Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS)

doi:10.1016/S0021-9150(98)00328-1

Atherosclerosis

Volume 144, Issue 2, June 1999, Pages 409-417

https://doi.org/10.1016/S0021-9150(98)00328-1 Get rights and content

Abstract

Twenty-five heterozygous familial hypercholesterolemic patients treated with LDL-apheresis and drugs and 11 patients treated with drugs underwent follow-up angiography 2.3 years later. One-hundred thirteen lesions were measured by quantitative angiography. Mean LDL-cholesterol levels during the trial were 140±34 mg/dl in the apheresis group and 170±58 mg/dl (P<0.05) in the control group. The mean changes in minimal lumen diameter of lesions were +0.19±0.30 mm (improved) in the apheresis group (n=76) and −0.44±0.40 mm (worsened) in the control group (n=37) (P<0.0001). When progression and regression were defined as a change in minimal lumen diameter of ±0.67 mm, in the apheresis group, two (8%) patients had progression, 19 (76%) stayed unchanged and four (16%) had regression, but in the control group seven (64%) patients had progression and four (36%) stayed unchanged. The frequency of regression or no change was significantly higher in the apheresis group than in the control group (P<0.004). Intensive cholesterol lowering therapy with LDL-apheresis and lipid lowering drugs can achieve a substantial decrease in LDL-cholesterol levels to induce regression of coronary lesions in familial hypercholesterolemic patients with advanced coronary artery disease.

Introduction

A subset of patients with heterozygous familial hypercholesterolemia (FH) and virtually all with homozygous FH do not achieve adequate low-density lipoprotein (LDL) cholesterol control with diet and drug therapy because of extremely high, initial lipid levels or drug intolerance [1], [2]. The LDL-apheresis technique using the Liposorber system, which is an automated dextran sulfate cellulose adsorption system (Kaneka, Japan), is a safe and effective method to selectively lower LDL for long-term treatment in patients with heterozygous FH [3], [4], [5]. Selective removal of apolipoprotein B-containing lipoproteins by LDL-apheresis combined with lipid lowering drug therapy is a better treatment option for refractory patients with FH [6].

Several randomized placebo-controlled trials have shown that LDL-cholesterol lowering by diet and combination drug therapy can induce regression of coronary lesions [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Non-controlled studies have suggested that LDL-apheresis can induce regression of coronary lesions in patients with FH refractory to diet and drug therapy [17], [18]. Although prospective controlled trials using LDL-apheresis have been recently reported, equivocal evidence of regression of coronary lesions was obtained during treatment with LDL-apheresis and medication [19], [20], [21].

The Japan LDL-Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS), involving 12 centers in Japan, began a trial in 1989, to test the hypothesis that LDL-apheresis combined with lipid lowering drug can retard progression or induce regression of coronary atherosclerotic lesions in FH patients who have advanced coronary artery disease and were resistant to diet and drug therapy.

Section snippets

Study patients

Patients of both sexes and age below 70 years, who had clinical features compatible with heterozygous FH and were scheduled to undergo coronary angiography, were recruited from the 12 centers. To be included, patients had to have tendon xanthomas, a mean of two consecutive serum total cholesterol levels ≧230 mg/dl, and a mean of two consecutive serum total triglyceride levels <210 mg/dl while they were treated for 8 weeks by a cholesterol lowering diet (equivalent to the American Heart

Patient characteristics

Baseline characteristics did not differ significantly between the LDL-apheresis and control groups (Table 1). By the standard criteria of a stenosis>50% being considered significant, 85% of the LDL-apheresis group had multivessel coronary artery disease. All patients were treated with lipid lowering drugs. In the LDL-apheresis group, pravastatin (20 mg/day), probucol (500–750 mg/day) and cholestyramine (18–27 g/day) were prescribed in 18 patients (72%), pravastatin and probucol in five (20%),

Discussion

We have demonstrated that the combination of LDL-apheresis and drugs is more effective than drugs alone in reducing LDL-cholesterol over a period of 28 months, and the greater decrease of LDL-cholesterol levels achieved with LDL-apheresis is clearly associated with angiographic evidence of regression and retardation of coronary artery lesions in FH patients with advanced coronary artery disease. Equivocal evidence of regression of coronary lesions had been obtained during treatment with

Acknowledgements

The authors report on behalf of the L-CAPS Study Group.

