RESEARCH LETTER
Paradoxical effect of lipid lowering therapy in homozygous familial hypercholesterolemia: Atherosclerotic plaque calcifications and increased cardiovascular events
Efeito paradoxal da terapêutica hipolipemiante em doentes com hipercolestrolemia familiar homozigótica: calcificações da placa aterosclerótica e eventos cardiovasculares acrescidos
Tiziana Sampietro, Francesco Sbrana
, Federico Bigazzi, Beatrice Dal Pino
Autor para correspondência
Lipoapheresis Unit - Reference Center for Diagnosis and Treatment of Inherited Dyslipidemias, Fondazione Toscana “Gabriele Monasterio”, Pisa, Italy
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To note the we recorded a significant reduction in Doppler-derived coronary flow reserve (from >2.00 to 1.74). Panel E - right coronary artery at CT coronary angiography with focal, eccentric calcified plaques (arrowheads); Panel F - calcified eccentric plaque of the anterior descending artery of the left coronary artery (arrowheads). Agatson score 69.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">LCCA: left common carotid artery; LICA: left internal carotid artery; RCCA: right common carotid artery; RICA: right internal carotid artery.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Homozygous familial hypercholesterolemia (HoFH) is a rare disease (OMM #143890) characterized by low-density lipoprotein cholesterol receptor gene mutations and progressive atherosclerosis, leading to death before the age of 30 if not treated. The high cardiovascular risk is hard to manage.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Fondazione Toscana Gabriele Monasterio is a cardiopulmonary tertiary-level Institute with 123 beds; >5000 hospital admissions per year, a cath-lab hub for acute coronary syndrome, adult and pediatric cardiac surgery center, referral facility for heart failure, primitive pulmonary hypertension patients and reference center for inherited dyslipidemias, rare lipid disorders with lipoprotein apheresis unit), HoFH clinical follow-up includes annually carotid artery ultrasound with intima-media thickness evaluation and stress echocardiography wall motion criteria with Doppler-derived coronary flow reserve of the mid-distal left anterior descending artery (LAD). This test is a valid tool for assessing inducible myocardial ischemia, LAD stenosis, and coronary microvascular dysfunction.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In view of the availability of new lipid lowering therapy (LLT), their role in coronary plaque and heart valves calcification is a particularly intriguing issue. HoFH represents per se a clinical model to assess these LLT interactions.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Since 2013, we have followed four siblings with compound heterozygotes for LDL-receptor gene mutations.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> All patients were asymptomatic for angina and/or dyspnea, a satisfactory lipid profile was obtained adding evolocumab to high-intensity statin therapy.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> During follow-up, two subjects developed significant coronary artery disease treated with percutaneous coronary revascularization while the 37-year old female twins presented, on a dipyridamole stress echocardiography, progressive CRF reduction and increased carotid calcification. Both subjects underwent computed tomography coronary angiography with evidence of diffuse non-critical calcific atherosclerotic disease (see <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Familial hypercholesterolemia shows altered endothelial function and reduced coronary vasodilatation capacity with subsequent coronary atherosclerosis due to vascular calcification. While the role of lipoproteins is well characterized in the pathogenesis of atherosclerotic plaques, their roles in plaque calcification are not well understood. In the arterial intima calcification process it is assumed that a role of spotty early-stage calcification perpetuates the inflammatory cycle leading to plaque instability followed by plaque macrocalcification.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Statin therapy, which reduces cardiovascular mortality, has been shown to exert its dual actions on plaque morphology, i.e., regression of atheroma and increment of macroscopic calcium deposits,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> while the PCSK9i effect is not univocal: for evolocumab there is evidence of inverse correlation between changes in LDL cholesterol and coronary plaque calcification.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Meanwhile alirocumab has been able to progressively reduce carotid plaque lipid core increasing the plaque fibrous tissue.