Comorbidity in lipoprotein apheresis: Their role in the era of new lipid-lowering therapies.

BACKGROUND: Despite advance in pharmacotherapy of lipid disorders, lipoprotein apheresis (LA) plays a leading role in the management of severe hypercholesterolemia and in atherosclerosis prevention. METHODS: Aim of this study was to retrospectively evaluate Charlson Comorbidity Index (CCI), presence of major comorbidity, and/or concomitant polypharmacy (definite as 5+ drugs daily) in patients with inherited dyslipidemias on chronic LA. RESULTS: Since 1994, we performed more than 500 LA treatment/year and followed a total of 83 patients (age 56 [47-65] years, male 75%). In subjects with more than 5 years of LA treatment (38 patients, age 54 [45-62] years, male 66%), at the end of the observation time (9 [7-16] years), patients had higher CCI, polypharmacy, anemia, heart failure, peptic ulcer disease, and benign prostatic hyperplasia. DISCUSSION: Even in the era of new lipid-lowering therapies, the LA treatment established itself as a safe and lifesaving intervention. Patients on chronic LA require a multidisciplinary approach to address their comorbidity and the apheresis unit's medical staff (doctors and nurses) play a pivotal role creating a bridge toward the general practitioner and other specialists for overcoming clinical issues.

Acute Increase in Ocular Microcirculation Blood Flow Upon Cholesterol Removal. The Eyes Are the Window of the Heart.

BACKGROUND: Lipoprotein apheresis acutely increases coronary microvascular blood flow. However, measurement techniques are time-consuming, costly, and invasive. The ocular vasculature may be an appropriate surrogate and an easily accessible window to investigate the microcirculation. Recent advances in ocular imaging techniques enable quick, noninvasive quantification of ocular microcirculation blood flow. The insights from these techniques represent a significant opportunity to study the short-term changes in optic disk blood flow after lipoprotein apheresis for inherited hypercholesterolemia. METHODS: This study was performed at the Italian Reference Center for Inherited Dyslipidemias in Tuscany. The study sample was comprised of 22 patients with inherited hypercholesterolemia who were previously studied for coronary microcirculation. Laser speckle flowgraphy (LSFG) was used to measure optic disk blood flow before and after lipoprotein apheresis. The main outcomes measures were average tissue blood flow (referred to as mean tissue) and arteriolar/venular average blood flow (referred to as mean vessel). Eyes were divided into 2 groups based on pre-lipoprotein apheresis optic disk blood flow values. P < .05 was considered statistically significant. RESULTS: After each lipoprotein apheresis treatment resulting in the reduction of plasma lipids, there was a concurrent increase in all optic disk microcirculatory parameters. The increase was statistically significant in eyes with lower pre-apheresis optic disk blood flow values (mean tissue +7.0%, P < .005; mean vessel +7.2%, P < .05). CONCLUSIONS: A single lipoprotein apheresis session resulted in a statistically significant short-term increase in optic disk blood flow. These findings together with previous coronary microcirculation data suggest a similar ocular and coronary blood flow response to lipoprotein apheresis. Ocular microcirculation may represent a versatile biomarker for evaluating systemic microcirculatory health, including coronary microcirculation. Hence, it is plausible that plasma lipoprotein levels may influence optic disk blood flow.

Reduced incidence of cardiovascular events in hyper-Lp(a) patients on lipoprotein apheresis. The G.I.L.A. (Gruppo Interdisciplinare Aferesi Lipoproteica) pilot study.

BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease. METHODS: We collected data of 23 patients (mean age 63 ± 9 years, male 77%; from hospital of Pisa 11/23, Pistoia 7/23, Verona 2/23, Padova 2/23 and Ferrara 1/23), with hyper-Lp(a), pre-apheresis LDL-cholesterol <100 mg/dL, cardiovascular disease, on maximally tolerated lipid lowering therapy and LA treatment (median 7 years, interquartile range 3-9 years). The LA treatment was performed by heparin-induced LDL precipitation apheresis (16/23), dextran-sulphate (4/23), cascade filtration (2/23) and immunoadsorption (1/23). The time lapse between first cardiovascular event and beginning of apheresis was 6 years (interquartile range 1-12 years). RESULTS: The recorded ACVE, before and after the LA treatment inception, were 40 and 10 respectively (p < 0.05), notably, the AVCE rates/year were 0.43 and 0.11 respectively (p < 0.05) with a 74% reduction of event occurrence. CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with hyper-Lp(a) and chronic ischemic heart disease on maximally tolerated lipid lowering therapy.

LDL apheresis improves coronary flow reserve on the left anterior descending artery in patients with familial hypercholesterolemia and chronic ischemic heart disease.

BACKGROUND: LDL apheresis (LA) influences the microcirculation, endothelial function and cardiovascular homeostasis. The aim of our study was to analyze temporal variations of coronary flow reserve (CFR) on the left anterior descending artery, obtained during dipyridamole stress echocardiography (DSE), in patients with severe familial hypercholesterolemia on LA (LA group) or not (not LA group) and ischemic heart disease (IHD). METHODS: The LA group consisted in 10 patients (mean age 65 ± 7 years, male 70%) with Familial Hypercholesterolemia and chronic IHD on maximally tolerated lipid lowering therapy and chronic LA treatment (median 7 years, interquartile range 6-14 years). Hyperlipoproteinemia (a) was also present in 6/10 subjects. LA was performed biweekly by dextran-sulfate or heparin-induced LDL precipitation technique. IHD was diagnosed at a mean age of 44 ± 8 years. The control group was matched for age, sex and follow-up period. CFR was calculated as the ratio between blood diastolic velocity sampled at peak stress with dipyridamole and baseline diastolic velocity (normal value > 2.0). No relevant comorbidities were present. RESULTS: During a median follow-up of 27 months (interquartile range 23-50 months), a significant increase in CFR (from 1.86 ± 0.47 to 2.25 ± 0.35; p < 0.001) was observed in LA group. During this period, no patients modified their anti-ischemic therapy and no cardiovascular events were reported. In the control group, during the study time (24 months - interquartile range 14-57 months) no significant variation in CFR was observed (from 2.08 ± 0.39 to 1.92 ± 0.26; p 0.283). CONCLUSION: Myocardial blood perfusion, measured as CFR by dipyridamole stress echocardiography-is increased in patients with severe familial hypercholesterolemia chronically treated with LA. DSE might be a reliable tool to monitor the therapeutic effect of lipid lowering therapy.

Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: After PCSK-9 antibodies what else?

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (-35%), LDL cholesterol (-51%) and Lp(a) levels (-20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

Cognitive impairment and polidistrectual atherosclerotic disease in chylomicronemia syndrome: a case report.

A case of chylomicronemia syndrome is reported in a 72-year-old male with distinctive features of chronic pancreatic damage, severe hypertriglyceridemia, polidistrectual atherosclerosis and premature cognitive impairment. Although the patient had a positive history for recurrent episodes of pancreatitis the characteristic lesions of the hyperchylomicronemia syndrome, such as eruptive xanthomas and lipemia retinalis, were not present and splenomegaly could not be documented due to a previous post-traumatic splenectomy. Based on clinical phenotype, an apolipoprotein C-II deficiency was excluded by a fresh plasma infusion test, in which clarification of the patient plasma was not obtained. The absence of changes in the lipoprotein electrophoretic plasma after heparin infusion can be secondary to a lipoprotein lipase deficiency, a rare genetic disorder with an incidence of one per million. In relation to the resistance to diet and drugs, plasma exchange therapy was performed. After 3 years of this treatment there was no significant progression of atherosclerosis.

Post-exercise contractility, diastolic function, and pressure: operator-independent sensor-based intelligent monitoring for heart failure telemedicine.

