Is it time for a paradigm shift? Inclusion of APOE on genetic dyslipidemia panels.

APOE codes for apolipoprotein E (ApoE), which plays an important role in lipid and lipoprotein metabolism and homeostasis of tissue lipid content. Several variants in APOE have been associated with inherited dyslipidemias, and a subsequent increased risk of developing premature coronary artery disease (CAD). However, these variants and their impact on risk can be thought of on a spectrum, with some being more monogenic in nature, and others contributing in a polygenic/multifactorial manner. Despite these known associations, there is often hesitancy around ordering APOE genetic testing due to the association with Alzheimer's disease. This paper aims to catalyze discussion around APOE testing and counseling strategies, highlight the nuances around this topic, and advocate for inclusion of APOE testing on dyslipidemia panels when an inherited dyslipidemia is suspected.

[DIAGNOSIS AND TREATMENT OF ELEVATED LIPOPROTEIN(A) IN ISRAEL: CONSENSUS STATEMENT FROM THE ISRAEL SOCIETY FOR RESEARCH, PREVENTION AND TREATMENT OF ATHEROSCLEROSIS AND ISRAEL SOCIETY FOR CLINICAL LABORATORY SCIENCES].

INTRODUCTION: Lipoprotein(a) [Lp(a)] is composed of 2 major protein components, a low-density lipoprotein (LDL) cholesterol-like particle containing apolipoprotein B (apo B) that is covalently bound to apolipoprotein(a). Its level is predominantly genetically determined, and it is estimated that 20% to 25% of the population have Lp(a) levels that are associated with increased cardiovascular risk. Elevated Lp(a) is related to increased vascular inflammation, calcification, atherogenesis and thrombosis, and is considered an independent and potentially causal risk factor for atherosclerotic cardiovascular diseases and calcified aortic valve stenosis. Recent data demonstrate that Lp(a) testing has the potential to reclassify patients' risk and improve cardiovascular risk prediction, and therefore could inform clinical decision-making regarding risk management. Statins and ezetimibe are ineffective in lowering Lp(a) levels, whereas proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have a modest effect on Lp(a) reduction. Nevertheless, RNA interference-based therapies with potent Lp(a)-lowering effects are in advanced stages of development, and clinical trials are underway to confirm their benefit in reducing cardiovascular events. This scientific consensus document was developed by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, and the Israeli Society for Clinical Laboratory Sciences, in order to create uniformity in Lp(a) measurement methods, indications for testing and reporting of the results, aiming to improve the diagnosis and management of elevated Lp(a) in clinical practice.

Endomyocardial biopsy in clinical practice: the diagnostic yield and insights from a 5-year single-center experience.

OBJECTIVES: Endomyocardial biopsy (EMB) is a diagnostic tool for evaluating various cardiac conditions, such as myocarditis and myocardial infiltrative diseases. It is also the gold standard screening technique for detecting allograft rejection after heart transplantation. Despite advances in noninvasive imaging modalities for myocardial tissue characterization, EMB is still necessary for making a definitive diagnosis and determining treatment for certain conditions. Herein, we report our recent experience using EMB and its diagnostic yield. METHODS AND RESULTS: We retrospectively reviewed EMBs performed at our institution from March 2018 through March 2023. Clinical data, including patient characteristics, indication and diagnostic yield of EMB, and procedure-related complications, were collected. Histopathological findings of the biopsies were recorded and classified based on the degree to which they matched the clinical diagnosis and cardiac magnetic resonance imaging (CMR) findings. A total of 212 EMBs obtained in 178 consecutive patients were retrospectively analyzed, with 42 biopsies performed for allograft rejection surveillance (10 patients) and the remaining performed for presumptive diagnosis of acute myocarditis or unexplained cardiomyopathy. Among the non-heart transplant cases, 54.7% of EMBs provided a clear diagnosis. The most common diagnosis was myocarditis (69%), followed by cardiac amyloidosis (CA) (26%). EMB was also helpful in detecting several rare cardiac conditions, such as eosinophilic granulomatosis with polyangiitis (EGPA), Fabry disease, and cardiac sarcoidosis. In a cohort of 101 patients who underwent both CMR and EMB, the results were concordant in 66% of cases. However, in 24.7% of patients, EMB was able to identify pathological conditions where CMR results were inconclusive, highlighting its complementary role in determining an accurate diagnosis. No complications were reported in any of the 212 EMBs performed. CONCLUSIONS: With advances in cardiac imaging modalities, EMB is not routinely indicated for the diagnosis of cardiomyopathy. However, EMB is still an important tool for diagnosing specific cardiac diseases and could be crucial for confirming the diagnosis. EMB is generally safe if performed at experienced centers.

