Non-invasive vascular measures as prognostic predictors for older patients with non-ST elevation acute coronary syndrome.

BACKGROUND: Adverse cardiac events are common in older patients with non-ST elevation acute coronary syndrome (NSTEACS), yet prognostic predictors are still lacking. This study investigated the long-term prognostic significance of non-invasive measures including endothelial function, carotid intima-media thickness (CIMT), and vascular stiffness in older NSTEACS patients referred for invasive treatment. METHODS: NSTEACS patients aged 75 years and older recruited to a multicentre cohort study (NCT01933581) were assessed for baseline endothelial function using endoPAT logarithm of reactive hyperemia index (LnRHI), CIMT using B-mode ultrasound, and vascular stiffness using carotid-femoral pulse wave velocity (cfPWV). Long-term outcomes included major adverse cardiovascular events (MACE), a composite of death, reinfarction, urgent revascularization, stroke/transient ischemic attack, and significant bleeding. RESULTS: Recruitment resulted in 214 patients assessed for LnRHI, 190 patients assessed for CIMT and 245 patients assessed for cfPWV. For LnRHI group (median follow-up 4.73 years [IQR: 1.41-5.00]), Cox regression analysis revealed a trend towards increased risk of MACE (HR: 1.24 [95% CI: 0.80-1.93]; P  = 0.328) and mortality (HR: 1.49 [95% CI: 0.86-2.59]; P  = 0.157), but no significance was reached. No difference for other components of MACE was found. For CIMT group (median follow up 4.74 years [IQR: 1.55-5.00]), no statistically significant difference in MACE was found (HR: 0.92 [95% CI: 0.53-1.59]; P  = 0.754). Similarly, for cfPWV group (median follow-up 4.96 years [IQR: 1.55-5.00]), results did not support prognostic significance (for MACE, HR: 0.95 [95% CI: 0.65-1.39]; P  = 0.794). CONCLUSION: Endothelial function, CIMT and vascular stiffness were proven unsuitable as strong prognostic predictors in older patients with NSTEACS. CLINICAL TRIAL REGISTRATION: NCT01933581.

Content and delivery preferences for information to support the management of high blood pressure.

Blood pressure(BP) management interventions have been shown to be more effective when accompanied by appropriate patient education. As high BP remains poorly controlled, there may be gaps in patient knowledge and education. Therefore, this study aimed to identify specific content and delivery preferences for information to support BP management among Australian adults from the general public. Given that BP management is predominantly undertaken by general practitioners(GPs), information preferences to support BP management were also ascertained from a small sample of Australian GPs. An online survey of adults was conducted to identify areas of concern for BP management to inform content preferences and preferred format for information delivery. A separate online survey was also delivered to GPs to determine preferred information sources to support BP management. Participants were recruited via social media. General public participants (n = 465) were mostly female (68%), >60 years (57%) and 49% were taking BP-lowering medications. The management of BP without medications, and role of lifestyle in BP management were of concern among 30% and 26% of adults respectively. Most adults (73%) preferred to access BP management information from their GP. 57% of GPs (total n = 23) preferred information for supporting BP management to be delivered via one-page summaries. This study identified that Australian adults would prefer more information about the management of BP without medications and via lifestyle delivered by their GP. This could be achieved by providing GPs with one-page summaries on relevant topics to support patient education and ultimately improve BP management.

Prospective study of early bereavement on psychological and behavioural cardiac risk factors.

