Monitoring the introduction of new drugs--Herceptin to cardiotoxicity.

Trastuzumab (Herceptin), currently prescribed for metastatic breast cancer, has recently been shown to be effective as adjuvant therapy in early receptor 2 (HER2)-positive breast cancer. Cardiotoxicity is a serious adverse effect. A decrease in left ventricular ejection fraction (LVEF) occurs in as many as 27% of women treated with trastuzumab when combined with standard chemotherapy. The pathophysiology of this effect, which differs from the cardiotoxicity of anthracyclines, remains poorly understood. While overt heart failure is reversed with standard therapy, the longer-term consequences of asymptomatic declines in LVEF remain unknown. Monitoring 3-monthly for 5-10% changes in LVEF, the criteria for cessation of trastuzumab therapy in the clinical trials, is not possible for the population of women who might benefit from trastuzumab for early breast cancer. Extension of this therapy to an older and less fit population than those enrolled in the trials, with less rigorous cardiac screening, may result in significantly more cardiotoxicity.

Why does the heart rate response to exercise predict adverse cardiac events?

The physiological mechanisms responsible for determining heart rate during exercise are complex, and further research into "chronotropic incompetence" is clearly required.

Effect of inhaled sulphur dioxide and carbon particles on heart rate variability and markers of inflammation and coagulation in human subjects.

OBJECTIVE: To measure the inflammatory and autonomic responses of healthy humans and patients with coronary artery disease to controlled concentrations of two specific components of vehicle derived air pollution, carbon particles and sulphur dioxide (SO2). METHODS: Placebo controlled, double blind, random order human challenge study examining the effects of carbon particles (50 microg/m3) and SO2 (200 parts per billion (ppb)) on heart rate variability (HRV) and circulating markers of inflammation and coagulation in healthy volunteers and patients with stable angina. RESULTS: In healthy volunteers, markers of cardiac vagal control did not fall in response to particle exposure but, compared with the response to air, increased transiently immediately after exposure (root mean square of successive RR interval differences (RMSSD) 15 (5) ms with carbon particles and 4 (3) ms) with air, p < 0.05). SO2 exposure resulted in no immediate change but a significant reduction in HRV markers of cardiac vagal control at four hours (RMSSD -2 (3.6) ms with air, -7 (2.7) ms with SO2, p < 0.05). No such changes were seen in patients with stable angina. Neither pollutant caused any change in markers of inflammation or coagulation at zero, four, or 24 hours. CONCLUSION: In healthy volunteers, short term exposure to pure carbon particles does not cause adverse effects on HRV or a systemic inflammatory response. The adverse effects of vehicle derived particulates are likely to be caused by more reactive species found on the particle surface. SO2 exposure does, however, reduce cardiac vagal control, a response that would be expected to increase susceptibility to ventricular arrhythmia.

Air pollution and the heart.

Despite legislation, leading to dramatic decreases in levels of air pollution since the time of the great smogs, a large body of epidemiological evidence has demonstrated that pollution continues to have adverse effects on human health. One striking finding from the epidemiological data is that patients with cardiovascular disease are susceptible to acute rises in ambient pollutants. Mortality and hospital admissions for myocardial infarction, congestive cardiac failure and cardiac arrhythmia all increase with a rise in the concentration of both particulate and gaseous pollutants. Before concluding that this association is a causal one, plausible pathophysiological mechanisms are required. Evidence is accumulating in support of two mechanistic hypotheses: inhalation of pollutants might provoke a local inflammatory response with the consequent release into the circulation of pro-thrombotic and inflammatory cytokines. A systemic response of this nature would put individuals with coronary atheroma at increased risk of cardiac events; exposure to pollutants may have an adverse effect on cardiac autonomic control, leading to an increased risk of arrhythmia in susceptible patients. Clarification of the pollutants involved and the precise mechanisms of action is essential in designing measures by which susceptible individuals might be protected from the adverse cardiovascular effects of air pollution.

Why cardiologists should be interested in air pollution.

Despite major improvements in air quality resulting from increasingly stringent legislation, there remains a strong association between daily mortality and current levels of air pollution. Growing epidemiological evidence suggests that many, perhaps the majority, of these deaths are caused by cardiovascular disease.