Variable clinical expression of a novel FLNC truncating variant in a large family.

BACKGROUND: Variants in Filamin-C (FLNC) have been associated with various hereditary cardiomyopathies. Recent literature reports a prevalence of sudden cardiac death (SCD) of 13-25% among carriers of truncating-variants, with mean age of 42±15 years for first SCD event. This study reports two familial cases of SCD and the results of cascade screening of their large family. METHODS: Molecular-autopsy of the SCD victims revealed a novel truncating-variant in the FLNC gene (chr 7:128496880 [hg19]; NM_001458.5; c.7467_7474del; p.(Ser2490fs)). We screened thirty-two family members following genetic counseling, and variant carriers underwent a comprehensive workup followed by consultation with a cardiologist with expertise in the genetics of cardiac diseases. RESULTS: Seventeen variant carriers were identified: ages between 9 and 85 (mean 47±26). Fifteen underwent clinical evaluation. To date, none of the identified carriers has had major adverse events. In evaluated patients, ECG showed right-axis deviation in 60% (n = 9). Holter recorded frequent premature ventricular contractions (PVCs) (991±2030 per 24 h) in 33% (n = 5) with 4 patients having polymorphic PVC morphology. Three carriers had echocardiographic evidence of mild left-ventricular (LV) systolic dysfunction and another with mild LV dilatation. Cardiac magnetic-resonance (CMR) exhibited late­gadolinium-enhancement in 10 out of 11 exams, mainly in the mid-myocardium and sub-epicardium, frequently involving the septum and the inferior-lateral wall. CONCLUSION: This large FLNC truncating variant carrier family exhibits high cardiomyopathy penetrance, best diagnosed by CMR, with variable clinical expressions. These findings present a challenge in SCD prevention management and underscoring the imperative for better risk stratification measures.

Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial.

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; P=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (P<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851705.

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). Objective: To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Method: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. Results: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. Conclusion: In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

Tumor-infiltrating lymphocyte transfusion in a patient with treatment refractory triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is treated with chemotherapy. Recently, programmed death 1 (PD1) inhibition, as well as antibody-drug conjugates, have been added to the available treatment regimen, yet metastatic disease is fatal. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TILs) has been well described in melanoma, but less data is available on other solid malignancies. CASE: Herein, we present a case of a 31-year-old patient diagnosed with Breast Cancer gene 1 (BRCA1) positive, TNBC. The patient's disease rapidly progressed while under standard treatment protocols. As a result, additional genetic testing of the tumor was carried out and revealed loss of BRCA1 heterozygosity, a double Tumor Protein 53 (TP53) mutation, and MYC amplification. Due to resistance to conventional therapy, an experimental approach was attempted using tumor-infiltrating lymphocytes in November 2021 at Hadassah University Medical Center. While receiving this treatment, the patient exhibited a reported subjective clinical improvement including a month spent out of the hospital. However, the final result, presumably due to Interleukin 2 (IL-2) toxicity, was the patient's passing. CONCLUSION: This case is unique and peculiar regarding the treatment modality chosen, due to the extremely refractory disease the patient suffered from. After standard therapies rapidly failed, adoptive cell therapy was attempted with the infusion of TILs. This treatment has been shown effective in melanoma, however, there is an extreme paucity of data on other solid tumors, including TNBC. Although the patient ultimately demised presumably due to treatment side effects, brief clinical benefit was apparent. Further studies are warranted.

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

Giant Intracardiac Lipoma: A Case Report and the Role of Multimodality Cardiac Imaging.

Cardiac lipomas, especially ones originating from the left ventricle, are extremely rare. They may be asymptomatic or may present with various non-specific symptoms. Herein, we report a case of a giant lipoma of the left ventricle, with frequent ventricular premature beats on electrocardiogram. An echocardiogram demonstrated a large hyperechoic mass occupying a significant portion of the left ventricle. We further describe the diagnostic workup utilizing multimodality cardiac imaging and treatment options. Cardiac MRI demonstrated fat suppression, and cardiac CT showed a homogenous low-attenuation mass suggesting lipomatous matter. The mass was subsequently surgically removed for pathology examination in order to rule out liposarcoma. Histopathology demonstrated mature adipocytes, entrapped myocytes with hypertrophy, and interstitial fibrosis foci confirming the diagnosis of lipoma.

