Laurence G. Howes

Can a heart failure-specific cardiac rehabilitation program decrease hospitalizations and improve outcomes in high-risk patients?

Background Heart failure is a common and costly condition, particularly in the elderly. A range of models of interventions have shown the capacity to decrease hospitalizations and improve health-related outcomes. Potentially, cardiac rehabilitation models can also improve outcomes. Aim To assess the impact of a nurse-coordinated multidisciplinary, cardiac rehabilitation program to decrease hospitalizations, increase functional capacity, and meet the needs of patients with heart failure. Method In a randomized control trial, a total of 105 patients were recruited to the study. Patients in the intervention group received an individualized, multidisciplinary 12-week cardiac rehabilitation program, including an individualized exercise component tailored to functional ability and social circumstances. The control group received an information session provided by the cardiac rehabilitation coordinator and then follow-up care by either their cardiologist or general practitioner. This trial was stopped prematurely after the release of state-based guidelines and funding for heart failure programs. Results During the study period, patients in the intervention group were less likely to have been admitted to hospital for any cause (44 vs. 69%, P = 0.01) or after a major acute coronary event (24 vs. 55%, P = 0.001). Participants in the intervention group were more likely to be alive at 12 months, (93 vs. 79%; P = 0.03) (odds ratio =3.85; 95% confidence interval = 1.0314.42; P = 0.0042). Quality of life scores improved at 3 months compared with baseline (intervention t = 4.37, P [ 0.0001; control t= 3.52, P [0.01). Improvement was also seen in 6-min walk times at 3 months compared with baseline in the intervention group (t = 3.40; P = 0.01). Conclusion This study shows that a multidisciplinary heart failure cardiac rehabilitation program, including an individualized exercise component, coordinated by a specialist heart failure nurse can substantially reduce both all-cause and cardiovascular readmission rates, improve functional status at 3 months and exercise tolerance.

The effects of dietary lipid modification on blood pressure, cardiovascular reactivity and sympathetic activity in man.

Objectives: To examine the effect of dietary lipid modification on 24-h ambulatory blood pressure, cardiovascular reactivity and sympathetic activity in man Design: Twenty-four normal volunteers consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized, crossover study of duration 6 weeks. Diets were isocaloric and balanced for sodium and potassium content Methods: Cardiovascular reactivity was assessed by measurement of blood pressure responses to incremental infusions of angiotensin II and noradrenaline, and to sympathetic reflex testing. Plasma noradrenaline spillover and clearance rates were estimated using [3H]-noradrenaline infusion Results: Total plasma cholesterol and low-density lipoprotein-cholesterol levels both fell significantly on the low-fat compared with the high-fat diet, as did heart rate and mean arterial pressure (recorded by 24-h ambulatory monitoring). These changes were accompanied by reductions in blood pressure responses to cold pressor testing and to noradrenaline infusion on the low-fat diet. Plasma noradrenaline spillover and clearance rates did not change. Post hoc analysis showed an association between oral contraceptive use and increased noradrenaline sensitivity on the high-fat diet among the females tested. Conclusion: Dietary fat intake alters heart rate, blood pressure and cardiovascular reactivity to noradrenaline in man without changes in basal noradrenaline metabolism.

Pressor dose responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.

Objective: To assess the relative contribution of impaired baroreceptor reflexes and enhanced cardiovascular reactivity to the exaggerated blood pressure rises which occur in quadriplegic spinal cord injury patients with automatic hyperreflexia. Design: Pressor dose responsiveness was evaluated by determining the steady-state dose of phenylephrine, α-methylnoradrenaline and angiotensin II required to achieve a blood pressure rise of 20mmHg and the steady-state dose of isoprenaline required to increase heart rate by 20 beats/min in eight quadriplegic spinal cord injury patients and eight control subjects. Results: The dose of phenylephrine α -methylnoradrenaline and angiotensin II to achieve a rise in blood pressure of 20mmHg was significantly reduced in the spinal cord injury group, whilst the dose of isoprenaline required to raise heart rate by 20 beats/min did not differ significantly from the control group. Baroreceptor sensitivity, assessed by straight line regression of change in heart period with change in blood pressure during steady-state infusions of phenylephrine, did not differ statistically between the two groups, but the results could not exclude some evidence of impairment in the spinal cord injury patients. Baroreceptor sensitivity was much less variable in spinal cord injury patients than in controls. Conclusions: These findings suggest that quadriplegic patients with spinal cord injury have exaggerated pressor responses with significantly less variability in baroreflex sensitivity. The former probably contributes to the autonomic hyperreflexia seen in these patients. The latter provides some support to the suggestion that centrally mediated psychogenic responses contribute to the variability in baroreceptor sensitivity seen in normal subjects.

Long-term pharmacokinetics of an extract of isoflavones from red clover (Trifolium pratense).

OBJECTIVESnTo study the pharmacokinetics of isoflavones from red clover (Trifolium pratense) after long-term administration as a once-daily dietary supplementary.nnnDESIGNnFourteen (14) subjects who had been consuming a low-isoflavone diet for 2 weeks were given an oral dose of two isoflavone tablets (approximately 80 mg of total isoflavones) daily for 2 weeks and appeared for a study day at 9:00 AM after an overnight fast on the day that they were to receive the last dose. Plasma samples were collected for a 48-hour period after the last dose. Plasma isoflavones were assayed by high-performance liquid chromatography (HPLC).nnnRESULTSnTrough plasma levels were significantly higher for daidzein and genistein after long-term dosing than levels taken prior to the commencement of the study and plasma levels of isoflavones after long-term dosing were in the range previously reported in populations that consume an isoflavone-rich diet. The plasma half-lives observed after long-term administration were, in most cases, consistent with once-daily administration.nnnCONCLUSIONSnIsoflavones have pharmacokinetic characteristics that suggest that once-daily administration is adequate when they are administered long-term as dietary supplements.

Arterial stiffness in insulin resistance: the role of nitric oxide and angiotensin II receptors.

The insulin resistance syndrome (INSR) is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged >20 years. Increased arterial stiffness has been proposed as a common pathway by which INSR leads to increased cardiovascular risk. We have reviewed the role of nitric oxide (NO) and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. There is emerging evidence that early stages of INSR may be characterized by increased basal nitric oxide activity and increased activity of non-NO vasodilators such as endothelial derived hyperpolarization factor (EDHF) which is manifest by reduced arterial stiffness. Depletion of NO or ineffectiveness of NO mediated vasodilator mechanisms associated with the progression of INSR to type 2 diabetes may result in increased arterial stiffness, which predicts the development of cardiovascular disease. Thus in the early stages of INSR, increased NO and EDHF activity may represent compensatory mechanisms to early vascular damage. The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R). Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. AT2R activity is increased in early in INSR and may contribute to the apparent increase in basal NO activity. AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act unopposed at AT2 receptors.

Cardiovascular Effects of Drugs Used to Treat Alzheimer’s Disease

Drugs that are used to treat Alzheimer’s disease include the acetyl cholinesterase inhibitors (ACHIs) donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine. Adverse cardiovascular events with these drugs are very uncommon. However, there is evidence that ACHI therapy is associated with a small but significant increase in the risk of syncope and bradycardia. There are also a few reports that these drugs may occasionally be associated with QT prolongation and torsades de pointes ventricular tachycardia. Adverse cardiovascular effects of ACHIs including syncope and bradycardia are less common than their adverse gastrointestinal effects, but they remain important considerations in susceptible individuals. In contrast, animal studies and some observational studies suggest that ACHIs may reduce myocardial infarction and cardiovascular mortality and have favourable effects on hemodynamics and survival in heart failure. Further research is required to confirm these potential beneficial effects. Little is known about the cardiovascular effects of memantine but there have been reports of bradycardia and reduced cardiovascular survival associated with its use.

Single-pill amlodipine/atorvastatin helps patients of diverse ethnicity attain recommended goals for blood pressure and lipids (the Gemini-AALA study)

