down and 5 min later, combined with BP measurement on active or passive standing. Home BP recordings performed by patients themselves may also be useful, while 24 h-Ambulatory Blood Pressure Monitoring (ABPM) may allow for detection of nocturnal hypertension and confirm the diagnosis. Current expert recommendations suggest treatment interventions if SBP exceeds 160-180 mmHg. Non-pharmacological strategies represent the first-line treatment approach and include head-up sleeping, avoiding supine position during the daytime, and having a snack before bedtime to lower supine BP using post-prandial hypotension. Pharmacological treatments may be considered if severe nSH persists. Short-acting antihypertensive medications administered at bedtime are preferably used in order to selectively lower supine BP and reduce pressure diuresis without worsening daytime hypotension.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

The management of syncope in older adults.

Syncope is a frequent symptom in older patients. The diagnostic and therapeutic management may be complex, particularly in older adults with syncope and comorbidities or cognitive impairment. Morbidity related to syncope is more common in older persons and ranges from loss of confidence, depressive illness and fear of falling, to fractures and consequent institutionalization. Moreover, advan-ced age is associated with short and long-term morbidity and mortality after syncope. A standardized approach may obtain a definite diagnosis in more than 90% of the older patients with syncope and may reduce diagnostic tools and hospitalizations. The initial evaluation, including anamnesis, medical examination, orthostatic hypotension test and electrocardiogram (ECG), may be more difficult in the elderly, specially for the limited value of medical history, particularly for the certain diagnosis of neuro-mediated syncope. For this reason neuroautonomic assessment is an essential step to confirm a suspect of neuromediated syncope. Orthostatic blood pressure measurement, head up tilt test, carotid sinus massage and insertable cardiac monitor are safe and useful investigations, particularly in older patients. The most common causes of syncope in the older adults are orthostatic hypotension, carotid sinus hypersensitivity, neuromediated syncope and cardiac arrhythmias. The diagnostic evaluation and the treatment of cardiac syncope are similar in older and young patients and for this reason will not be discussed. In older patients unexplained falls could be related to syncope, particularly in patients with retrograde amnesia. There are no consistent differences in the treatment of syncope between older and younger population, but a specific approach is necessary for orthostatic hypotension, drug therapy and pacemaker implantation.

Patterning activities of vertebrate hedgehog proteins in the developing eye and brain.

BACKGROUND: The hedgehog (hh) family of secreted signaling proteins is responsible for developmental patterning in a variety of systems, including the neural tube, limbs and somites. Within the neural tube, at the level of the spinal cord, products of the vertebrate gene sonic hedgehog (shh) are proposed to function as a ventral patterning influence, with the capability of inducing floor plate and motor neurons. RESULTS: We report the isolation of tiggy-winkle hedgehog (twhh), a novel member of the zebrafish hh gene family. Both twhh and shh are expressed in the ventral midline of the embryonic zebrafish neural tube and brain, but twhh expression becomes limited to the neural tube, whereas shh is also expressed in the notochord. Both genes are expressed in the developing brain, in domains that include a discrete region in the floor of the diencephalon, located between the sites of the future optic stalks. Using pax-2 and pax-6 as markers of proximo-distal fate within the developing eye, we found that ectopic expression of either hh gene promoted proximal fates and suppressed distal fates. In contrast, proximal fates were lost in cyclops mutant embryos, which lack twhh- and shh-expressing forebrain cells. Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. CONCLUSIONS: These findings suggest that secreted signals encoded by members of the hedgehog gene family, emanating from the ventral midline of the neural tube, not only play important roles in dorso-ventral patterning of the brain but also appear to constitute an early patterning activity along the proximo-distal axis of the developing eyes.

Wnt4 affects morphogenesis when misexpressed in the zebrafish embryo.

The Wnts are a family of secreted glycoproteins involved in cell-cell signalling and pattern formation during development, although the extent to which various Wnts are functionally equivalent remains unclear. We have cloned zebrafish (Danio rerio) wnt4, characterized its expression, and compared its activity relative to other Wnts. The wnt4 transcript is first detected early in somitogenesis, in the dorsocaudal region of the forebrain, and then appears in the dorsal and lateral regions of the caudal hindbrain and neural keel. During somitogenesis, wnt4 appears in the floor plate, and this expression is absent in cyclops mutants, which lack floor plate. wnt4 is also expressed in the developing pronephros and gill slit. To characterize the biological activity of wnt4, synthetic zebrafish wnt4 mRNA was injected into embryos of zebrafish and Xenopus laevis. The phenotypic effects of misexpression in the zebrafish include cyclopia, misfolding in the brain, and an anteriorly forking notochord. Comparison of the phenotypes arising from misexpression of wnt4 and Xwnt-5A in both organisms suggests close parallels in the response to these Wnts. Our data suggest that wnt4, like Xwnt-5A, inhibits cell movements, and that these Wnts define a functional class distinct from the class which includes Wnt-1, Xwnt-3A and Xwnt-8.

Are protein synthesis inhibition and phase shifting of the circadian clock in Gonyaulax correlated?