Mitral valve prolapse: From new mechanisms to diagnostic challenges.

Mitral valve prolapse (MVP) is the most common primary valvular abnormality, associated with various degrees of incompetent function and sequelae, including heart failure and sudden cardiac death. Recent improvements in echocardiographic techniques and new insights into mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. Here we review the genetic etiology, clinical significance, diagnosis, and treatment options for MVP patients.

Is Bicuspid Aortic Valve Morphology Genetically Determined? A Family-Based Study.

Bicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives.

Bicuspid Aortic Valve: Genetic and Clinical Insights.

Bicuspid aortic valve (BAV) is the most common valvular congenital heart disease, with a prevalence of 0.5 to 2% in the general population. Patients with BAV are at risk for developing cardiovascular complications, some of which are life-threatening. BAV has a wide spectrum of clinical presentations, ranging from silent malformation to severe and even fatal cardiac events. Despite the significant burden on both the patients and the health systems, data are limited regarding pathophysiology, risk factors, and genetics. Family studies indicate that BAV is highly heritable, with autosomal dominant inheritance, incomplete penetrance, variable expressivity, and male predominance. Owing to its complex genetic model, including high genetic heterogenicity, only a few genes were identified in association with BAV, while the majority of BAV genetics remains obscure. Here, we review the different forms of BAV and the current data regarding its genetics. Given the clear heritably of BAV with the potential high impact on clinical outcome, the clinical value and cost effectiveness of cascade screening are discussed.

Predictors of Hypoxemia and Related Adverse Outcomes in Patients Hospitalized with COVID-19: A Double-Center Retrospective Study.

Hypoxemia is a hallmark of coronavirus disease 2019 (COVID-19) severity. We sought to determine predictors of hypoxemia and related adverse outcomes among patients hospitalized with COVID-19 in the two largest hospitals in Jerusalem, Israel, from 9 March through 16 July 2020. Patients were categorized as those who developed reduced (<94%) vs. preserved (≥94%) arterial oxygen saturation (SpO2) within the first 48 h after arrival to the emergency department. Overall, 492 hospitalized patients with COVID-19 were retrospectively analyzed. Patients with reduced SpO2 were significantly older, had more comorbidities, higher body surface area (BSA) and body mass index (BMI), lower lymphocyte counts, impaired renal function, and elevated liver enzymes, c-reactive protein (CRP), and D-dimer levels as compared to those with preserved SpO2. In the multivariable regression analysis, older age (odds ratio (OR) 1.02 per year, p < 0.001), higher BSA (OR 1.16 per 0.10 m2, p = 0.003) or BMI (OR 1.05 per 1 kg/m2, p = 0.011), lower lymphocyte counts (OR 1.72 per 1 × 103/µL decrease, p = 0.002), and elevated CRP (1.11 per 1 mg/dL increase, p < 0.001) were found to be independent predictors of low SpO2. Severe hypoxemia requiring ventilatory support, older age, and pre-existing comorbidities, including underlying renal dysfunction and heart failure, were found to be significantly associated with in-hospital mortality. These findings suggest that assessment of predictors of hypoxemia early at the time of hospitalization with COVID-19 may be helpful in risk stratification and management.

Cost-effectiveness analysis of screening for first-degree relatives of patients with bicuspid aortic valve.

AIMS: Bicuspid aortic valve (BAV) is the commonest congenital heart valve malformation, and is associated with life-threatening complications. Given the high heritability index of BAV, many experts recommend echocardiography screening for first-degree relatives (FDRs) of an index case. Here, we aim to evaluate the cost-effectiveness of such cascade screening for BAV. METHODS AND RESULTS: Using a decision-analytic model, we performed a cost-effectiveness analysis of echocardiographic screening for FDRs of a BAV index case. Data on BAV probabilities and complications among FDRs were derived from our institution's BAV familial cohort and from the literature on population-based BAV cohorts with long-term follow-up. Health gain was measured as quality-adjusted life years (QALYs). Cost inputs were based on list prices and literature data. One-way and probabilistic sensitivity analyses were performed to account for uncertainty in the model's variables. Screening of FDRs was found to be the dominant strategy, being more effective and less costly than no screening, with savings of €644 and gains of 0.3 QALY. Results were sensitive throughout the range of the main model's variables, including the full range of reported BAV rates among FDRs across the literature. A gradual decrease of the incremental effect was found with the increase in screening age. CONCLUSION: This economic evaluation model found that echocardiographic screening of FDRs of a BAV index case is not only clinically important but also cost-effective and cost-saving. Sensitivity analysis supported the model's robustness, suggesting its generalization.