BACKGROUND: New sensors for intelligent remote monitoring of the heart should be developed. Recently, a cutaneous force-frequency relation recording system has been validated based on heart sound amplitude and timing variations at increasing heart rates. AIM: To assess sensor-based post-exercise contractility, diastolic function and pressure in normal and diseased hearts as a model of a wireless telemedicine system. METHODS: We enrolled 150 patients and 22 controls referred for exercise-stress echocardiography, age 55 +/- 18 years. The sensor was attached in the precordial region by an ECG electrode. Stress and recovery contractility were derived by first heart sound amplitude vibration changes; diastolic times were acquired continuously. Systemic pressure changes were quantitatively documented by second heart sound recording. RESULTS: Interpretable sensor recordings were obtained in all patients (feasibility = 100%). Post-exercise contractility overshoot (defined as increase > 10% of recovery contractility vs exercise value) was more frequent in patients than controls (27% vs 8%, p < 0.05). At 100 bpm stress heart rate, systolic/diastolic time ratio (normal, < 1) was > 1 in 20 patients and in none of the controls (p < 0.01); at recovery systolic/diastolic ratio was > 1 in only 3 patients (p < 0.01 vs stress). Post-exercise reduced arterial pressure was sensed. CONCLUSION: Post-exercise contractility, diastolic time and pressure changes can be continuously measured by a cutaneous sensor. Heart disease affects not only exercise systolic performance, but also post-exercise recovery, diastolic time intervals and blood pressure changes--in our study, all of these were monitored by a non-invasive wearable sensor.

Arterial pressure changes monitoring with a new precordial noninvasive sensor.

BACKGROUND: Recently, a cutaneous force-frequency relation recording system based on first heart sound amplitude vibrations has been validated. A further application is the assessment of Second Heart Sound (S2) amplitude variations at increasing heart rates. The aim of this study was to assess the relationship between second heart sound amplitude variations at increasing heart rates and hemodynamic changes. METHODS: The transcutaneous force sensor was positioned in the precordial region in 146 consecutive patients referred for exercise (n = 99), dipyridamole (n = 41), or pacing stress (n = 6). The curve of S2 peak amplitude variation as a function of heart rate was computed as the increment with respect to the resting value. RESULTS: A consistent S2 signal was obtained in all patients. Baseline S2 was 7.2 +/- 3.3 mg, increasing to 12.7 +/- 7.7 mg at peak stress. S2 percentage increase was + 133 +/- 104% in the 99 exercise, + 2 +/- 22% in the 41 dipyridamole, and + 31 +/- 27% in the 6 pacing patients (p < 0.05). Significant determinants of S2 amplitude were blood pressure, heart rate, and cardiac index with best correlation (R = .57) for mean pressure. CONCLUSION: S2 recording quantitatively documents systemic pressure changes.

Diastolic time - frequency relation in the stress echo lab: filling timing and flow at different heart rates.

UNLABELLED: A cutaneous force-frequency relation recording system based on first heart sound amplitude vibrations has been recently validated. Second heart sound can be simultaneously recorded in order to quantify both systole and diastole duration. AIMS: 1- To assess the feasibility and extra-value of operator-independent, force sensor-based, diastolic time recording during stress. METHODS: We enrolled 161 patients referred for stress echocardiography (exercise 115, dipyridamole 40, pacing 6 patients).The sensor was fastened in the precordial region by a standard ECG electrode. The acceleration signal was converted into digital and recorded together with ECG signal. Both systolic and diastolic times were acquired continuously during stress and were displayed by plotting times vs. heart rate. Diastolic filling rate was calculated as echo-measured mitral filling volume/sensor-monitored diastolic time. RESULTS: Diastolic time decreased during stress more markedly than systolic time. At peak stress 62 of the 161 pts showed reversal of the systolic/diastolic ratio with the duration of systole longer than diastole. In the exercise group, at 100 bpm HR, systolic/diastolic time ratio was lower in the 17 controls (0.74 +/- 0.12) than in patients (0.86 +/- 0.10, p < 0.05 vs. controls). Diastolic filling rate increased from 101 +/- 36 (rest) to 219 +/- 92 ml/m2* s-1 at peak stress (p < 0.5 vs. rest). CONCLUSION: Cardiological systolic and diastolic duration can be monitored during stress by using an acceleration force sensor. Simultaneous calculation of stroke volume allows monitoring diastolic filling rate.Stress-induced "systolic-diastolic mismatch" can be easily quantified and is associated to several cardiac diseases, possibly expanding the spectrum of information obtainable during stress.

