Precision Medicine Approach for Cardiometabolic Risk Factors in Therapeutic Apheresis.

Lipoprotein apheresis (LA) is currently the most powerful intervention possible to reach a maximal reduction of lipids in patients with familial hypercholesterolemia and lipoprotein(a) hyperlipidemia. Although LA is an invasive method, it has few side effects and the best results in preventing further major cardiovascular events. It has been suggested that the highly significant reduction of cardiovascular complications in patients with severe lipid disorders achieved by LA is mediated not only by the potent reduction of lipid levels but also by the removal of other proinflammatory and proatherogenic factors. Here we performed a comprehensive proteomic analysis of patients on LA treatment using intra-individually a set of differently sized apheresis filters with the INUSpheresis system. This study revealed that proteomic analysis correlates well with routine clinical chemistry in these patients. The method is eminently suited to discover new biomarkers and risk factors for cardiovascular disease in these patients. Different filters achieve reduction and removal of proatherogenic proteins in different quantities. This includes not only apolipoproteins, C-reactive protein, fibrinogen, and plasminogen but also proteins like complement factor B (CFAB), protein AMBP, afamin, and the low affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) among others that have been described as atherosclerosis and metabolic vascular diseases promoting factors. We therefore conclude that future trials should be designed to develop an individualized therapy approach for patients on LA based on their metabolic and vascular risk profile. Furthermore, the power of such cascade filter treatment protocols may improve the prevention of cardiometabolic disease and its complications.

Lipoprotein(a): the underutilized risk factor for cardiovascular disease.

Raised lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor and predictor of adverse outcomes. Challenges remain with regards to the screening, diagnosis and management of this condition. Although further prospective randomised controlled data is required, there is growing evidence suggesting that lowering Lp(a) may reduce the risk of cardiovascular events and ameliorate symptoms.

Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.

Cascade testing using DNA-mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty-five probands from six UK centres were tested for 18 low-density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct-sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty-one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty-eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.

Efficacy criteria and cholesterol targets for LDL apheresis.

Low density lipoprotein (LDL) apheresis is now accepted as the treatment of choice for patients with homozygous familial hypercholesterolaemia and for heterozygotes with cardiovascular disease refractory to lipid-lowering drug therapy. However, a paucity of evidence has meant that detailed guidance on the extent of cholesterol reduction required to prevent the onset or progression of cardiovascular disease in these high risk patients is lacking. This review defines criteria for expressing the efficacy of apheresis, proposes target levels of total and LDL cholesterol for homozygotes and heterozygotes based on recent follow-up studies and suggests a scheme for monitoring cardiovascular disease in these patients. Establishing a uniform approach to data collection would facilitate the setting up of national or multi-national registers and might eventually provide the information needed to formulate evidence-based guidelines for LDL apheresis.

LDL-apheresis: indications and clinical experience in a tertiary cardiac centre.

OBJECTIVE: To determine the efficacy and safety of liposorber D low-density lipoprotein (LDL) apheresis system in high-risk cardiac patients. DESIGN: Retrospective analysis of 466 treatments undertaken in eight patients with coronary heart disease. Five patients had severe heterozygous familial hypercholesterolaemia (FH), one had severe hypertriglyceridaemia and two were cardiac transplant recipients with FH intolerant to statins. Acute reductions during single sessions and preprocedural long-term changes in lipoprotein subfractions, laboratory safety parameters, adverse events and clinical outcome were recorded. RESULTS: In 352 treatments performed in seven patients, acute reductions averaged 52.8% (standard deviation: 8.61%) for total cholesterol (TC), 61.8% (10.13%) for LDL-cholesterol (LDL-C), 21.1% (9.66%) for high-density lipoprotein cholesterol (HDL-C), 71.1% (median) for lipoprotein (a) [Lp(a)] and 44.5% (14.42%) for triglycerides (p < 0.05). Long-term reductions of TC, LDL-C, Lp(a) and triglycerides by 18.1%, 21.7%, 9.4% (median) and 19.8%, respectively, were achieved. HDL-C was increased by 7.5%. Results from the patient with severe hypertriglyceridaemia were analysed separately because of markedly elevated TC and triglycerides. Technical and clinical complications were mild and showed an incidence of 16.65% and 12.45% respectively. The most common clinical event was transient hypotension (5.8%), whereas vascular access difficulties (11.3%) represented a common technical problem. All patients demonstrated clinical improvement. However, two patients treated via a central line developed septicaemia, resulting in endocarditis in one of them. CONCLUSION: Liposorber D is a simple, safe and effective modality in reducing atherogenic lipoproteins in dyslipidaemic high-risk cardiac patients. The treatment via an arteriovenous fistula is the preferred vascular access in this type of patient.

Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: results of a randomised double blind placebo controlled study.

BACKGROUND: Hypercholesterolemia is frequent after heart transplantation. Statins can reduce cholesterol levels but their use in heart transplant patients is complicated by pharmacokinetic interactions with cyclosporin and the risk of serious adverse effects including rhabdomyolysis. Fluvastatin has been used safely to treat hypercholesterolemia in renal transplant patients but there are few data relating to its use after heart transplantation. Therefore, we conducted a randomised blinded placebo controlled trial. METHODS AND RESULTS: Seventy-nine patients, 3 months to 12 years after heart transplantation with a low density lipoprotein (LDL) cholesterol between 3.5 and 8.0 mmol/l were randomly assigned, in a 2:1 ratio, to receive either fluvastatin 40 mg od (n=52) or matching placebo (n=27). Changes in total cholesterol (TC) in the fluvastatin and placebo groups were -17.0% and +4.5%, respectively, (p<0.001); the corresponding changes in LDL were -20.5% and +4.8% (P<0.001) and in triglycerides -14.5% and +7.1% (p=0.012) at the end of the 1-year study period. Withdrawals were more frequent in the fluvastatin group (23% vs. 11% p=0.24). Two deaths occurred during the study (the rate expected from International Society of Heart Lung Transplantation registry) and appeared to be unrelated to the study medication. There were no episodes of rhabdomyolysis or other serious drug-related side effects. CONCLUSIONS: Fluvastatin (40 mg/day) was both an effective and a safe treatment for hypercholesterolemia in patients who had undergone heart transplantation more than 3 months previously.

Incidence and clinical relevance of coronary calcification detected by electron beam computed tomography in heart transplant recipients.

BACKGROUND: Patients treated by cardiac transplantation who survive beyond one year are at significant risk from fatal coronary artery disease. The development of coronary artery calcification in these patients is discussed and methods available to detect it are reviewed. OBJECTIVES: To assess the clinical importance of coronary artery calcium in heart transplant recipients. METHODS: In a cohort of 102 cardiac transplant recipients, electron beam computed tomography was used to measure calcium in the coronary arterial wall 63 days to 9.1 years (median 4.6 years) after transplantation. The results were compared with angiographic findings and with conventional coronary disease risk factors. The patients were followed for a mean of 2.12 years (1.2-4.02 years) to assess the relationship between these findings and future cardiac events. RESULTS: Forty-one (40.2%) had a stenosis of > 24% in one or more major coronary artery at angiography. Forty-six (45%) had a coronary calcium score > 0. The absence of calcium had a negative predictive value with respect to angiographic disease in any vessels of 87.5%. Logistic regression revealed that dyslipidaemia, systemic hypertension and organ ischaemic time were significant predictors of calcification. At follow-up, both an abnormal coronary angiogram and coronary calcium were found to be the only significant predictors of late events. Multivariate analysis suggested that the detection of coronary calcium did not offer any additional predictive information over that provided by the angiogram itself. CONCLUSION: Electron beam computed tomography is well suited to the assessment of calcium in the coronary arteries of heart transplant recipients, although the mechanisms of this calcification remain poorly understood. Calcium is detected more frequently than would be suggested by studies using intravascular ultrasound. It is associated with the presence of angiographic disease, and with some conventional risk factors for coronary disease. At follow-up the presence of coronary calcium was associated with an adverse clinical outcome, as it is in conventional ischaemic heart disease.

Donor ACE gene polymorphism: a genetic risk factor for accelerated coronary sclerosis following cardiac transplantation.

AIMS: To investigate the role of angiotensin converting enzyme (ACE) (I/D) gene polymorphism in the development of coronary sclerosis after cardiac transplantation. METHODS AND RESULTS: Eighty cardiac transplant recipients (44 transplant associated coronary artery disease; 36 non-transplant associated coronary artery disease) and their donors were genotyped by polymerase chain reaction. The allele frequencies of the recipients in the transplant associated coronary artery disease and non-transplant associated coronary artery disease groups (I = 0.47 and 0.48, D = 0.53 and 0.52, respectively) did not differ significantly between the groups. However, there was a negative association between the frequency of the I allele in the donor and the development of transplant associated coronary artery disease. The D allele in the donor population of the non-transplant associated coronary artery disease group had a significantly (P < 0.01) lower frequency (0.35) than either the transplant associated coronary artery disease group (0.53) or that of the general population (0.57). Other factors analysed were recipient family history, cholesterol levels, age, sex and body mass index, donor age and acute rejection, of which the significant (P < 0.05) factors were acute rejection and sex of the recipient. CONCLUSION: These results suggest that the ACE genotype of the donor organ may be an additional risk factor for the development of coronary artery disease following cardiac transplantation and that tissue rather than circulating ACE could be implicated in the pathogenesis of this disease.

Determinants of transplant-related coronary calcium detected by ultrafast computed tomography scanning.

Coronary calcium detected by ultrafast computed tomography (CT) has been shown to be a marker of coronary artery disease in heart transplant recipients. The objective of this study was to examine the possible determinants of coronary calcium after heart transplantation. Over a 15-month period, 102 consecutive cardiac transplant recipients (mean age 53 years, 88 men) underwent ultrafast CT scanning of the heart, in addition to coronary angiography, to determine coronary calcium score on their annual follow-up (a median of 4.6 years [range 63 days to 9.1 years] after transplant). The following data were also recorded: the recipient's sex and date of birth, date of transplantation, date of ultrafast computed tomography and coronary angiography; recipient pretransplant diagnosis, history of diabetes mellitus and systemic hypertension, fasting lipid profile, immunosuppression, number of rejection episodes, and donor organ ischemic time. Forty six patients (45.1%) had total calcium scores >0 and 41 (40.2%) had at least 1 major coronary with angiographic narrowing >24%. On univariate analysis, coronary calcium was significantly associated with dyslipoproteinemia, total cholesterol was >6.0 mmol/L (240 mg/dl), triglycerides were >3.0 mmol/L (265 mg/dl), and lipoprotein(a) >30 mg/ dl; > or =25% angiographic disease was significantly associated with coronary calcium and dyslipoproteinemia. Logistic regression revealed that dyslipoproteinemia, systemic hypertension, and donor ischemic time were significant predictors of coronary calcium in transplanted hearts. We conclude that the prevalence of coronary calcium in heart transplant recipients is high and is related to recipient dyslipoproteinemia, systemic hypertension, and donor organ ischemic time.

The prognostic significance of non-invasive cardiac tests in heart transplant recipients.

The long-term mortality and morbidity of cardiac transplant recipients is related to their subsequent development of accelerated coronary atheroma and its complications. Coronary angiography was compared with non-invasive clinical assessment to see which was better in predicting clinical outcome. Ninety-one consecutive transplant recipients (mean age 53 years), in whom investigations had been performed (exercise electrocardiography, rest and exercise radionuclide ventriculography, 2-D echocardiography and coronary angiography), were followed up for a mean period of 2.1 years. Eighteen patients had 31 cardiac events. There were five cardiac-related deaths, 17 myocardial infarctions and/or onsets of heart failure, eight percutaneous transluminal coronary angioplasties and one coronary artery bypass graft. With cardiac event-free survival as the dependent variable and the results of the above investigations as independent variables, a series of univariate, bivariate and regression analyses were performed. On bivariate analysis, an echocardiographic ejection fraction of > 60% significantly predicted both survival free of myocardial infarction and/or heart failure and/or cardiac death and survival free of any cardiac event (P = 0.001 for both). Absence of coronary angiographic disease (both of < 25% and of < 50% luminal narrowing in any vessel) significantly predicted survival free of any cardiac event (P = 0.00004 and 0.015, respectively). Neither radionuclide ventriculography nor exercise electrocardiography were significant predictors of event free survival. In conclusion, echocardiography is at least as important as coronary angiography in the follow-up and prognostic assessment of cardiac transplant recipients.

