Advances in targeting LDL cholesterol: PCSK9 inhibitors and beyond.

There is a direct relationship between the duration and level of exposure to low density lipoprotein cholesterol (LDL-C) levels over one's lifespan and cardiovascular events. Early treatment to lower elevated LDL-C is crucial for better outcomes with multiple therapies currently available to reduce atherogenic lipoproteins. Statins remain the foundation of LDL-C lowering therapy as one of the most cost-effective drugs to reduce atherosclerotic events (ASCVD) and mortality. Nonetheless, LDL-driven goal attainment remains suboptimal globally, highlighting a considerable need for non-statin therapies to address residual risk related to statin intolerance, non-adherence, and inherited lipoprotein disorders. LDL-C lowering interventions beyond statins include ezetimibe, PCSK9 monoclonal antibodies, inclisiran and bempedoic acid with specific guideline recommendations as to when to consider each. For patients with homozygous familial hypercholesterolemia requiring more advanced therapy, lomitapide and evinacumab are available, providing mechanisms that are not LDL receptor dependent. Lipoprotein apheresis remains an effective option for clinical familial hypercholesterolemia as well as elevated lipoprotein (a). There are investigational therapies being explored to add to our current armamentarium including CETP inhibitors, a third-generation PCSK9 inhibitor (small recombinant fusion protein oral PCSK9 inhibitor) and gene editing which aims to directly restore or disrupt genes of interest at the DNA level. This article is a brief review of the pharmacotherapy options beyond statins for lowering LDL-C and their impact on ASCVD risk reduction. Our primary aim is to guide physicians on the role these therapies play in achieving appropriate LDL-C goals, with an algorithm of when to consider each based on efficacy, safety and outcomes.

A system approach to improving guideline-directed therapy for cardio-renal-metabolic conditions: The "beyond diabetes" initiative.

Objective: Despite demonstrating improvements in cardiovascular disease, kidney disease, and survival outcomes, guideline-directed antihyperglycemic medications such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like-peptide-1 receptor agonists (GLP1-RA), are underutilized. Many obstacles constrain their use including lack of systematic provider and patient education, concern for medication side effects, and patient affordability. Methods: We designed a multimodality, systems-based approach to address these challenges with the goal of increasing medication utilization across the largest healthcare system in New York State. This multispecialty collaborative included provider and patient education, an electronic health record-enabled platform to identify eligible patients, and access to pharmacists for medication guidance and addressing insurance coverage barriers. Surveys were administered following grand rounds lectures and knowledge-based questionnaires were given before and after case-based sessions for housestaff, with results analyzed using a two-sided Student's t-test. Rates of first prescriptions of SGLT2i/GLP1-RA in combined and individual analyses were compared between the pre- and post-education periods (6 months prior to 3/31/2021 and 6 months post 8/19/2021), and the change in prescriptions per 100 eligible-visits was assessed using the incidence density approach. Results: Among grand rounds participants, 69.3% of respondents said they would make changes to their clinical practice. Knowledge increased by 14.7% (p-value <0.001) among housestaff following case-based sessions. An increase in SGLT2i/GLP1-RA prescribing was noted for eligible patients among internal medicine, cardiology, nephrology, and endocrinology providers, from 11.9 per 100 eligible visits in the pre-education period to 14.8 in the post-education period (absolute increase 2.9 [24.4%], incidence risk ratio 1.24 [95% CI 1.18-1.31]; p-value <0.001). Increases in prescribing rates were also seen among individual medical specialties. Conclusions: Our "Beyond Diabetes" initiative showed an improvement in provider knowledge-base and was associated with a modest, but statistically significant increase in the use of SGLT2i and GLP1-RA throughout our healthcare system.

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association.

The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.

De novo ulcerative colitis and Takotsubo cardiomyopathy following sleeve gastrectomy.

The increasing prevalence of severe obesity is a major public health concern. Bariatric surgery is an important treatment option for severe obesity due to its long-term sustained result. Multiple studies have shown that patients have an increased risk of developing inflammatory bowel disease following bariatric surgery. Takotsubo syndrome usually presents as acute left ventricular systolic dysfunction without corresponding obstructive coronary artery disease after an acute stress episode. We describe a unique case of a patient who developed de novo ulcerative colitis and takotsubo cardiomyopathy shortly after sleeve gastrectomy. The patient made a successful recovery due to prompt recognition and appropriate treatment.

Implementation of Novel Lipid Therapies in a Refractory Heterozygous Familial Hypercholesterolemia Patient With Atherosclerotic Disease.

Compound heterozygous familial hypercholesterolemia patients are phenotypically similar to homozygous familial hypercholesterolemia patients, present with significant elevations of low-density lipoprotein cholesterol, and are at risk of cardiovascular disease. Although new treatment options are emerging, the stepwise approach to the use of different therapies has not been well described. (Level of Difficulty: Intermediate.).

Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels.