BACKGROUND: Increasing evidence supports the role of emotional stress in the onset of cardiovascular disease. Although bereavement is a major emotional stress with both acute and more long-term features, the mechanism of its association with cardiovascular risk is not well understood, in particular because of limited studies of acute bereavement. The aim of the study was to identify psychological and behavioural changes in acute bereavement and potential modifiers of these changes. METHODS: Bereaved (n= 62) and non-bereaved individuals (n= 50) were evaluated within 2 weeks and at 6 months following loss using the Centre for Epidemiologic Studies -- Depression, Spielberger State Anxiety and Anger, Social Support Questionnaire and changes in appetite, cigarette and alcohol consumption, cortisol and lipids. RESULTS: Compared with non-bereaved, acutely bereaved had increased symptoms of depression (26.7 +/- 1.7 vs 5.9 +/- 0.7, P < 0.001), anxiety (47.4 +/- 2.0 vs 28.2 +/- 1.4, P < 0.001) and anger (median 16.0 vs 15.0, P < 0.001). Greater depressive symptoms were associated with being unprepared for the death, decreased sleep duration and younger age. Acutely, bereaved slept less than non-bereaved (5.8 +/- 0.2 vs 7.2 +/- 0.2 h, P < 0.001). Reduced sleep time was associated with increased anger and depression and decreased satisfaction with social support. Compared with the non-bereaved, the acutely bereaved had higher cortisol (median 306 vs 266, P= 0.003), reduced appetite (P < 0.001) and lower total cholesterol (median 4.9 vs 5.4, P= 0.006) and low-density lipoprotein (median 2.4 vs 2.9, P < 0.001). CONCLUSION: These results offer insight into the psychological, behavioural and physical changes that may contribute to cardiovascular risk in bereavement.

Increased sensitivity to isoprenaline following digoxin pretreatment in anaesthetised and conscious dogs.

STUDY OBJECTIVE: The aim of the study was to evaluate the effect of chronic digoxin therapy on cardiac sensitivity to isoprenaline. DESIGN: Responses to isoprenaline were examined in both conscious and anaesthetised dogs pretreated with digoxin, and compared with conscious or anaesthetised controls with no digoxin pretreatment. Isoprenaline infusion (0.001-0.1 micrograms.kg-1.min-1) in pretreated groups was performed 7 d after digoxin dosing was stopped, when plasma digoxin concentrations were zero. SUBJECTS: Mongrel dogs of either sex (15-25 kg) were used in the experiments, done under anaesthetic. They were divided into three groups (n = 6 per group): group A were controls; groups B and C were pretreated with digoxin 500-750 micrograms.d-1, for 14 d (B) and 7 d (C). For the experiments in conscious animals, six mongrel dogs (25-30 kg) and two greyhounds (25-30 kg) were used; group D (n = 6) were treated with digoxin for 20-40 d; group E (n = 2) were treated for 7 d. MEASUREMENTS AND RESULTS: Heart rate, blood pressure and myocardial contractility (dP/dt: integrated isometric tension) were measured during isoprenaline infusion. Digoxin pretreatment for 14 d did not significantly change the chronotropic or depressor responses to isoprenaline in anaesthetised dogs but there was a 10-fold increase in inotropic sensitivity to isoprenaline following withdrawal. When the pretreatment period was reduced to 7 d there was no change in any of the responses to isoprenaline. In conscious dogs there was also a significant increase in inotropic sensitivity to isoprenaline after digoxin withdrawal, but this was not so marked as in anaesthetised dogs. In conscious dogs chronotropic sensitivity to isoprenaline was also increased. CONCLUSIONS: It is possible that the inotropic effect maintained during the 2 weeks of digoxin treatment may cause substantial withdrawal of sympathetic tone to the heart, with a consequent increase in beta adrenoceptor number or sensitivity, which could be detected a week after digoxin withdrawal.

HMG CoA reductase inhibition reduces sarcolemmal Na(+)-K(+) pump density.

OBJECTIVES: HMG CoA reductase inhibitors reduce cellular availability of mevalonate, a precursor in cholesterol synthesis. Since the cholesterol content of cell membranes is an important determinant of Na(+)-K(+) pump function we speculated that treatment with HMG CoA reductase inhibitors affects Na(+)-K(+) pump activity. METHODS: We treated rabbits and rats for 2 weeks with the HMG CoA reductase inhibitor lovastatin and measured Na(+)-K(+) pump current (I(p)) in isolated rabbit cardiac myocytes using the whole cell patch-clamp technique, K-dependent p-nitrophenyl phosphatase (p-NPPase) activity in crude myocardial and skeletal muscle homogenates, and vanadate-facilitated 3H-ouabain binding in intact skeletal muscle samples from rats. RESULTS: Treatment with lovastatin caused statistically significant reductions in I(p), myocardial and skeletal muscle K-dependent p-NPPase activity and 3H-ouabain binding in the myocardium and skeletal muscle. The lovastatin-induced decrease in I(p) was eliminated by parenteral co-administration of mevalonate. However, this was not related to cardiac cholesterol content. CONCLUSIONS: Treatment with lovastatin reduces Na(+)-K(+) pump activity and abundance in rabbit and rat sarcolemma.