Magnetic resonance coronary angiography in heart transplant recipients.

BACKGROUND: Magnetic resonance angiography (MRA) using segmented k-space fast low-angle shot imaging has recently been used to demonstrate the proximal coronary arteries in healthy subjects and in patients with coronary artery disease. We assessed the sensitivity and specificity of coronary MRA in heart transplant recipients and investigated the feasibility of coronary MRA in patients with metallic sutures and clips in the chest. MATERIALS AND METHODS: Sixteen cardiac transplant patients aged 57.2 +/- 7.9 years (mean +/- SD) were recruited. Forty-eight arterial segments were evaluated, including the left main artery (LMA), left anterior descending artery (LADA) and right coronary artery (RCA). We excluded the left circumflex artery which could not be imaged accurately. The average time between heart transplant operation and MRA was 6 years, whereas that between MRA and X-ray angiography was 4 months. The coronary MRA was interpreted by two experienced investigators who were blinded to the coronary X-ray angiography results. Similarly, the coronary X-ray angiography results were interpreted by two experienced investigators blinded to the MRA results. The coronary arterial segments were classified by MRA as being normal or as having an amount of disease that was significant (> 50% lesion) or insignificant (< 50% lesion). RESULTS: There were 28 true-negative, five true-positive, four false-negative and six false-positive results. Of the 28 true-negative cases, 13 were in the LMA, six in the LADA and nine in the RCA. There was one false-positive LMA, two false-positive LADA and three false-positive RCA stenoses. There were four false-negative results in the LADA and one in the RCA. Clips precluded evaluation in one LMA, one LADA and one RCA. One LMA and one LADA were not evaluated as a result of poor images. One false-positive RCA stenosis was caused by a metallic clip. Three of the false-negative LADA stenoses had lesions in the distal third of the artery. The sensitivity, specificity, negative and positive predictive values were generally poor for the left coronary artery. The best results were for the RCA (sensitivity 100%, specificity 75%, positive predictive value 50% and negative predictive value 100%). The specificity in the left coronary arteries (LMA and LADA) was 86%, but the other indicators were all poorer. For the RCA, LMA and LADA combined, the overall sensitivity was 56%, specificity 82%, predictive accuracy 45% and negative predictive value 88%. In three patients, < 50% RCA lesions were seen in the MRA data, which were all confirmed by angiography. No < 50% lesions were seen in the LMA or in the LADA by MRA or by X-ray angiography. CONCLUSION: Coronary MRA using the segmented fast low-angle shot technique is feasible in heart transplant recipients but the sensitivity and specificity of this method are limited. Further developments in coil design, rapid imaging techniques and respiratory monitoring methods are necessary to improve the accuracy of coronary MRA.

Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia.

The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia (type IIb). After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy. Total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were measured at monthly intervals. Apolipoproteins (apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen were measured before and after each treatment. Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol (2.0 vs. 1.1 mmol/l, p = 0.003) and lowering LDL cholesterol (1.7 vs. 0.4 mmol/l, p = 0.0001) whereas Bezafibrate SR was more effective in reducing triglycerides (by 41% vs. 17%, p = 0.001) and fibrinogen (by 23% vs. 3%, p = 0.004). Compared with simvastatin monotherapy, combined drug therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events.

Coronary artery surgery in women compared with men: analysis of coronary risk factors and in-hospital mortality in a single centre.