Importance: Low-density lipoprotein cholesterol (LDL-C) is typically estimated with the Friedewald or Martin/Hopkins equation; however, if triglyceride levels are 400 mg/dL or greater, laboratories reflexively perform direct LDL-C (dLDL-C) measurement. The use of direct chemical LDL-C assays and estimation of LDL-C via the National Institutes of Health Sampson equation are not well validated, and data on the accuracy of LDL-C estimation at higher triglyceride levels are limited. Objective: To compare an extended Martin/Hopkins equation for triglyceride values of 400 to 799 mg/dL with the Friedewald and Sampson equations. Design, Setting, and Participants: This cross-sectional study evaluated consecutive patients at clinical sites across the US with patient lipid distributions representative of the US population in the Very Large Database of Lipids from January 1, 2006, to December 31, 2015, with triglyceride levels of 400 to 799 mg/dL. Data analysis was performed from November 9, 2020, to March 23, 2021. Main Outcomes and Measures: Accuracy in LDL-C classification according to guideline-based categories and absolute errors between estimated LDL-C and dLDL-C levels. Patients were randomly assigned 2:1 to derivation and validation data sets. Levels of dLDL-C were measured by vertical spin-density gradient ultracentrifugation. The LDL-C levels were estimated using the Friedewald method, with a fixed ratio of triglycerides to very low-density lipoprotein cholesterol (VLDL-C ratio of 5:1), extended Martin/Hopkins equation with a flexible ratio, and Sampson equation with VLDL-C estimation by multiple least-squares regression. Results: A total of 111 939 patients (mean [SD] age, 52 [13] years; 65.0% male) with triglyceride levels of 400 to 799 mg/dL were included, representing 2.2% of 5 081 680 patients in the database. Across all individual guideline LDL-C classes (<40, 40-69, 70-99, 100-129, 130-159, 160-189, and ≥190), estimation of LDL-C by the extended Martin/Hopkins equation was most accurate (62.1%) compared with the Friedewald (19.3%) and Sampson (40.4%) equations. In classifying LDL-C levels less than 70 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (67.3%) compared with Friedewald (5.1%) and Sampson (26.4%) equations. In addition, for classifying LDL-C levels less than 40 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (57.2%) compared with the Friedewald (4.3%) and Sampson (14.4%) equations. However, considerable underclassification of LDL-C occurred. The magnitude of error between the Martin/Hopkins equation estimation and dLDL-C was also smaller: at LDL-C levels less than 40 mg/dL, 2.7% of patients had 30 mg/dL or greater differences between dLDL-C and estimated LDL-C using the Martin/Hopkins equation compared with the Friedewald (92.5%) and Sampson (38.7%) equations. Conclusions and Relevance: In this cross-sectional study, the extended Martin/Hopkins equation offered greater LDL-C accuracy compared with the Friedewald and Sampson equations in patients with triglyceride levels of 400 to 799 mg/dL. However, regardless of method used, caution is advised with LDL-C estimation in this triglyceride range.

Early use of PCSK9 inhibitor therapy after heart transplantation from a hepatitis C virus positive donor.

Although statin therapy is a primary treatment to prevent cardiac allograft vasculopathy (CAV), its use may be delayed due to pharmacologic interactions in the early post-transplant period among heart transplant (HT) recipients with hepatitis C virus positive (HCV+) donors. Further examination of the possible benefits of early, nonstatin lipid-lowering therapies (LLT), such as PCSK9 inhibitors (PCSK9i), among this specific subset of transplant recipients is therefore becoming increasingly important. We report a 60-year-old man who received a HT from a HCV+ donor for end-stage ischemic cardiomyopathy. In the early post-transplant period, there was concern for drug-drug interactions between statin, immunosuppressant, and direct acting antiviral (DAA) therapy. In addition, prior to transplant, he reported statin-associated muscle symptoms in response to multiple statins, which persisted despite attempts to re-challenge and use an every-other-day dosing strategy. Therefore, the patient was started on PCSK9i therapy after transplantation and while receiving curative DAA therapy for HCV. As the number of HT recipients of HCV+ donors continue to rise, investigation into the safety and benefits of early use of PCSK9i for the reduction of CAV and improved cardiovascular and mortality outcomes should be pursued.

Primary and Novel Lipid-Lowering Therapies to Reduce Risk in Patients With Peripheral Arterial Disease.

PURPOSE OF REVIEW: The diagnosis of peripheral arterial disease (PAD) is a high-risk marker for accelerated atherosclerotic cardiovascular disease (ASCVD) and is associated with substantial morbidity and mortality. In addition to common, modifiable cardiovascular disease risk factors that contribute to PAD, which include hypertension, diabetes mellitus, and smoking, an elevation in concentrations of serum atherogenic lipoproteins (lipids) is an increasingly recognized contributor to premature atherosclerosis. RECENT FINDINGS: The recognition and inclusion of PAD as a marker of higher-cardiovascular risk demonstrates the need to aggressively reduce elevations in atherogenic lipoproteins, particularly low-density-lipoprotein cholesterol. In addition to diet, lifestyle, and statin therapy, there is evidence that novel, pharmacologic lipid-lowering treatments improve specific outcomes in patients with PAD as primary and adjunctive therapy. In this review, we discuss the efficacy and evolving roles of statin and novel nonstatin therapies on outcomes in patients with PAD.

