ICIN/NWC
Einthoven Dissertation Prizes
2006
As far back as 1990, the Netherlands Society of Cardiology (NVVC) and the Interuniversity Cardiology Institute of the Netherlands (ICIN) started to organise a competition for the best three PhD theses on a cardiovascular subject published during the previous year. Sanofi-Aventis has sponsored this competition from the very beginning. The prize carries the name of one ofthe great men in the history of cardiology: Willem Einthoven (1860-1927), the pioneer of the human electrocardiograph. In this 17th edition of the Einthoven Prize the jury, consisting of representatives of the NVVC and the ICIN, reviewed a total of 18 dissertations. The jury was impressed and pleased by the scientific quality of the work laid before them. It has not been easy to choose three candidates for the final round but nevertheless three nominees have, of course, emerged. The three nominees will present their work at the spring congress ofthe NVVC, which will be held in Amsterdam on 21 and 22 April 2006. The ultimate winner ofthe first, second and third prize will be chosen by the audience after the presentations. Summaries ofthe three nominated PhD theses are given below.
Professor C.A. Visser Chairman of the Jury Molecular defects in the metabolism of the HDL particle and the consequences for atherosclerosis progression Coronary artery disease (CAD) is a major cause of mortality in Western society; despite a number of therapeutic modalities that can mitigate the progression of atherosclerosis, the underlying process ultimately leads to CAD. This underscores the need for additional therapeutic strategies. In this respect, increasing the plasma levels of high-density lipoprotein cholesterol (HDL-C) holds great promise. In fact, epidemiological studies have unequivocally shown an inverse relation between HDL-C levels and CAD risk. A considerable number of proteins are involved in HDL-C metabolism, and therapeutic interventions that alter the activity ofthese proteins will theoretically result in increased HDL-C levels, which will in turn ultimately lead to prevention of CAD. Kees Hovingh and colleagues have been studying the consequences of genetic defects in the genes encoding for these pivotal proteins in HDL-C metabolism. The studies focussed on mutations in all currently known key role players in HDL-C metabolism: apolipoproteinA-I (apoA-I, the major protein constituent of HDL-C), ATP binding cassette Al (ABCAI, the protein that pumps cholesterol out ofcells and transfers it to HDL), lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP) and scavenger receptor BI (SR-BI). The effects of these mutations on lipids, lipoproteins and atherosclerosis progression are described in detail in this thesis. Intima media thickness (IMT) measurements, assessed by noninvasive ultrasonography, were used for the staging of atherosclerosis in the study subjects, and the validity and applicability of this surrogate marker for atherosclerosis progression are also described in detail. Low levels of apoA-I caused by a novel mutation underlies a detrimental lipoprotein profile, associated
198
with accelerated arterial wall thickening. It is of note that the extent of atherosclerosis in these carriers was similar to the burden of premature arterial wall abnormalities seen in familial hypercholesterolaemia (FH), a genetic disorder which is associated with an approximately eightfold increased risk for CAD. These data thus not only emphasise the crucial role of apoA-I in the protection against CAD, but also indicate that therapeutic interventions that increase apoA-I may be equally effective to reduce CAD risk as drugs that lower LDL-C. Other defects that lead to HDL-C deficiency (ABCAI and LCAT deficiency) were also found to be associated with increased atherosclerosis progression, but this effect was less pronounced. Our finding that endothelial function is decreased in ABCA1 heterozygotes is in line with the finding of increased arterial wall thickening in these subjects. What is strikingly, however, is the finding that endothelial function was restored completely and instantaneously after a single rapid infusion of apoA-I. This finding indicates that HDL-C increase is not only likely to slow down the progression ofarterial wall thickening, but also exerts direct beneficial effects on the arterial wall. The insight given into the relative importance of the different proteins in HDL-C metabolism is of great interest since it can assist in the prioritising of targets to increase HDL-C levels. In fact, the use of apoAIM,,,o infusion as a therapeutic agent, the materialisation of a number of CETP inhibitors, and the discovery of ABCAI agonists could partly be considered as a successful exploitation of knowledge obtained from these 'extreme genetic' studies that have successfillly investigated the relationship between HDL-C and atherogenesis. E G.K. Hovingh Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands Netherlands Heart Journal, Volume 14, Number 5, May 2006
C
ICIN/NWC Figure 1. Bootstrap estimates ofdifferences in direct medical costs and quality-adjusted life years after on-pump and off-pump coronary bypass surgery. The solid lines indicate threshold values society is 'willing to pay' for one quality-adjusted life year gained ($ 20,000) or 'willing to accept' for one quality adjusted lifr year lost ($40,000). On-pump surgery compared with off-pump surgery was under societal acceptability threshold values in 5% of the 500 estimates. This indicates that off-pump surgery was more cost-eff-ective in 95% of the estimates (4above solid lines).
