Marc Hartmann

Relation Between Progression and Regression of Atherosclerotic Left Main Coronary Artery Disease and Serum Cholesterol Levels as Assessed With Serial Long-Term (≧=">12 Months) Follow-Up Intravascular Ultrasound

Background—The relation between serum lipids and risk of coronary events has been established, but there are no data demonstrating directly the relation between serum low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol versus serial changes in coronary plaque dimensions. Methods and Results—We performed standard analyses of serial intravascular ultrasound (IVUS) studies of 60 left main coronary arteries obtained 18.3±9.4 months apart to evaluate progression and regression of mild atherosclerotic plaques in relation to serum cholesterol levels. Overall, there was (1) a positive linear relation between LDL cholesterol and the annual changes in plaque plus media (P&M) cross-sectional area (CSA) (r =0.41, P <0.0001) with (2) an LDL value of 75 mg/dL as the cutoff when regression analysis predicted on average no annual P&M CSA increase; (3) an inverse relation between HDL cholesterol and annual changes in P&M CSA (r =−0.30, P <0.02); (4) an inverse relation between LDL cholesterol and annual changes in lumen CSA (r =−0.32, P <0.01); and (5) no relation between LDL and HDL cholesterol and the annual changes in total arterial CSA (remodeling). Despite similar baseline IVUS characteristics, patients with an LDL cholesterol level ≥120 mg/dL showed more annual P&M CSA progression and lumen reduction than patients with lower LDL cholesterol. Conclusions—There is a positive linear relation between LDL cholesterol and annual changes in plaque size, with an LDL value of 75 mg/dL predicting, on average, no plaque progression. HDL cholesterol shows an inverse relation with annual changes in plaque size.

Relationship Between Cardiovascular Risk as Predicted by Established Risk Scores Versus Plaque Progression as Measured by Serial Intravascular Ultrasound in Left Main Coronary Arteries

Background—Intravascular ultrasound (IVUS) is increasingly used as an end point in studies aimed at reducing progression or inducing regression of coronary artery disease. However, data linking serial changes by IVUS with clinical outcomes are scarce. Methods and Results—In the absence of a validated risk score for secondary prevention, we compared 3 established risk scores for primary prevention—PROCAM, SCORE, and Framingham—with plaque progression and lumen reduction as assessed with serial IVUS (follow-up, 18±9 months) in atherosclerotic left main coronary arteries of 56 patients with established atherosclerosis. For all 3 algorithms, patients at highest estimated risk of events showed greater plaque progression than patients at lowest risk (P<0.05 to <0.01). There were positive linear relationships between the risk of clinical events and plaque progression (r=0.41 to 0.60; P<0.002 to <0.0001). This translated into a greater decrease in lumen dimensions with increasing risk (P<0.05, PROCAM and SCORE). Risk prediction using the PROCAM algorithm showed the strongest relation with serial IVUS. During follow-up, 18 patients suffered from adverse cardiovascular events; these patients had an annual plaque progression that was significantly greater than other patients (25.2±19.4% versus 5.9±15.6%, P<0.001). Conclusions—There was a positive linear relationship between the estimated risk of clinical events derived from all 3 established risk-score algorithms and the extent of plaque progression measured by serial IVUS. This translated into stenosis progression (reduction in lumen dimensions) with increasing clinical risk.

Serial intravascular ultrasound assessment of changes in coronary atherosclerotic plaque dimensions and composition: an update

This manuscript reviews the use of serial intravascular ultrasound (IVUS) examination of coronary atherosclerosis in recent observational studies and randomized trials that revealed the effects of cholesterol-lowering and lipid-modifying therapies and offered novel insight into plaque progression and regression. We discuss the value of plaque progression-regression as complementary imaging endpoint and potential surrogate marker of cardiovascular event risk. In addition, the progress in serial assessment of coronary plaque composition and plaque vulnerability by radiofrequency-based analyses is reviewed. Finally, we report on the evaluation of true vessel remodelling in recent serial IVUS trials and discuss the future perspective of serial invasive imaging of coronary atherosclerosis.

Between-centre reproducibility of volumetric intravascular ultrasound radiofrequency-based analyses in mild-to-moderate coronary atherosclerosis : An international multicentre study