Cardiac reflections and natural vibrations: force-frequency relation recording system in the stress echo lab.

BACKGROUND: The inherent ability of ventricular myocardium to increase its force of contraction in response to an increase in contraction frequency is known as the cardiac force-frequency relation (FFR). This relation can be easily obtained in the stress echo lab, where the force is computed as the systolic pressure/end-systolic volume index ratio, and measured for increasing heart rates during stress. Ideally, the noninvasive, imaging independent, objective assessment of FFR would greatly enhance its practical appeal. OBJECTIVES: 1 - To evaluate the feasibility of the cardiac force measurement by a precordial cutaneous sensor. 2 - To build the curve of force variation as a function of the heart rate. 3 - To compare the standard stress echo results vs. this sensor operator-independent built FFR. METHODS: The transcutaneous force sensor was positioned in the precordial region in 88 consecutive patients referred for exercise, dipyridamole, or pacing stress. The force was measured as the myocardial vibrations amplitude in the isovolumic contraction period. FFR was computed as the curve of force variation as a function of heart rate. Standard echocardiographic FFR measurements were performed. RESULTS: A consistent FFR was obtained in all patients. Both the sensor built and the echo built FFR identifiy pts with normal or abnormal contractile reserve. The best cut-off value of the sensor built FFR was 15.5 g * 10-3 (Sensitivity = 0.85, Specificity = 0.77). Sensor built FFR slope and shape mirror pressure/volume relation during stress. This approach is extendable to daily physiological exercise and could be potentially attractive in home monitoring systems.

In vitro modulation of intracellular oxidative stress of endothelial cells by diagnostic cardiac ultrasound.

Diagnostic cardiac ultrasound are commonly assumed to pose no hazard to the patient-but this is not synonymous with being biologically inert. The production of intracellular reactive oxygen species (ROS) on endothelial cells is a key modulator of atheroprotective (at low level) and atherogenic (at high levels) actions. The aim of the study was to evaluate in vitro the effects on intracellular ROS of endothelial cells after ultrasound exposure of variable duration with commercially available cardiac imaging systems. Endothelial cells fluorescence was evaluated in vitro after sham (transducer off) exposure to ultrasound and after 5', 15' and 30' of ultrasound irradiation with second harmonic 1.3/2.6 MHz cardiac ultrasound scan (mechanical index 1.5). Intracellular ROS were 83 at baseline, and rose to 86, 112 and 122 fluorescence intensity at 1 h incubation after 5', 15' and 30' of ultrasound exposure respectively (P<0.01 for 30' versus baseline and 5' comparison). There were microscopic signs of endothelial damage only following 30' stage. Ultrasound exposure induced significant DNA laddering and LDH leakage after 15' of ultrasound exposure. Effects on endothelial cells could be reproduced by adding exposed extracellular medium to unexposed cells, and could be prevented removing exposed medium from cell culture or pretreating the medium with catalase. Cardiac ultrasound of current clinical diagnostic use increases intracellular oxidative stress on endothelial cells in vitro. This increase is accompanied by morphological evidence of endothelial damage only after longer exposure times, persists 1 h after withdrawal of ultrasound, and can be modulated over a wide range according to the duration of ultrasound exposure. Free radical production in the extracellular medium is the likely mediator of ultrasound effect.