We describe a method whereby the effect of protein synthesis inhibitors upon protein synthesis in Gonyaulax cultures may be reliably measured. Using this method, we found that protein synthesis inhibition and clock resetting were correlated, but that the correlation was not as close as has been reported in other systems. The effect of the inhibitors anisomycin and cycloheximide upon phase shifting of the circadian clock was a function of the illumination and temperature conditions to which the cells were subjected, but these factors did not appear to influence the inhibition of protein synthesis by these drugs. Cellular protein synthesis did not recover immediately from the inhibitors' effects; depending upon the previous concentration of the inhibitor, translational recovery from the drugs may require hours. This observation has important implications for the analysis of any phase response curve when the stimulus is a chemical.

Angiotensin sensitivity and prostaglandins in dogs with renal hypertension.

During established two-kidney one clip hypertension in dogs blood pressure is elevated despite only slightly raised plasma renin activity. Dose dependent effects of exogenous angiotensin II on systemic and renal haemodynamics were examined before and after induction of this type of hypertension in conscious dogs. There was no difference in the response of blood pressure to angiotensin II in each group, suggesting that altered pressor sensitivity to angiotensin II is not the cause of the persisting hypertension. However sodium excretion, effective renal plasma flow and glomerular filtration rate were all decreased by angiotensin II in the normotensive group, but were unchanged or increased in the hypertensive group. Renal prostaglandin E excretion was also increased in the hypertensive animals, and further increased during infusion with angiotensin II. The altered renal response to angiotensin II in the hypertensive group may reflect changes in occupancy of angiotensin II receptors and/or enhanced renal release of vasodilator prostaglandins.

Undertreatment of hypertension in community-dwelling older adults: a drug-utilization study in Dicomano, Italy.

OBJECTIVE: To define: (1) the prevalence of and (2) factors associated with undertreatment of hypertension in older persons; and (3) the prevalence of specific drug regimens and reasons for their selection. PARTICIPANTS: Cross-sectional survey of persons aged > or =65 years living in Dicomano, Italy. MAIN OUTCOME MEASURES: Prevalence of untreated and uncontrolled hypertension, both defined on the basis of two blood pressure (BP) cut-off points (> or =140/90 and > or =160/90 mm Hg) and of the presence of pharmacological treatment Predictors of undertreatment were analysed for the higher BP cut-off only. RESULTS: Five hundred of 692 (72.3%) and 380/692 (54.9%) participants met the 140/90 and the 160/90 mm Hg BP criterion, respectively. Of the latter, 162 (42.6%) were untreated, 119 (31.3%) had uncontrolled and 99 (26.1%) controlled hypertension. Women [odds ratio (OR), 0.4; 95% confidence interval (CI), 0.2-0.7], participants with coronary artery disease (CAD) (OR, 0.2; 95% CI, 0.1-0.6), stroke (OR, 0.3; 95% CI, 0.1-0.7), and preserved cognitive status (Mini Mental State Examination score >21: 0.3; 95% CI, 0.2-0.7) were more frequently treated. Uncontrolled hypertension was less likely in women (OR, 0.5; 95% CI, 0.3-1.0) and CAD patients (OR, 0.3; 95% CI, 0.1-0.7). Angiotensin converting enzyme (ACE)-inhibitors (55%), calcium (Ca)-antagonists (31%) and diuretics (20%) were the drugs most commonly prescribed. ACE-inhibitors were preferred, and diuretics rarely used, in diabetic subjects. Ca-antagonists were used mostly in CAD participants. CONCLUSIONS: Hypertension is undertreated in the majority of noninstitutionalized older adults, especially in men with impaired cognition and no vascular disease. Drug regimens are mostly based on ACE-inhibitors and Ca-antagonists, as a result of associated clinical conditions, requiring individualized treatment.

Methodology of head-up tilt testing potentiated with sublingual nitroglycerin in unexplained syncope.

Shortened head-up tilt testing (HUT) potentiated with sublingual nitroglycerin (60 degrees passive standing for 20 minutes followed, if negative, by 400 microg of sublingual nitroglycerin spray with the test continuing for another 20 minutes) differs from conventional nitroglycerin HUT for a shorter drug-free phase (20 vs 45 minutes). To compare the positivity rate of the 2 protocols, both tests were performed in a randomized sequence in 10 patients with unexplained syncope (study 1), and another 42 patients were randomly assigned either to conventional or to shortened nitroglycerin HUT (study 2). To evaluate the reproducibility of the shortened nitroglycerin HUT, another 38 patients with unexplained syncope underwent 2 consecutive tests within a 7+/-8 day interval (study 3). Finally, to evaluate the specificity of the test, 47 control subjects underwent shortened nitroglycerin HUT (study 4). Seven positive responses were observed during shortened nitroglycerin HUT, and there were 8 positive responses during conventional nitroglycerin HUT (p = NS) in the study 1 group. Fifteen positive (71%) responses, 5 negative responses, and 1 exaggerated response were observed during shortened nitroglycerin HUT; 16 positive (76%, p = NS vs. shortened nitroglycerin HUT), 3 negative, and 2 exaggerated responses were observed during conventional nitroglycerin HUT in the study 2 group. During the first test, 21 patients (55%) had a positive, 15 patients had a negative, and 2 patients had an exaggerated response in study group 3. During the second test, 15 positive (39%), 19 negative, and 4 exaggerated responses were observed. Thus, the reproducibility was 67% for a positive and 94% for a negative test. In control subjects, 2 positive (4%) responses, 38 negative, and 7 exaggerated responses were observed with a specificity of 96% in study group 4. In patients with unexplained syncope, shortened nitroglycerin HUT allowed a positivity rate similar to that of the conventional test. Moreover, the shortened test provided a high specificity and adequate reproducibility for both the positive and the negative responses.