On-pump versus off-pump surgery 4*
I
%.O
I
c
a
-0.1
-0.05
0
0.05
0.1
Dibrence In qualy ad4usted life years
Coronary revascularisation: stent implantation, on-pump or off-pump bypass surgery Coronary revascularisation by means of surgery or percutaneous intervention (PCI) plays an important role in the management of patients with ischaemic heart disease. Coronary bypass surgery without cardiopulmonary bypass (off-pump surgery) has been reintroduced into clinical practice to avoid complications related to the use of cardiopulmonary bypass. The invention of the Octopus cardiac wall stabiliser at the University Medical Centre Utrecht has greatly facilitated the safe construction of bypasses on all territories of the beating heart during the off-pump procedure. The Octopus study was conducted in the Netherlands to investigate the possible benefits of off-pump surgery over the routine revascularisation methods. The present thesis comprises the primary outcomes ofthe Octopus study concerning cardiac outcome and cost-effectiveness, three subanalyses using data from the Octopus study cohort and a meta-analysis ofpublished randomised comparisons of on-pump and off-pump surgery. The Octopus study comprised two multicentre randomised trials. In the Octostent trial, patients eligible for PCI were randomised to stent implantation or offpump surgery (280 patients). At one year, cardiac event-free survival in the stent group was 85.5% and in the off-pump surgery group 91.5% (difference 6.0%, 95% CI -13.5 to 1.4). A reintervention was needed in 10.1 and 2.1% ofthe patients, respectively. Stent implantation reduced direct medical costs by £2813 (26.0%) per patient (p=0.01) and was more cost-effective than off-pump surgery. In the Octopump trial, patients eligible for bypass surgery were randomised to on-pump or off-pump surgery (281 patients). At one year, cardiac event-free survival in the on-pump group was 90.6% and in the off-pump group 88.0% (difference 2.6%,95% CI -4.6 to 9.8). Off-pump surgery was associated with £2089 (14.1%) lower direct medical costs per patient (p
Einthoven Dissertation Prizes
2006
As far back as 1990, the Netherlands Society of Cardiology (NVVC) and the Interuniversity Cardiology Institute of the Netherlands (ICIN) started to organise a competition for the best three PhD theses on a cardiovascular subject published during the previous year. Sanofi-Aventis has sponsored this competition from the very beginning. The prize carries the name of one ofthe great men in the history of cardiology: Willem Einthoven (1860-1927), the pioneer of the human electrocardiograph. In this 17th edition of the Einthoven Prize the jury, consisting of representatives of the NVVC and the ICIN, reviewed a total of 18 dissertations. The jury was impressed and pleased by the scientific quality of the work laid before them. It has not been easy to choose three candidates for the final round but nevertheless three nominees have, of course, emerged. The three nominees will present their work at the spring congress ofthe NVVC, which will be held in Amsterdam on 21 and 22 April 2006. The ultimate winner ofthe first, second and third prize will be chosen by the audience after the presentations. Summaries ofthe three nominated PhD theses are given below.