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Lipoprotein apheresis (LA) is an extracorporeal therapy which removes apolipoprotein B-containing particles from the circulation. We evaluated techniques and efficiency of lipoprotein apheresis procedures applied to patients with familial and non-familial hypercholesterolemia (FH) at our center.
We retrospectively evaluated 250 LA procedures applied to 27 patients with dyslipidemia between March 2011 and August 2019.
A total of 27 patients, of whom 19 (70.4%) were male and 8 (29.6%), female, were included. Eighteen (66.7%), 6 (22.2%) and 3 (11.1%) patients were diagnosed with non-FH, homozygous FH (HoFH) and heterozygous FH (HeFH), respectively. Two different apheresis techniques, direct adsorption of lipoproteins (DALI) (48.8%) and double filtration plasmapheresis (DFPP) (51.2%), were used. The change in the serum total cholesterol (TC) level was the median 302 mg/dl (171–604 mg/dl) (60.4%) in HoFH patients, 305 mg/dl (194–393 mg/dl) (60.8%) in HeFH patients and 227 mg/dl (75–749 mg/dl) (65.3%) in non-FH patients. The change in the serum low-density lipoprotein (LDL) level was the median 275 mg/dl (109–519 mg/dl) (64.2%), 232 mg/dl (207–291 mg/dl) (64.5%) and 325 mg/dl (22–735 mg/dl) (70.9%) in patients with HoFH, HeFH and non-FH, respectively. A significantly effective reduction in serum lipid levels, including TC, LDL and triglycerides, was achieved in all patients, regardless of the technique, p < .001. The decrease in the serum TC and LDL levels was significantly higher in the DFPP, compared to the DALI, being 220 mg/dl (−300 to 771) vs 184 mg/dl (64–415), p < .001 and 196 mg/dl (11–712) vs 157 mg/dl (54–340), p < .001, respectively.
Our results showed that LA is a highly effective treatment in reducing serum lipid levels and safe, without any major adverse event.
Lipoprotein apheresis efficacy, challenges and outcomes: A descriptive analysis from the UK Lipoprotein Apheresis Registry, 1989–2017
2019, Atherosclerosis
In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011.
Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients.
Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA.
The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias.
Atherosclerosis in cholesterol-fed rabbits and in homozygous and heterozygous LDL receptor-deficient humans
2018, Atherosclerosis
A phenocopy is an environmentally-defined phenotype that mimics another, genetically-determined phenotype. The severity of hypercholesterolaemia, extent of down regulation of LDL receptor expression and aortic root localisation of atherosclerosis in cholesterol-fed rabbits strikingly resemble the cardinal features of homozygous familial hypercholesterolaemia (FH) in humans, suggesting that the former is a phenocopy of the latter.
This review compares the metabolic and pathological consequences of induced hypercholesterolaemia in rabbits with those of homozygous FH and contrasts their ease of reversibility on resumption of a normal diet with the refractoriness to lipid-lowering therapy of homozygotes, in whom major adverse cardiovascular events and survival depend upon the prevailing level of serum cholesterol. The monofactorial nature of the atherosclerosis in both situations corroborates Anitschkow's concept that “Cholesterin ist alles.”
In contrast, atherosclerosis in heterozygous FH differs in several respects from that of homozygotes, notably the lack of aortic root involvement and in its multifactorial aetiology, with raised LDL cholesterol, male gender, low HDL cholesterol and raised lipoprotein (a) all contributing to its clinical expression. In angiographic trials of LDL-lowering therapy regression of coronary lesions was observed in FH heterozygotes whereas they progressed in non-FH subjects. Similarly, carotid artery plaques progressed less in FH heterozygotes than in non-FH subjects, in both instances despite FH patients having higher LDL cholesterol levels on treatment.
These findings suggest that, compared with non-FH subjects, atherosclerotic lesions in FH heterozygotes may be hyper-responsive to LDL-lowering therapy, whereas treatment of homozygous FH remains a major challenge.
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The study of small-molecule metabolites may assist in cardiovascular risk monitoring during therapy. We assessed whether acute changes in the metabolome by lipoprotein apheresis are able to predict changes in microvascular function.