Interactions of beta-adrenoceptor antagonists and thyroid hormones in the control of heart rate in the dog.

Propranolol, sotalol and nadolol have been infused into conscious dogs, and doses at which the three drugs are equipotent as beta-adrenoceptor antagonists determined. In euthyroid dogs, sotalol was more effective at lowering heart-rate than an equivalent dose of propranolol, while an equivalent dose of nadolol was without effect. Hyperthyroidism potentiated the lowering of heart-rate by sotalol, but inhibited that by propranolol. The effect of sotalol on heart-rate was correlated with its prolongation of the Q-T interval of the ECG. That of propranolol was correlated with its prolongation of the P-R interval. Nadolol did not affect P-R interval or Q-T interval except at relatively high dosage. We conclude that the tachycardia of hyperthyroidism is not affected by blockade of beta-adrenoceptors and therefore that it is not mediated by adrenergic mechanisms. The effectiveness of propranolol and sotalol in lowering heart-rate must be due to actions peculiar to those drugs, and not to beta-adrenoceptor antagonism.

Inhibitory regulation by co-released peptides of catecholamine secretion by the canine adrenal medulla.

1. We have stimulated the peripheral end of the cut left splanchnic nerve in anaesthetized dogs while collecting the venous effluent of the left adrenal gland for catecholamine estimation. 2. With low frequency stimulation the resting output of catecholamines was inhibited but at high frequencies it was augmented. 3. The inhibition of catecholamine output by low frequency stimulation was reversed by opiate antagonists (naloxone and nalmefene) but enhanced by angiotensin converting enzyme inhibitors (captopril and enalapril).

Cardiovascular actions of prostaglandin C in the cat and dog.

1 Prostaglandin C(2) causes a prolonged fall in arterial blood pressure in the cat.2 At constant heart rate this fall in arterial pressure is accompanied by falls in stroke volume, left ventricular end diastolic pressure, and left ventricular dP/dt max.3 If mean aortic pressure and left ventricular end diastolic pressure are held constant as well as heart rate, prostaglandins C(2) and E(2) do not affect dP/dt max in the cat.4 In the dog, under similarly controlled conditions, prostaglandins C(2) and E(2) raise dP/dt max.5 We conclude that prostaglandins E(2) and C(2) have no direct inotropic action in the cat, but both have a direct positive inotropic action in the dog.

Metabolic requirements for release of endogenous noradrenaline during myocardial ischaemia and anoxia.

The metabolic conditions required for noradrenaline (NA) release from ischaemic and anoxic perfused hearts of the rat were studied. Forty minutes of flow reduction to approximately 0.25 ml g-1 min-1 did not elicit enhanced noradrenaline overflow from the isolated heart perfused with normoxic perfusate even in the absence of added substrate. Enhanced overflow did occur when substrate-free ischaemia was induced after a 60 min period of substrate-free perfusion. Noradrenaline overflow was enhanced by perfusion at normal flow rates with an anoxic (Po2 less than or equal to 1 mmHg) perfusate containing no substrate. Such enhanced overflow occurred in the absence of calcium in the perfusate and was almost completely abolished by the addition of 11 mM glucose. Enhanced noradrenaline overflow occurring either during low flow ischaemia after substrate deprivation or during anoxic substrate-free perfusion at normal flow rates was markedly suppressed by desipramine. Exocytotic noradrenaline overflow induced by electrical stimulation of the left cervico-thoracic ganglion continued unchanged during 60 min of anoxia if the perfusate contained 11 mM glucose. In the absence of added substrate there was a decline in the overflow induced by such stimulation which was more rapid with anoxic than normoxic perfusate. Re-introduction of calcium, oxygen and substrate after 10, 20 or 30 min of calcium-free, substrate-free, anoxic perfusion was associated with a massive overflow of the intracellular enzyme lactate dehydrogenase. At 10 min there was an associated transient minor increase in NA overflow but at 20 and 30 min the overflow of NA, elevated as a result of anoxic perfusion, returned to pre-anoxic levels on the re-introduction of substrate and oxygen. 7 These studies demonstrate a central role for the metabolic status of the sympathetic nerve terminal in determining the magnitude ofexocytotic and nerve-impulse independent noradrenaline release from the heart. During the course of myocardial ischaemia in vivo nerve-impulse independent release would be expected to occur only in regions of severe flow reduction. This may produce heterogeneous stimulation of the myocardium.