Research

Background and Aims

Cardiovascular diseases (CVD), such as coronary and peripheral artery disease, angina pectoris, high arterial or pulmonary blood pressure and stroke, represent the number one cause of death worldwide. CVD affects 1 in every 6 Australians (over 3.2 million people), increasing to 1 in 4 by mid-century. Every 10 minutes an Australian dies from CVD. Of the 50,292 who died in 2004, 60% had not reached average life expectancy.

Several factors currently contribute to “unnecessary” treatments costing the health system billions of dollars every year:

• Our current measures of risk are too crude
• The actual causes and risk factors are not known
• Lack of efficacious therapeutic options

Therefore, the major research direction of the CVH is to identify and target the underlying mechanisms of cardiovascular disease within the blood vessel, to be able to preserve and improve health, as well as to cure rather than treat symptoms of vascular diseases. This will ultimately result in a decline of CVD morbidity, mortality and disability.

Major Reseach Directions

Major directions of the Centre for Vascular Health
The CVH aims at reliably diagnosing vascular diseases such as atherosclerosis and hypertension long before the manifestation of symptoms becomes apparent and to then initiate preventative therapies, which are monitored by reliable biomarkers. If events occur, they will be treated in a curative, anti-remodelling manner.

• Early Diagnosis
  The CVH aims to develop reliable early diagnostic tools. These will enable clinicians and health care providers to identify individual patients ‘at risk’, which will allow effectively treating those 5% that will suffer from a cardiovascular event in the following five years, and not the 95% patients that may present some classical risk factors but will actually not suffer from a cardiovascular event. The latter shall only be continuously monitored for a worsening of their risk profile and risk.
• Primary Prevention
  The CVH’s objective is to initiate mechanism-based therapies in those patients that have been identified to be ‘at risk’. Since these novel therapies do not target a symptom (e.g. hypertension) but a mechanism (e.g. the underlying cause of hypertension) they will prevent the manifestation of the disease and its symptoms. Effective therapy will be monitored by the same diagnostics that are used to identify the ‘at risk’ individuals.
• Cure
  In those cases, where the ideal time-point for diagnosis and prevention has been missed, a mechanism-based therapy shall be initiated that induces anti-remodelling to a full remission of a thickened or atherosclerotic vessel wall (such as recently shown for Sildenafil or Imatinib).

Research Strategies

The CVH Research Strategies
Each of the CVH three overall aims will require two strategies: Early Diagnosis requires reliable, predictive risk factors and innovative imaging techniques to localise this risk; Primary Prevention requires mechanism-based drugs and tight therapeutic monitoring; Cure requires the use of anti-remodelling drugs and again therapeutic monitoring, most likely though using different diagnostics applied during early prevention.

The research at the CVH pursues 6 strategies:

• Risk-marker / risk-factor discovery
  The CVH aims at identifying plasma or blood cell based proteins, peptides, or modifications thereof, as well as cellular metabolites that are associated with disease development, risk, or relevant outcomes. Hypotheses will be generated in high-risk populations and then validated in large prospective trials.
• Innovative imaging
  Clinical and molecular imaging technologies will localise an individual’s risk to one or more specific vascular beds such as the coronary, cerebral, pulmonary or peripheral circulation, at a stage where no morphological changes can be observed, but where altered molecular, cellular or vascular functions are present.
• Mechanism-based drugs
  The development of mechanism-based therapeutics will allow a shift from symptom-based therapy (e.g. to treat arterial hypertension with vasodilators) to a therapy that targets a disease mechanism (e.g. the molecular target leading to hypertension or at least causing it). It is also anticipated that several of the current symptom-based diagnoses will be subdivided into several mechanism-based diagnoses, e.g. further subgroups of the 95% essential hypertensive. In an even further reaching strategy such sub-grouping of patients will eventually allow the genetics of vascular diseases to be defined.
• Therapeutic monitoring for risk stratification
  Therapeutic monitoring will ensure that a mechanism-based therapy can be tailored to an individual patient and then fully embraces the concept of Personalised Medicine. The individual therapeutic dosage and add-on therapy in a patient will no longer rely on generalisations in large patient cohorts where a statistical significance cannot be traced back to an individual patient. Instead, it will be possible to monitor and – if needed – intensify the therapy based on relevant predictors of outcome to improve therapeutic efficacy from currently 40% to ideally complete event prevention.
• Anti-remodelling
  Novel therapeutics for anti-remodelling will in those cases, where the ideal time-point for early diagnosis and therapy was missed, target those remodelling mechanisms that have led to intimal wall thickening and atherosclerotic lesion development. Ideally, the disease process can be fully reversed as recently shown for pulmonary hypertension.
• Therapeutic monitoring of anti-remodelling
  This strategy will ensure – similar to therapeutic monitoring for risk stratification - that a mechanism-based therapy can be tailored to an individual patient and again embraces the concept of Personalised Medicine, though at a later stage of disease. The CVH predicts that an entirely different set of biomarkers and in vitro diagnostics will be used for therapeutic monitoring of anti-remodelling (versus risk stratification) because the initial disease triggers may no longer drive the disease progression at this stage.
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Research Programs

The CVH has three major Research and Development projects under way:

• Risk markers / Risk factors / Therapeutic monitoring (early and late) (Development of new in vitro Diagnostics)
• Innovative Imaging
• Mechanism-Based Drugs