The Gemini-AALA (Australia, Asia, Latin America, Africa/Middle East) study evaluated the efficacy and safety of single-pill amlodipine/atorvastatin (Caduet) for the treatment of patients of diverse ethnicity with concomitant hypertension and dyslipidaemia. This was a 14-week, open-label study including patients from 27 countries across the Middle East, Asia-Pacific, Africa and Latin America. Eight dosage strengths of single-pill amlodipine/atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80 and 10/80u2009mg) were titrated to improve blood pressure and lipid control. Blood pressure and lipid goals were determined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines, respectively (blood pressure, <140/90 or <130/80u2009mmu2009Hg; low-density lipoprotein cholesterol (LDL-C), <4.1 to <2.6u2009mmolu2009l−1 (<160 to <100u2009mgdl−1)). Overall, 1649 patients received study medication. Most patients (91.4%) had ⩾1 cardiovascular risk factor (as defined by NCEP ATP III guidelines) in addition to hypertension/dyslipidaemia, and 61.7% had coronary heart disease/risk equivalent. At baseline, mean blood pressure was 146.6/88.3u2009mmu2009Hg and LDL-C was 3.4u2009mmolu2009l−1 (130.2u2009mgdl−1). At week 14, 55.2% of patients reached both blood pressure and lipid goals, 61.3% reached blood pressure goal and 87.1% reached lipid goal (34.0% were at lipid goal at baseline). Mean blood pressure reduction was 20.2/11.4u2009mmu2009Hg. For patients who were lipid-lowering drug naive at baseline, mean reduction in LDL-C was 41.0%. Treatment-related adverse events led to the discontinuation of 3.6% of patients. Single-pill amlodipine/atorvastatin therapy was well tolerated and effective for the reduction of blood pressure and lipids to recommended goals in patients from diverse ethnic backgrounds.

The withdrawal of torcetrapib from drug development: implications for the future of drugs that alter HDL metabolism

In December 2006, Pfizer withdrew torcetrapib, a cholesterol ester transferase protein (CETP) that elevates plasma HDL levels, from further development following an excess in mortality in the active treatment arm of the study. Although torcetrapib successfully elevated HDL levels, significant increases in blood pressure were observed in three surrogate outcome studies that were conducted over the approximate same time period. Two of these studies examined carotid intima-medial thickness and one examined coronary artery atheroma load and none of the studies found a significant benefit in favour of torcetrapib therapy. It is likely that the torcetrapib-induced increase in blood pressure contributed to the apparent adverse effect of the drug on mortality and further studies are needed to determine why this occurred and whether it is a class effect of CETP inhibitors. In addition, further research is needed to determine whether the manner which CETP alters vascular biology and, in particular, the effect that it has on vascular inflammation associated with denuded endothelium. Despite disappointing results so far, CETP inhibitors should not be abandoned as much remains to be learnt from them and they may yet prove to be a valuable class of lipid-modifying drug.

Evidence for functional expression of vascular angiotensin II type 2 receptors in patients with insulin resistance

Aim:u2002 Angiotensin II type 2 (AT2) receptors are believed to become over‐expressed in response to cardiovascular damage and to mediate beneficial effects (e.g. vasodilation). It is unknown whether AT2 receptors are functionally expressed in patients with insulin resistance (INSR). In this study, we investigated the role of the highly selective AT2 receptor antagonist, PD123319, on arterial stiffness and haemodynamic parameters in patients with INSR, compared with an age‐ and gender‐matched control (N) group to determine whether there is functional expression of vascular AT2 receptors in patients with INSR.

Arterial stiffness indices in healthy volunteers using non-invasive digital photoplethysmography.

Background. Increased arterial stiffness is a marker of cardiovascular damage, even in the absence of clinically apparent disease. It is likely to become an important clinical tool in cardiovascular risk assessment. Aims and methods. We studied a group of healthy subjects and measured their arterial stiffness by digital photoplethysmography. We aimed to obtain a range of arterial stiffness values, and investigated the influence of age, gender, race, body mass index, fasting lipids and haemodynamic factors. Results. One hundred and fifty‐two healthy subjects, aged between 18 and 67 years, on no medications and with no significant medical illnesses were recruited. The population was predominantly Caucasian (n = 112). Two measures of arterial stiffness were obtained: stiffness index (SI), a measure of large arterial stiffness, and reflection index (RI), a measure of small to medium‐sized arterial stiffness. SI and RI were significantly correlated with age, total cholesterol, low‐density lipoprotein‐cholesterol, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Race was a significant independent predictor of SI. Conclusion. Digital photoplethysmography is a portable, operator‐independent, reproducible and simple method of measuring arterial stiffness. Ranges of normality of arterial stiffness will depend on the individuals age, race, lipid levels, HR and blood pressure.