Aims: To assess for the first time in a multicentre design the between-centre reproducibility of volumetric virtual histology intravascular ultrasound (VH-IVUS) measurements with a semi-automated, computer-assisted contour detection system in mild-to-moderately diseased coronary segments. Methods and results: Analysts of four European IVUS centres performed independent IVUS analyses (in total 7,188 cross-sectional analyses) and obtained volumetric data to evaluate the reproducibility of volumetric VH-IVUS measurements in 36 coronary segments (length 20.0±0.4 mm) from patients with stable angina. Geometric and compositional VH-IVUS measurements were highly correlated for the different comparisons. Overall intraclass correlation for vessel, lumen, plaque volume and plaque burden were 0.98, 0.92 0.95, and 0.86, respectively; for fibrous, fibro-lipidic, necrotic core and calcified volumes overall intraclass correlations were 0.95, 0.93, 0.99, and 1.00, respectively. There were significant but small differences for vessel, lumen, fibrous and calcified volumes, and there was no significant difference for plaque volume. Of the plaque components necrotic core and calcified volume showed on average the highest reproducibility. Conclusions: These findings underline the necessity to centrally analyse IVUS data obtained in multicentre studies addressing mild-to-moderately diseased coronary arteries. In addition, pooling VH-IVUS data from different studies, analysed at different centres, may be problematical.

Acute left ventricular failure in a patient with hydroxychloroquine-induced cardiomyopathy

We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy.

Three-year clinical outcome after treatment of chronic total occlusions with second-generation drug-eluting stents in the TWENTE trial

To compare long‐term outcome of patients treated for chronic total occlusion (CTO) lesions versus patients treated for non‐CTO lesions only.

Three-year safety and efficacy of treating all-comers with newer-generation Resolute Integrity or PROMUS Element stents in the randomised Dutch PEERS (TWENTE II) trial

AIMS The aim of this report was to assess the three-year safety and efficacy of implanting newer-generation Resolute Integrity zotarolimus-eluting stents (ZES) versus PROMUS Element everolimus-eluting stents (EES) in all-comers. METHODS AND RESULTS In the randomised, multicentre, investigator-initiated DUTCH PEERS trial, a total of 1,811 all-comers were 1:1 randomly assigned to treatment with ZES versus EES. A total of 1,293 patients (72%) were treated for complex lesions and 455 patients (25%) were treated for multiple lesions. The primary endpoint target vessel failure (TVF) is a composite of cardiac death, target vessel-related myocardial infarction or target vessel revascularisation. Adverse clinical events were independently adjudicated. Three-year follow-up data were obtained in 1,807 patients (99.8%, four withdrawals). Both the ZES and EES groups showed favourable outcomes with a similar incidence of TVF (10.7% vs. 10.3%; pLog-rank=0.77) and the individual components thereof: cardiac death (3.2% vs. 3.1%; pLog-rank=0.87), target vessel-related myocardial infarction (2.8% vs. 2.2%; pLog-rank=0.44) and target vessel revascularisation (6.0% vs. 6.2%; pLog-rank=0.87). In addition, the incidence of definite or probable stent thrombosis was similar for patients treated with ZES versus EES (1.4% vs. 1.1%; pLog-rank=0.66). CONCLUSIONS The safety and efficacy of treating all-comers with newer-generation Resolute Integrity and PROMUS Element stents was found to be extended up to three years.

Major dehiscence of infected aortic valve prosthesis with ''rocking motion'' but without diastolic paravalvular regurgitation

We present a case of a 66-year-old patient with infective endocarditis of an aortic valve bioprosthesis with major dehiscence and extensive “rocking motion” but without any diastolic paravalvular regurgitation as assessed with radiography and transesophageal echocardiography.

How should I treat multiple coronary aneurysms with severe stenoses

BACKGROUND: A 46-year-old male, with a history of old myocardial infarction in the first diagonal branch (D1) treated with balloon angioplasty three years before, was admitted to our institution because of chest pain on effort. He underwent coronary angiography which revealed multiple coronary aneurysms in the left anterior descending artery (LAD) and the D1 with severe stenoses in the LAD, D1, and the obtuse marginal branch. INVESTIGATION: Coronary angiography, fractional flow reserve, scintigraphy, coronary computed tomography. DIAGNOSIS: Multiple coronary aneurysms with severe stenoses. MANAGEMENT: Percutaneous coil embolisation and stenting.

Is size really all that matters? Remarks on size and necrotic core content of atherosclerotic plaques.