[TREATMENT OF HOMOZYGOTES OF FAMILIAL HYPERCHOLESTEROLEMIA: RECOMMENDATIONS OF THE ISRAELI SOCIETY OF ATHEROSCLEROSIS].

INTRODUCTION: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder caused by mutations affecting the function of the LDL receptor. In the Israeli population, the carrier heterozygote state is quite common, with the prevalence of 1:250, and the estimated prevalence of homozygote (hoFH) patients is 1:500,000. The life span of untreated hoFH patients is significantly shortened due to premature atherosclerosis and cardiovascular mortality. The basis of the appropriate treatment for hoFH is aggressive lipid lowering therapy from an early age and therefore, our approach is intensive LDL-C lowering as soon as the diagnosis is made. We recommend referring patients with hoFH to lipid-specialist clinics .We recommend genetic evaluation to confirm the diagnosis and cascade screening of family members for heterozygosity. Lipid goals are as recommended by the European Atherosclerosis Society. Aggressive and low as possible LDL-C targets (at least 50% reduction) are recommended. The initial treatment is high-dose potent statin and additional ezetimibe10 mg daily. PCSK9 inhibitor - Evolocumab is a novel additional option for hoFH with residual LDL receptor activity. The most effective method of reduction of plasma LDL levels is LDL-C apheresis. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that should be added to reduce the frequency of the apheresis procedures.

[UPDATED ISRAELI GUIDELINES FOR THE TREATMENT OF DYSLIPIDEMIA 2020].

INTRODUCTION: Despite the impressive decline in mortality from atherosclerotic cardiovascular diseases (ASCVD), these diseases still account for a large proportion of the overall morbidity and mortality worldwide. A vast amount of research has demonstrated the key role played by circulating lipoproteins, and especially low-density lipoprotein (LDL), in the etiology of atherosclerosis, and numerous studies have proven the efficacy of interventions that lower the atherogenic lipoproteins in reducing morbidity and mortality from ASCVD. While previous guidelines placed an emphasis on the use HMG-CoA reductase inhibitors (statins) for the treatment of dyslipidemia, recent studies have shown that other LDL cholesterol lowering drugs, including ezetimibe and the PCSK9 inhibitors, can provide additional benefit when used in combination with (and in certain cases instead of) statins. These studies have also shown that blood LDL cholesterol levels lower than previously recommended targets provide additional benefit, without evidence of a threshold beyond which the benefit ceases and without excess adverse effects. The updated guidelines were formulated by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, the Israel Society of Internal Medicine, the Israeli Heart Association, the Israeli Neurology Association and the Israel Association of Family Medicine. They provide recommendations for revised risk stratification of patients, novel target goals, and the use of evidence-based treatment and follow-up strategies with reference to specific patient sub-groups.

Imaging in Cardio-oncology: An Overview of an Emerging Medical Discipline.

The world of cardio-oncology is an evolving field involving the assessment of cardiovascular disease in patients suffering from cancer. Cancer and cardiovascular diseases are the two leading causes of morbidity and mortality in the developed world. Globally, cancer is diagnosed in 12.7 million patients annually, and cancer incidence is projected to increase by 40% in high-income countries from 2008 to 2030. Chemotherapy is the main treatment for most cancers and improves survival, but is associated with significant cardiotoxicity. In recent years, the introduction of new biological anti-cancer treatments in addition to "classic" chemotherapy has further improved survival, but has also introduced new cardiovascular side effects beyond "pure" myocardial damage. The increasing number of patients with cancer and cancer survivors, and the growing complexity of cancer treatment and cardiovascular side effects, call for teamwork including cardiologists with specific training and expertise working in teams with oncologists, hematologists, and others. The purpose of this review was to describe the clinical background and importance of cardio-oncology, with an emphasis on the use of imaging in this clinical setting.

Usefulness of Gemcabene in Homozygous Familial Hypercholesterolemia (from COBALT-1).

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was -26% (p = 0.004) at Week 4 (300 mg), -30% (p = 0.001) at Week 8 (600 mg), and -29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients.