Christian Werner, MD, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
Michael Böhm, MD, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to heart failure or stroke. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Several mechanisms govern the progression of myocardial damage to end-stage chronic heart failure (CHF). Chronic neuroendocrine activation, comprising the RAS, sympathetic nervous system and the release of cytokines, leads to remodelling processes and via forward / backward failure to clinical symptoms of CHF. Therefore, combined RAS inhibition is especially effective to improve neuroendocrine blockade in CHF patients with repetitive cardiac decompensations.
Key words: angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin-angiotensin system, chronic heart failure, clinical trials.

Sheldon Tobe, MD, FRCP(C), Assistant Professor of Medicine, Nephrology, University of Toronto; Division Director Nephrology, Sunnybrook & Women's College Health Sciences Centre, Toronto, ON.
Sudha Cherukuri, MD, DNB(Nephrology), Clinical Fellow, University of Toronto, Toronto, ON.

Isolated systolic hypertension (ISH) is a common disorder in the elderly. Several studies have shown a constant positive and graded association between the level of systolic blood pressure and subsequent mortality from cardiovascular disease and stroke. ISH is defined as an elevated systolic pressure above 160mmHg and a diastolic pressure below 90mmHg. Arterial stiffening is the main cause of increasing systolic pressure in the elderly. The finding of high systolic blood pressure with diastolic below 90mmHg is a marker of higher cardiovascular risk and an indication to follow this patient more closely. The placebo-controlled SHEP and Syst-Eur trials have demonstrated that the treatment of ISH with diuretics or long-acting calcium channel blockers results in a marked reduction in cardiovascular events and stroke.
Key words: hypertension, isolated systolic hypertension, clinical trials, drug therapy, elderly.

Cynthia Jackevicius, BScPhm, MSc
Practice Leader,
Pharmacy Department,
Associate, Women's Health Program,
University Health Network-Toronto General Hospital,
Assistant Professor,
University of Toronto, Toronto, ON.

Coronary heart disease (CHD) is a major economic burden on the health care system, with the total cost of the morbidity and mortality associated with cardiovascular disease in Canada estimated at $18.0 billion in 1994.¹ Effective prevention and treatment decrease morbidity and mortality associated with CHD. A controversial issue in recent years has been whether the reduction of cholesterol results in a decline in subsequent CHD events and mortality in patients older than 65 years of age.² Several observational studies have suggested that elevated cholesterol levels may not be a significant cardiovascular risk factor in older people. However, a recent study investigated this hypothesis and found that after adjustment for risk factors and indicators of frailty, such as low serum albumin, elevated total cholesterol levels do predict increased risk for death from CHD in older adults.³

Three recently published, landmark trials focusing on the benefits of statins in the prevention of secondary coronary events showed that statins improve patient outcomes with minimal adverse effects.

Ruwaida Dhala, BSc, MSc

Vaccination has one of the greatest impacts on disease prevention. Most vaccines generate protective immune responses against a pathogen, preventing disease initiation. Often the immunity generated by vaccines to specific pathogens is lifelong. Preventative vaccines are not effective in cancer prevention, however, mostly because cancer antigens elicit poor immune responses. For this reason many cancers evade the immune system. Cancer vaccine strategy focuses on eliciting anti-tumour responses in patients that are already afflicted with cancer. These vaccines will presumably prevent cancer progression and reoccurrence rather than prevent cancer initiation.

In order for the body to mount an immune response, the invading pathogen, or components of it, must be exposed to the immune system. There are two major components of the immune system, humoral and cellular. Humoral immunity is involved in the generation of antibody responses. These antibodies are usually directed against extracellular pathogens such as bacteria. Most preventative vaccines rely on this arm of the immune system.

Barry J. Goldlist MD, FRCPC, FACP

The first five international conferences on Alzheimer's Disease were meant for scientists, as there was essentially nothing available for clinical use. This year's meeting was quite different. The recent licensing of donepezil in Canada and the United States will soon be followed by numerous new drugs, many of which will have novel modes of action. The importance of Canadian research in this field was highlighted by the active participation in the program of Howard Feldman (Vancouver), Serge Gauthier (Montreal) and Ken Rockwood (Halifax). One of the keynote presentations was by Peter St. George Hyslop, Director of the Centre for Research in Neurodegenerative Disorders at the University of Toronto.

The meeting still emphasized basic science, particularly in the area of molecular genetics and molecular biology, but there were more than enough sessions for clinicians and clinical investigators. One interesting symposium concerned itself with the design of clinical trials for demonstrating disease course-altering effects (rather than just symptomatic improvement). It seems that for the immediate future, staggered start and withdrawal design will be the standard. The theory is that if a drug truly alters the disease course, patients starting the active drug later (i.e. placebo changed to active drug) will never achieve the same benefit as the group started on active drug (i.e. active drug to active drug). Similarly, early withdrawal patients (i.e. active drug changed to placebo) would have a better end result than patients never on active drug (placebo to placebo). Preliminary evidence was presented that suggested a new drug, propentofylline, might have such an effect. This drug is not a cholinesterase inhibitor such as donepezil, but rather is felt to be a microglial cell modulator, and thus inhibits some of the inflammatory response seen in various dementias.

Farther from clinical applicability, but still exciting was a round table discussion entitled "Beyond Cholinesterase Inhibitors: Toward the Next Generation of AD Therapeutics." Presentations on possible therapeutic interventions, such as modulating b-amyloidogenesis, inhibiting neurofibrillary degeneration or using muscarinic agonists. It seems quite likely that the 7th International Symposium in the year 2000 will be even more exciting for clinicians.