Placebo-controlled biofeedback blood pressure effect in hypertensive humans.

The role of biofeedback in blood pressure control remains ill-defined because of nonspecific (placebo) effects, small study numbers, and the technical limitations of continuous pressure feedback. Clarification of its potential is awaited by those seeking a nonpharmacological approach to blood pressure control. This study examines the capability for systolic pressure lowering of 5 mm Hg or more using continuous pressure feedback in a statistical sample of untreated, well-characterized, mildly hypertensive individuals. Subjects were randomized in a double-blind study to active or placebo biofeedback. Placebo consisted of a modified contingency approach, using a partial disguise based on a digital high pass filter with 15 elements. Blood pressure-lowering capability was assessed during two laboratory sessions. Continuous visual feedback resulted in 11 of 28 subjects on active treatment and 12 of 28 on placebo treatment lowering their systolic pressure by 5 mm Hg or more (11 +/- 5.6 and 12 +/- 8.4 mm Hg, respectively; P = NS). Prestudy pressure was well-matched (153 +/- 9/97 +/- 4 and 154 +/- 8/98 +/- 4 mm Hg, respectively). An initial small difference in diurnal profile did not change. These findings indicate that among mildly hypertensive individuals, almost half can lower systolic pressure at will for short periods. This capability is independent of the real or placebo nature of the feedback signal. We conclude that there is no specific short-term biofeedback pressure-lowering capability in hypertensive individuals. Further exploration is needed to determine whether specific components of the placebo effect can be delineated, whether personality characteristics influence the response, and whether further biofeedback training can alter the outcome.

Continuous, non-invasive volume-clamp blood pressure: determinants of performance.

OBJECTIVE: To test a prototype hydraulic, non-invasive, continuous finger blood pressure monitor based on the volume-clamp principle for procedure-related factors likely to influence precision. DESIGN: The influence of these factors was determined by repeatability of finger blood pressure measurement and the relationship to contralateral arm-cuff blood pressure. METHODS: Repeated blood pressure measurements from three different fingers were made in 60 subjects following re-initialization of the device and re-insertion of the finger into the cuff. Repeatability was assessed in relation to simultaneous arm-cuff readings. Drift in arm-finger discrepancy was measured over a 1-h period. Finger diameter, drug therapy and presence of peripheral vascular disease were correlated with arm-finger blood pressure difference. RESULTS: Repeatability coefficients (twice the SD of the arm-finger difference) across device re-initialization were large, but similar to parallel repeated arm blood pressure determinations: 17.6 and 17.1 mmHg for systolic blood pressure (SBP) and 13.9 and 13.6 mmHg for diastolic blood pressure (DBP), respectively. Withdrawing and re-inserting the finger reduced repeatability substantially, with a 50% increase in repeatability coefficient. A trend towards a progressive 9-mmHg increase was observed in overestimation of SBP over the 1-h period. Mean +/- SD pooled arm-finger blood pressure differences were -10.8 +/- 14.6 mmHg for SBP and 4.5 +/- 9.4 mmHg for DBP. Blood pressure measured in different fingers was similar on average, with repeatability no poorer than for re-insertion of the same finger. The presence of peripheral vascular disease in 15 subjects correlated with a smaller arm-finger difference for DBP. CONCLUSIONS: Variations in positioning of the finger within the cuff influences blood pressure measurement during volume-clamp plethysmography, reducing its precision. Finger SBP exceeds brachial auscultatory readings and has similar precision.

Positive inotropic effects of histamine in anaesthetized dogs.

1 The cardiovascular effects of histamine were examined in dogs anaesthetized with pentobarbitone 2 The effect of histamine on heart rate, blood pressure, left ventricular pressure, dP/dtmax and dP/dt: IIT (integrated isometric tension) was compared in the presence and absence of autonomic reflexes and blood pressure control. 3 In innervated animals with no attempt to control blood pressure, histamine produced dose-dependent decreases in blood pressure and heart rate and either positive or negative inotropic actions. 4 When autonomic reflexes were abolished, this variability in inotropic response was reduced and histamine produced a slight positive inotropic response. There was a decrease in blood pressure and a positive chronotropic response to histamine. 5 When blood pressure was controlled and the cardiac nerves were intact, histamine produced a decrease in heart rate. However, in the denervated animals, there was a slight increase in heart rate. 6 Inotropic responses to histamine in the blood pressure controlled groups were less variable than when blood pressure was uncontrolled. In all of these animals there was an increase in contractility, the increase being more marked in the denervated group. 7 The H2-receptor agonist impromidine produced a positive inotropic action in intact animals with uncontrolled blood pressure.

Na+ influx and Na(+)-K+ pump activation during short-term exposure of cardiac myocytes to aldosterone.

To examine the effect of aldosterone on sarcolemmal Na+ transport, we measured ouabain-sensitive electrogenic Na(+)-K+ pump current (Ip) in voltage-clamped ventricular myocytes and intracellular Na+ activity (alpha iNa) in right ventricular papillary muscles. Aldosterone (10 nM) induced an increase in both Ip and the rate of rise of alpha iNa during Na(+)-K+ pump blockade with the fast-acting cardiac steroid dihydroouabain. The aldosterone-induced increase in Ip and rate of rise of alpha iNa was eliminated by bumetanide, suggesting that aldosterone activates Na+ influx through the Na(+)-K(+)-2Cl- cotransporter. To obtain independent support for this, the Na+, K+, and Cl- concentrations in the superfusate and solution of pipettes used to voltage clamp myocytes were set at levels designed to abolish the inward electrochemical driving force for the Na(+)-K(+)-2Cl- cotransporter. This eliminated the aldosterone-induced increase in Ip. We conclude that in vitro exposure of cardiac myocytes to aldosterone activates the Na(+)-K(+)-2Cl- cotransporter to enhance Na+ influx and stimulate the Na(+)-K+ pump.

Cyclosporine and FK506 differentially regulate the sarcolemmal Na(+)-K(+) pump.

Cyclosporine A (CsA) and FK506, important immunosuppressants, have been shown to inhibit the enzymatic equivalent of the Na(+)-K(+) pump (Na(+), K(+)-ATPase) in renal tissue. A similar effect in the heart may contribute to the adverse effects of these agents that include calcification, contractile dysfunction, and altered calcium handling. However, inhibition of the pump has not been demonstrated in cardiac myocytes. We isolated single ventricular myocytes from control rabbits and from rabbits administered CsA or FK506 for 1 week. Na(+)-K(+) pump current (I(p)) was measured using the whole-cell patch-clamp technique. When patch pipettes contained Na(+) in a concentration ([Na](pip)) near physiological intracellular levels mean I(p) of cardiac myocytes from rabbits with serum CsA levels within the therapeutic range was significantly lower than mean I(p) of cardiac myocytes from controls. Treatment had no effect on I(p) measured using a [Na](pip) expected to nearly saturate intracellular binding sites. The CsA-induced inhibition of I(p) was dependent on the K(+) concentration in pipette solutions. Mean I(p) in myocytes from rabbits with serum levels of FK506 within the therapeutic range was similar to mean I(p) in myocytes from controls, whereas FK506 in a dose inducing serum levels severalfold above the therapeutic range caused significant pump inhibition. Using ion-sensitive microelectrodes we showed the intracellular Na(+) activity in papillary muscles isolated from rabbits treated with CsA was significantly higher than in papillary muscles from control rabbits, indicating that CsA causes pump inhibition in intact myocytes with a physiological intracellular milieu.

Hyperaldosteronemia in rabbits inhibits the cardiac sarcolemmal Na(+)-K(+) pump.

Aldosterone upregulates the Na(+)-K(+) pump in kidney and colon, classical target organs for the hormone. An effect on pump function in the heart is not firmly established. Because the myocardium contains mineralocorticoid receptors, we examined whether aldosterone has an effect on Na(+)-K(+) pump function in cardiac myocytes. Myocytes were isolated from rabbits given aldosterone via osmotic minipumps and from controls. Electrogenic Na(+)-K(+) pump current, arising from the 3:2 Na(+):K(+) exchange ratio, was measured in single myocytes using the whole-cell patch clamp technique. Treatment with aldosterone induced a decrease in pump current measured when myocytes were dialyzed with patch pipette solution containing Na(+) in a concentration of 10 mmol/L, whereas there was no effect measured when the solution contained 80 mmol/L Na(+). Aldosterone had no effect on myocardial Na(+)-K(+) pump concentration evaluated by vanadate-facilitated [(3)H]ouabain binding or by K(+)-dependent paranitrophenylphosphatase activity in crude homogenates. Aldosterone induced an increase in intracellular Na(+) activity. The aldosterone-induced decrease in pump current and increased intracellular Na(+) were prevented by cotreatment with the mineralocorticoid receptor antagonist spironolactone. Our results indicate that hyperaldosteronemia decreases the apparent Na(+) affinity of the Na(+)-K(+) pump, whereas it has no effect on maximal pump capacity.