We performed mass-spectrometry-based profiling of 186 metabolites in peripheral plasma of 21 hyperlipidemic patients before and after a single session of lipoprotein apheresis. To evaluate the capability of metabolites to predict microvascular outcome after apheresis, patients were stratified according to improvement and deterioration of retinal endothelial function. Endothelial function was assessed as the relative change in retinal vessel diameter in response to flicker light stimulation.
We observed pronounced but not uniform changes in the metabolome after a single session of lipoprotein apheresis. Improvements in microvascular function were associated with a decline in lysophosphatidylcholines C14:0, C16:0, C16:1, C18:0, C18:1, C18:2, C20:4, C28:0, C28:1; in the amino acid serine and the dicarboxyacylcarnitine C12-DC. A positive relationship was found for methionine and ornithine. Applying decision tree and receiver–operator characteristic curve analysis, a change in serine of smaller than 11% by lipoprotein apheresis predicted an improvement of microvascular function with high sensitivity.
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Lipoprotein apheresis (LA) is an extracorporeal technique which permits the unselective or specific removal of lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100-containing lipoproteins from plasma. LA represents a selective upgrade (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) which was used in the seventies to treat severe hypercholesterolemia. The primary reason for using is the treatment of homo-, double- (or compound) and heterozygous familial hypercholesterolemia (Hoz-, DHtz,- Htz,-FH). This technique has also been shown to be efficacious in the treatment of other severe forms of hyperlipoproteinemia such as: hyperLp(a)lipoproteinemia, the familial combined hyperlipoproteinemia and other varieties associated with an elevated cardiovascular risk (CVR) when used in patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, continuous, and personalized form of therapy. A therapy based solely on current available drugs does not achieve the desired results in the Hoz- and DHtz forms of FH or in approximately 10–20% of the Htz form. For the aforementioned clinical conditions, LA treatment offers a necessary therapeutic approach. LA can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which appears, rather frequently after vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Clinical trials have shown that statins provide a major reduction in cardiovascular morbidity and mortality, but often fail to attain desirable LDL-cholesterol target level in Hoz- and DHtz- (Compound) FH high cardiovascular risk patients. Intolerance to statins is also relatively frequent in Htz-FH and non-FH patients. LA has effectively replaced pharmacological cholesterol-lowering therapy for decades. Young high CVR risk patients survived to adulthood thanks only to LA. More recently, promising novel compounds aimed at other molecular targets are being studied for the treatment of severe dyslipidemia: Lomitapide, Mipomersen, PCSK9 inhibitors and HDL-enhancers. It is expected that these potent new agents will be combined with LA in the treatment of the most severe forms of hyperlipidemia.
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Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS)

Abstract

Introduction

Section snippets

Study patients

Patient characteristics

Discussion

Acknowledgements

Lancet

Atherosclerosis

Lancet

Lancet

Hemodynamic changes in the peripheral circulation after repeat low density lipoprotein apheresis in familial hypercholesterolemia

Circulation

Three different schedules of low-density lipoprotein apheresis compared with plasmapheresis in patients with homozygous familial hypercholesterolemia

Am J Med

The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of the NHLBI type II coronary intervention study

Circulation

Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens

J Am Med Assoc

Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B

New Engl J Med

Coronary angiographic changes with lovastatin therapy. The monitored atherosclerosis regression study (MARS)

Ann Intern Med

Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atherosclerosis Intervention Trial

Circulation

Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. the Stanford Coronary Risk Intervention Project (SCRIP)

Circulation