OBJECTIVE: To determine differences in coronary risk factors between women and men and their relation to in-hospital mortality associated with coronary artery bypass grafting. DESIGN: Prospective observational study. SETTING: A regional cardiothoracic centre. PATIENTS: 482 (362 (75%) men and 120 (25%) women) consecutive patients who had primary isolated coronary artery bypass grafting. RESULTS: The women were on average three years older than the men (63 v 60 years, P < 0.001). Women more frequently had hypertension (47% v 33%, P < 0.01), diabetes mellitus (21% v 10%, P < 0.005), hypothyroidism (9% v 2%, P < 0.003), and a family history of premature coronary heart disease (49% v 31%, P < 0.0006). More of the men were cigarette smokers (67% v 45%, P > 0.00001). Many of the women and men had dyslipidaemia. Postmenopausal women had a higher concentration of serum total cholesterol than men of a comparable age, (7.3 mmol/l v 6.5 mmol/l, P = 0.0002). Although arterial grafts were often used in both sexes, they were more often used in men than in women (91% v 78% respectively, P = 0.0003). In-hospital mortality was 2.1% (1.4% in men and 4.2% in women, P = 0.14). The estimated one year probability of survival in men who had survived 30 days was 0.99 with 95% confidence interval 0.98 to approximately 1 while that for women was 0.97 with 95% confidence interval 0.91 to approximately 1. Univariate analysis showed that preoperative history of diabetes mellitus was a predictor of mortality (P = 0.03). CONCLUSION: There were differences in the incidence and type of risk factors in men and women who had coronary artery bypass grafting. Preoperative diabetes mellitus was a predictor of in-hospital mortality.

Coronary endothelial function in cardiac transplant recipients with accelerated coronary disease.

BACKGROUND: Previous studies with the endothelium-dependent vasodilator substance P have shown a preserved vasodilator response in cardiac transplant recipients with angiographically normal coronary arteries. Although endothelial dysfunction is known to occur in cardiac transplant recipients with accelerated coronary disease, the degree to which the endothelium is affected is not known precisely. The aim of the present study was to examine endothelial function in accelerated coronary disease following cardiac transplantation. METHODS: Thirteen cardiac transplant recipients with epicardial coronary disease underwent substance P infusion. The response to incremental doses of substance P was measured in smooth segments of affected coronary arteries. Substance P was infused over 2 min with a starting dose of 1.4 pmol/min and a maximum of 22.4 pmol/min, reached by doubling the dose in steps, followed by an infusion of 2 mg isosorbide dinitrate over 2 min. RESULTS: Substance P caused less vasodilation at lower concentrations, with a significantly higher dose required to achieve half maximal dilation compared with cardiac transplant recipients with no coronary disease. The mean maximal dilatation achieved with substance P was 22.98 +/- 4.62% compared to 21.95 +/- 4.9% with isosorbide dinitrate; the latter value was not significantly different from the maximal dilation achieved in cardiac transplant recipients without coronary disease. CONCLUSIONS: In cardiac transplant recipients with accelerated coronary disease the functional vasodilatory ability of the coronary endothelium is impaired in segments of apparently unaffected epicardial arteries, which may lead to an increase in the resting vasoconstrictor tone and have important functional and therapeutic implications.

A randomized pilot trial of low-dose combination lipid-lowering therapy following coronary artery bypass grafting.

Vein graft atherosclerosis is a common and serious complication of coronary artery bypass grafting (CABG). There is mounting evidence that lipoprotein abnormalities play an equally important role in the development of lesions in saphenous vein grafts after CABG as in native coronary vessel disease. The potential benefit of low-dose lipid lowering combination therapy in these patients has not been investigated. In a randomized, double-blind, placebo-controlled study, we compared the efficacy and safety of a low-dose combination of colestipol 10 g and simvastatin 10 mg/day (CS) to colestipol 10 mg and bezafibrate 400 mg/day (CB) for 2 months in 33 patients with serum total cholesterol > 6.5 mmol/l and triglyceride < 4.5 mmol/l who had undergone CABG for severe coronary artery disease. In the CS group, total cholesterol decreased by 29% and low-density lipoprotein (LDL) cholesterol by 42%; similarly, CB reduced total cholesterol by 17%, LDL cholesterol by 23%, triglyceride by 19%, and increased high-density lipoprotein (HDL) cholesterol by 14%. Lipoprotein (a) and hemostatic factors were unaffected by either therapy in this study. Both combination therapies were well tolerated with no significant clinical or biochemical side effects. We conclude that low-dose combinations of colestipol and simvastatin or colestipol and bezafibrate are effective and well tolerated in the management of moderate hyperlipidemia in patients who had undergone CABG.