Angiotensin regulates the selectivity of the Na+-K+ pump for intracellular Na+.

Treatment of rabbits with angiotensin-converting enzyme (ACE) inhibitors increases the apparent affinity of the Na+-K+ pump for Na+. To explore the mechanism, we voltage clamped myocytes from control rabbits and rabbits treated with captopril with patch pipettes containing 10 mM Na+. When pipette solutions were K+ free, pump current (Ip) for myocytes from captopril-treated rabbits was nearly identical to that for myocytes from controls. However, treatment caused a significant increase in Ip measured with pipettes containing K+. A similar difference was observed when myocytes from rabbits treated with the ANG II receptor antagonist losartan and myocytes from controls were compared. Treatment-induced differences in Ip were eliminated by in vitro exposure to ANG II or phorbol 12-myristate 13-acetate or inclusion of the protein kinase C fragment composed of amino acids 530-558 in pipette solutions. Treatment with captopril had no effect on the voltage dependence of Ip. We conclude that ANG II regulates the pump's selectivity for intracellular Na+ at sites near the cytoplasmic surface. Protein kinase C is implicated in the messenger cascade.

Amiodarone inhibits the Na(+)-K+ pump in rabbit cardiac myocytes after acute and chronic treatment.

Amiodarone has been shown to affect cell membrane physicochemical properties, and it may produce a state of cellular hypothyroidism. Because the sarcolemmal Na(+)-K+ pump is sensitive to changes in cell membrane properties and thyroid status, we examined whether amiodarone affected Na(+)-K+ pump function. We measured Na(+)-K+ pump current (Ip) using the whole-cell patch-clamp technique in single ventricular myocytes isolated from rabbits. Chronic treatment with oral amiodarone for 4 weeks reduced i.p. when myocytes were dialyzed with patch-pipettes containing either 10 mM Na+ or 80 mM Na+. In myocytes from untreated rabbits, acute exposure to amiodarone in vitro reduced i.p. when patch pipettes contained 10 mM Na+ but had no effect on i.p. at 80 mM Na+. Amiodarone had no effect on the voltage dependence of the pump or the affinity of the pump for extracellular K+ either after chronic treatment or during acute exposure. We conclude that chronic amiodarone treatment reduces overall Na(+)-K+ pump capacity in cardiac ventricular myocytes. In contrast, acute exposure of myocytes to amiodarone reduces the apparent Na+ affinity of the Na(+)-K+ pump. An amiodarone-induced inhibition of the hyperpolarizing Na(+)-K+ pump current may contribute to the action potential prolongation observed during treatment with this drug.

The effect of exercise on circulating immunoreactive calcitonin in men.

Moderate-duration exercise increases serum catecholamine and serum calcium levels and might as a result be also expected to increase the levels of circulating serum immunoreactive human calcitonin (HCT). To explore this possibility, HCT was studied during and after moderate duration symptom-limited dynamic exercise in 13 healthy males, mean age 28 +/- 6.9 (SD) years. The mean duration of exercise using the Bruce treadmill protocol was 14.1 +/- 2.2 (SD) minutes. The mean heart rate (HR) peaked at 185 +/- 6 (SD) bpm which was 96.1% of the predicted maximal HR for age. Values for HCT, uncorrected for changes in plasma volume, showed a minimal decrease in the recovery phase, whilst HCT corrected for changes in plasma volume did not alter during exercise or recovery. The serum parathyroid hormone (PTH) also did not change. At peak exercise, uncorrected but not corrected values for plasma noradrenaline, adrenaline and dopamine had increased significantly. Corrected plasma total calcium increased during recovery. In summary, dynamic weight-bearing moderate-duration exercise did not elevate HCT in healthy males.