Atherosclerotic coronary heart disease remains the leading cause of morbidity and mortality in populations with so-called western lifestyle. During the last two decades intravascular ultrasound (IVUS) allowed us to study the atherosclerotic disease process in the coronary vessel wall in vivo [1–4]. By use of motorized pullback systems, volumetric IVUS data could be obtained that turned out to be ideal for such studies [5–7]. As a result, our insights have been extended from beyond what was known from histopathology and angiographic studies. Serial studies with grey-scale IVUS enriched our understanding of the disease mechanisms involved (e.g., vascular remodelling and progression–regression) and permit an early estimation of the potential effectiveness of new pharmacological anti-atherosclerotic concepts [5, 8, 9]. Intravascular ultrasound assessment of clinically highly successful pharmacological interventions demonstrated some effects on plaque progression–regression and on vascular remodelling; however, these effects on plaque dimensions were relatively small [8]. The discordance between significant clinical benefit and only mild effects on plaque size could be explained by an additional beneficial effect on plaque composition that may lead to stabilisation of the atheroma. Conventional grey-scale IVUS is limited in the assessment of plaque composition [2, 10]. For that reason, a novel approach for radiofrequency (RF)-based analysis of IVUS data was developed which quantifies coronary plaque components and permits the detection of features of plaque vulnerability (e.g., necrotic core and thin-cap fibro-atheroma) [10–13]. As recently demonstrated in mild-to-moderately diseased coronary arterial segments in vivo, volumetric RF-based IVUS analysis shows a relatively high measurement reproducibility for both interobserver and between centre-comparisons [14, 15]. Despite some limitations, studies with RF-based IVUS go beyond the scope of plaque size measurement and may provide additional information on the nature and the “pathology” of coronary atherosclerosis. Post-mortem studies of coronary arterial specimen previously provided evidence that the necrotic core size and relative necrotic core content of a plaque are features of plaque instability that are related to coronary events [16–18]. Because of the known limitations of grey-scale IVUS in the assessment of plaque composition, conventional IVUS could only be used to examine the size of the cavities inside ulcerated ruptured plaques, which were considered to reasonably correspond with the necrotic core volume prior to plaque rupture [1, 3, 6]. In correspondence with grey-scale IVUS data of our own group [1], the volumetric RF-based IVUS data of Xu et al. [19] published in the present edition of the International Journal of Cardiovascular Imaging, show that the (absolute) volume of the necrotic core was greater in larger plaques. Kaple et al. [20] recently showed with RF-based IVUS in 90 de-novo coronary lesions that the site of the largest necrotic core was more often proximal to the minimal lumen site where vessel dimensions were larger. They also demonstrated a relation between positive vascular remodelling and greater size of necrotic core [20]. Missel et al. [21] analyzed registry data of 225 patients with non-ST elevation acute coronary syndromes to show that necrotic core volume was significantly larger in patients with elevated cardiac enzymes; they found that the percentage of necrotic core and its ratio to dense calcium were positively associated with increased risk. In the study by Xu et al. [19] volumetric RF-based (Virtual Histology) IVUS of 224 target lesions showed a significant linear relation between plaque volume and the absolute amount of tissue components. To put it in other words: the greater the plaque, the greater the volume of each plaque component (e.g. necrotic core tissue). However, the authors found no relation between overall plaque volume and the relative content of necrotic core tissue. That is, larger (more advanced) plaques did not show a significantly higher percentage of necrotic core [19], which is consistent with registry data that were recently published by Qian et al. [22]. But is plaque size all that matters for the vulnerability and the necrotic core content of coronary plaques? The data of some other studies actually suggest a somewhat more loose relation between plaque size and the actual amount of necrotic core. The results of the serial multicenter, randomized, placebo-controlled pharmacological intervention trial Integrated Biomarker And Imaging Study-2 (IBIS-2)—for instance—support this idea [23]. The study assessed changes in volumetric plaque composition as an endpoint to test the effect of the inhibition of the enzyme lipoprotein-associated phospholipase-A2 with darapladib. The placebo group was treated with maximum current therapies (including intense statin therapy) and finally showed non-significant decrease in plaque volume but a significant increase in absolute and relative necrotic core content; darapladib treatment, on the other hand, stopped necrotic core increase [23]. While the design of the IBIS-2 trial is serial, the observational study by Xu et al. has a cross-sectional design (assessment at one time); therefore, these findings may not actually reflect plaque progression, which is a dynamic process over time. Several factors and mechanisms other than plaque size could co-determine the relative extent of necrotic core tissue; examples may be: acute coronary syndromes; an increased “inflammatory status”; increased major cardiovascular risk factors such as diabetes; and/or genetic factors. Xu et al. [19] performed in their study some subgroup analyses based on such clinical characteristics (patients with and without acute coronary syndrome and diabetes mellitus); but in these (partly rather small) subgroups, findings were essentially similar to the overall population. This is in contrast to the outcomes of several other studies, which suggested a relatively higher necrotic core content in patients with acute coronary syndromes and with diabetes mellitus [24–27]. The analysis of data from large serial IVUS studies with RF-based assessment of plaque composition will be required to obtain further insight into this interesting matter. Optical coherence tomography (OCT), a light-based technique for invasive coronary imaging, permits an even more detailed assessment of coronary plaques at higher resolution [28–30]. As OCT is limited in penetration depth, IVUS and OCT may complement each other [31, 32]. Therefore, the combined use of both techniques in serial trials may significantly advance our knowledge of coronary atherosclerosis and its progression. There is obviously a strong relation between plaque size and features of plaque vulnerability; however, we would expect that future advanced coronary imaging studies may reveal that the size of the atherosclerotic plaque is not all that matters.