A comparison of the beta1-selectivity of three beta1-selective beta-blockers.

OBJECTIVE: To determine the relative beta1-selectivity of three beta-blockers (nebivolol, bisoprolol and atenolol), administered orally at normal therapeutic doses, by assessing their impact on the beta2-mediated, haemodynamic and biochemical responses to a terbutaline infusion, which decreases serum potassium and increases serum glucose and insulin. METHODS: Twenty-four healthy volunteers (14 men, 10 women), with no history of respiratory disease, attended on five separate occasions; beta-blockers (nebivolol 5 mg, bisoprolol 10 mg, atenolol 50 and 100 mg) or placebo were supplied in random order. Three baseline blood samples were collected at 65-85 min post-beta-blocker. A 60-min terbutaline infusion was started 90 min after taking the beta-blocker. Blood samples were taken and blood pressure and heart rate recorded at 15 min intervals up to 30-min post-infusion. Blood samples were analysed for serum potassium, glucose and insulin concentrations. RESULTS: Terbutaline increased heart rate. Pretreatment with nebivolol caused a modest and non-significant reduction in terbutaline-induced tachycardia whilst bisoprolol produced a more marked effect. Atenolol at both 50 and 100 mg doses caused a highly significant reduction in terbutaline-induced tachycardia. All active preparations had a comparable impact on the terbutaline-induced increase in systolic blood pressure, but the drugs had no impact on the changes produced in diastolic blood pressure. After pretreatment with placebo, the terbutaline infusion caused a significant decrease in serum potassium and increases in serum glucose and insulin. Pretreatment with nebivolol had no discernible effect on potassium compared with placebo. In contrast, when compared with either placebo or nebivolol, bisoprolol (P < 0.01) and both doses of atenolol (P < 0.001) significantly attenuated the hypokalaemic effect of terbutaline. Treatment with nebivolol and bisoprolol modestly but significantly reduced the terbutaline-induced increases in glucose (P < 0.05). The blocking effects of both doses of atenolol were highly significant (P < 0.001) when compared with placebo and also significant (P < 0.05 and P < 0.01, respectively) when compared with nebivolol and bisoprolol. A similar pattern of responses with the different beta-blocker treatments was observed for the effects on insulin concentrations during the terbutaline infusion. CONCLUSION: The beta1-selectivity of three different beta1-blockers has been demonstrated in healthy volunteers using the blocking of biochemical and haemodynamic responses to a beta2 stimulus. Terbutaline alone caused an increase in heart rate, a rise in systolic blood pressure, a fall in serum potassium and a rise in both serum glucose and insulin. In this study, for both haemodynamic and biochemical responses, atenolol 100 mg had the greatest beta2-blocking effect, nebivolol 5 mg the least. Bisoprolol 10 mg and atenolol 50 mg had intermediate effects; bisoprolol was the more beta1-selective of these two.

Heart rate variability--a therapeutic target?

Reduced heart rate variability (HRV) is a powerful and independent predictor of an adverse prognosis in patients with heart disease and in the general population. The HRV is largely determined by vagally mediated beat to beat variability, conventionally known as respiratory sinus arrhythmia. Thus, HRV is primarily an indicator of cardiac vagal control. It is still unclear whether the relationship between measures of cardiac vagal control and mortality is causative or mere association. Possible mechanisms by which cardiac vagal activity might beneficially influence prognosis include a decrease in myocardial oxygen demand, a reduction in sympathetic activity and a decreased susceptibility of the ventricular myocardium to lethal arrhythmia. In animals, augmentation of cardiac vagal control by nerve stimulation or by drugs is associated with a reduction in sudden death in susceptible models. In humans a number of drugs which have been shown to reduce mortality and sudden death in large randomised trials can also be demonstrated to increase HRV. As a result of this evidence, it has been suggested that the effect of drugs or other therapeutic manoeuvres on HRV might be used to predict clinical efficacy. The use of HRV as a therapeutic target is discussed in this review.

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that these agents are not only tolerated but are associated with acute improvements in haemodynamics and diastolic function. Further studies are merited to assess the possible role of ACE inhibitors in aortic stenosis both before and after valve replacement. Potential benefits may include prevention of LVH, improved diastolic function, reduction of arrhythmias and preservation of left ventricular function.