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">We decided to intensify the high-intensity statin therapy opting for rosuvastatin because, compared to atorvastatin, it might be more effective at reducing coronary atherosclerotic plaque volume, even if there is a lack of long-term evidence on cardiovascular outcomes.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The cases reported herein underline the difficulty of managing patients at high risk to develop coronary heart disease as HoFH, with respect to <span class="elsevierStyleItalic">“null receptor</span>” HoFH in which, instead, the lipoprotein apheresis treatment, keep the patient free of cardiovascular events and allows the complete regression of lipid deposition.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding sources</span><p id="par0040" class="elsevierStylePara elsevierViewall">No financial support was received.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding sources" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:2 [ "identificador" => "xack623599" "titulo" => "Acknowledgments" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1507 "Ancho" => 3008 "Tamanyo" => 335258 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Panel A - baseline focal intimal hyperplasia (1 mm - arrowhead) of the right carotid bulb (long axis view); Panel B - baseline focal intimal hyperplasia (1.1 mm - arrowheads) of the left carotid bulb (long axis view); Panel C - 2 years’ follow-up of focal intimal hyperplasia (1 mm - arrowhead) of the right carotid bulb (long axis view); Panel D - 2 years follow-up with hyper-echogenicity and dimensional reduction (0.8 mm - arrowheads) at left carotid bulb (long axis view). We recorded a significant reduction in Doppler-derived coronary flow reserve (from 2.57 to 1.90). Panel E - right coronary artery at CT coronary angiography with focal, eccentric calcified plaques (arrowheads); Panel F - calcified eccentric plaque of the common trunk of the left coronary artery (arrowhead); Panel G - calcified eccentric plaque of the diagonal branch of the left coronary artery (arrowheads). Agatson score 93.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">LCCA: left common carotid artery; LECA: left external carotid artery; LICA: left internal carotid artery; RICA: right internal carotid artery.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1507 "Ancho" => 3008 "Tamanyo" => 353586 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Panel A - baseline right carotid bulb (long axis view); Panel B - baseline focal intimal hyperplasia (1.0 mm - arrowhead) of the left carotid bulb (long axis view); Panel C - 2 years’ follow-up of the right carotid bulb with presence of eccentric calcified plaque (1.4 mm - long axis - yellow arrowheads; short axis view - red arrowheads); Panel D - 2 years follow-up of focal intimal hyperplasia (1.1 mm - arrowhead) of the lest carotid bulb (long axis view). To note the we recorded a significant reduction in Doppler-derived coronary flow reserve (from >2.00 to 1.74). Panel E - right coronary artery at CT coronary angiography with focal, eccentric calcified plaques (arrowheads); Panel F - calcified eccentric plaque of the anterior descending artery of the left coronary artery (arrowheads). Agatson score 69.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">LCCA: left common carotid artery; LICA: left internal carotid artery; RCCA: right common carotid artery; RICA: right internal carotid artery.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homozygous familial hypercholesterolemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "A. Nohara" 1 => "H. Tada" 2 => "M. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 12 | 5 | 17 |
| 2024 Outubro | 60 | 31 | 91 |
| 2024 Setembro | 55 | 26 | 81 |
| 2024 Agosto | 49 | 31 | 80 |
| 2024 Julho | 40 | 34 | 74 |
| 2024 Junho | 50 | 28 | 78 |
| 2024 Maio | 32 | 23 | 55 |
| 2024 Abril | 33 | 23 | 56 |
| 2024 Maro | 33 | 24 | 57 |
| 2024 Fevereiro | 28 | 20 | 48 |
| 2024 Janeiro | 23 | 22 | 45 |
| 2023 Dezembro | 19 | 28 | 47 |
| 2023 Novembro | 34 | 30 | 64 |
| 2023 Outubro | 40 | 17 | 57 |
| 2023 Setembro | 38 | 21 | 59 |
| 2023 Agosto | 32 | 28 | 60 |
| 2023 Julho | 31 | 9 | 40 |
| 2023 Junho | 30 | 13 | 43 |
| 2023 Maio | 26 | 27 | 53 |
| 2023 Abril | 23 | 3 | 26 |
| 2023 Maro | 28 | 18 | 46 |
| 2023 Fevereiro | 26 | 22 | 48 |
| 2023 Janeiro | 11 | 13 | 24 |
| 2022 Dezembro | 34 | 17 | 51 |
| 2022 Novembro | 38 | 29 | 67 |
| 2022 Outubro | 45 | 24 | 69 |
| 2022 Setembro | 110 | 100 | 210 |
| 2022 Agosto | 32 | 54 | 86 |
| 2022 Julho | 18 | 21 | 39 |
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