Professor C.A. Visser Chairman of the Jury Molecular defects in the metabolism of the HDL particle and the consequences for atherosclerosis progression Coronary artery disease (CAD) is a major cause of mortality in Western society; despite a number of therapeutic modalities that can mitigate the progression of atherosclerosis, the underlying process ultimately leads to CAD. This underscores the need for additional therapeutic strategies. In this respect, increasing the plasma levels of high-density lipoprotein cholesterol (HDL-C) holds great promise. In fact, epidemiological studies have unequivocally shown an inverse relation between HDL-C levels and CAD risk. A considerable number of proteins are involved in HDL-C metabolism, and therapeutic interventions that alter the activity ofthese proteins will theoretically result in increased HDL-C levels, which will in turn ultimately lead to prevention of CAD. Kees Hovingh and colleagues have been studying the consequences of genetic defects in the genes encoding for these pivotal proteins in HDL-C metabolism. The studies focussed on mutations in all currently known key role players in HDL-C metabolism: apolipoproteinA-I (apoA-I, the major protein constituent of HDL-C), ATP binding cassette Al (ABCAI, the protein that pumps cholesterol out ofcells and transfers it to HDL), lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP) and scavenger receptor BI (SR-BI). The effects of these mutations on lipids, lipoproteins and atherosclerosis progression are described in detail in this thesis. Intima media thickness (IMT) measurements, assessed by noninvasive ultrasonography, were used for the staging of atherosclerosis in the study subjects, and the validity and applicability of this surrogate marker for atherosclerosis progression are also described in detail. Low levels of apoA-I caused by a novel mutation underlies a detrimental lipoprotein profile, associated
198
with accelerated arterial wall thickening. It is of note that the extent of atherosclerosis in these carriers was similar to the burden of premature arterial wall abnormalities seen in familial hypercholesterolaemia (FH), a genetic disorder which is associated with an approximately eightfold increased risk for CAD. These data thus not only emphasise the crucial role of apoA-I in the protection against CAD, but also indicate that therapeutic interventions that increase apoA-I may be equally effective to reduce CAD risk as drugs that lower LDL-C. Other defects that lead to HDL-C deficiency (ABCAI and LCAT deficiency) were also found to be associated with increased atherosclerosis progression, but this effect was less pronounced. Our finding that endothelial function is decreased in ABCA1 heterozygotes is in line with the finding of increased arterial wall thickening in these subjects. What is strikingly, however, is the finding that endothelial function was restored completely and instantaneously after a single rapid infusion of apoA-I. This finding indicates that HDL-C increase is not only likely to slow down the progression ofarterial wall thickening, but also exerts direct beneficial effects on the arterial wall. The insight given into the relative importance of the different proteins in HDL-C metabolism is of great interest since it can assist in the prioritising of targets to increase HDL-C levels. In fact, the use of apoAIM,,,o infusion as a therapeutic agent, the materialisation of a number of CETP inhibitors, and the discovery of ABCAI agonists could partly be considered as a successful exploitation of knowledge obtained from these 'extreme genetic' studies that have successfillly investigated the relationship between HDL-C and atherogenesis. E G.K. Hovingh Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands Netherlands Heart Journal, Volume 14, Number 5, May 2006
C
ICIN/NWC Figure 1. Bootstrap estimates ofdifferences in direct medical costs and quality-adjusted life years after on-pump and off-pump coronary bypass surgery. The solid lines indicate threshold values society is 'willing to pay' for one quality-adjusted life year gained ($ 20,000) or 'willing to accept' for one quality adjusted lifr year lost ($40,000). On-pump surgery compared with off-pump surgery was under societal acceptability threshold values in 5% of the 500 estimates. This indicates that off-pump surgery was more cost-eff-ective in 95% of the estimates (4above solid lines).
On-pump versus off-pump surgery 4*
I
%.O
I
c
a
-0.1
-0.05
0
0.05
0.1
Dibrence In qualy ad4usted life years
Coronary revascularisation: stent implantation, on-pump or off-pump bypass surgery Coronary revascularisation by means of surgery or percutaneous intervention (PCI) plays an important role in the management of patients with ischaemic heart disease. Coronary bypass surgery without cardiopulmonary bypass (off-pump surgery) has been reintroduced into clinical practice to avoid complications related to the use of cardiopulmonary bypass. The invention of the Octopus cardiac wall stabiliser at the University Medical Centre Utrecht has greatly facilitated the safe construction of bypasses on all territories of the beating heart during the off-pump procedure. The Octopus study was conducted in the Netherlands to investigate the possible benefits of off-pump surgery over the routine revascularisation methods. The present thesis comprises the primary outcomes ofthe Octopus study concerning cardiac outcome and cost-effectiveness, three subanalyses using data from the Octopus study cohort and a meta-analysis ofpublished randomised comparisons of on-pump and off-pump surgery. The Octopus study comprised two multicentre randomised trials. In the Octostent trial, patients eligible for PCI were randomised to stent implantation or offpump surgery (280 patients). At one year, cardiac event-free survival in the stent group was 85.5% and in the off-pump surgery group 91.5% (difference 6.0%, 95% CI -13.5 to 1.4). A reintervention was needed in 10.1 and 2.1% ofthe patients, respectively. Stent implantation reduced direct medical costs by £2813 (26.0%) per patient (p=0.01) and was more cost-effective than off-pump surgery. In the Octopump trial, patients eligible for bypass surgery were randomised to on-pump or off-pump surgery (281 patients). At one year, cardiac event-free survival in the on-pump group was 90.6% and in the off-pump group 88.0% (difference 2.6%,95% CI -4.6 to 9.8). Off-pump surgery was associated with £2089 (14.1%) lower direct medical costs per patient (p