PCSK9 inhibition in patients with heart transplantation: A case series.

PCSK9 inhibitors are potent low-density lipoprotein cholesterol-lowering medications. There is a lack of data regarding safety and efficacy of PCSK9 inhibitors in cardiac transplant patients. In this case series, we provide data supporting the low-density lipoprotein-lowering efficacy and short-term safety of PCSK9 inhibitors in three cardiac transplant patients.

Three-dimensional echocardiography demonstrates a skewered left ventricular thrombus in a patient with a heart transplant.

A left ventricular (LV) false tendon is a frequently visualized structure in echocardiography with unclear clinical significance. We present the case of a false tendon serving as a nidus for thrombus in a post-orthotopic heart transplantation patient. Three-dimensional transthoracic echocardiography (3DTTE) was utilized to visualize a LV mass and facilitate its identification as a thrombus as well as the surrounding structures. Using datasets from 3DTTE, the lack of ventricular wall attachment and circumferential formation of the thrombus around the false tendon was identified. Serial imaging demonstrated resolution of the thrombus with anticoagulation.

Utilization of and Adherence to Guideline-Recommended Lipid-Lowering Therapy After Acute Coronary Syndrome: Opportunities for Improvement.

In addition to aggressive lifestyle and nonlipid risk factor modification, statin therapy improves cardiovascular disease outcomes following acute coronary syndromes. Despite established benefits of treatment, contemporary registries reveal substantial underutilization of and nonadherence to statin therapy for secondary prevention. In randomized controlled trials investigating statin therapy, including moderate-intensity statin plus ezetimibe therapy, rates of nonadherence are reported in up to 40% of subjects. Durable strategies to address gaps in lipid lowering for secondary prevention are essential to maximize reduction in cardiovascular disease risk.

Fibrotic atrial cardiomyopathy, atrial fibrillation, and thromboembolism: mechanistic links and clinical inferences.

The association of atrial fibrillation (AF) with ischemic stroke has long been recognized; yet, the pathogenic mechanisms underlying this relationship are incompletely understood. Clinical schemas, such as the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score, incompletely account for thromboembolic risk, and emerging evidence suggests that stroke can occur in patients with AF even after sinus rhythm is restored. Atrial fibrosis correlates with both the persistence and burden of AF, and gadolinium-enhanced magnetic resonance imaging is gaining utility for detection and quantification of the fibrotic substrate, but methodological challenges limit its use. Factors related to evolution of the thrombogenic fibrotic atrial cardiomyopathy support the view that AF is a marker of stroke risk regardless of whether or not the arrhythmia is sustained. Antithrombotic therapy should be guided by a comprehensive assessment of intrinsic risk rather than the presence or absence of AF at a given time.

Dilemmas in end-stage heart failure.

Heart failure (HF), a complex clinical syndrome due to structural or functional disorder of the heart, is a major global health issue, with a prevalence of over 5.8 million in the USA alone, and over 23 million worldwide. As a leading cause of hospitalizations among patients aged 65 years or older, HF is a major consumer of healthcare resources, creating a substantial strain on the healthcare system. This paper discusses the epidemiology of HF, financial impact, and multifaceted predicaments in end-stage HF care. A search was conducted on the U.S. National Library of Medicine website (www.pubmed.gov) using keywords such as end-stage heart failure, palliative care, ethical dilemmas. Despite the poor prognosis of HF (worse than that for many cancers), many HF patients, caregivers, and clinicians are unaware of the poor prognosis. In addition, the unpredictable clinical trajectory of HF complicates the planning of end-of-life care, such as palliative care and hospice, leading to underutilization of such resources. In conclusion, ethical dilemmas in end-stage HF are numerous, embroiling not only the patient, but also the caregiver, healthcare team, and society.

Mechanisms of myocardial ischemia-reperfusion injury and the cytoprotective role of minocycline: scope and limitations.

Deep insight into the complex mechanisms of myocardial ischemia-reperfusion injury has been attained in the past years. Minocycline is a second-generation tetracycline with US FDA approval for clinical use in various infections. Lately, several noninfectious cytoprotective activities of minocycline have been discovered as well. There now exists encouraging evidence of its protective role in cardiovascular pathology and its activity against myocardial ischemia-reperfusion injury. In this article, an overview of the major mechanisms involved in myocardial ischemia-reperfusion injury is presented. This is followed by an analysis of the mechanisms by which minocycline exerts its cytoprotective role and of studies that have been conducted in order to analyze minocycline, along with a review of the scope and limitations of its role as a cytoprotective agent.

Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease.

Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This "omic" approach recently resulted in new targets for reducing CVD events.

Effect of ß-blocker cessation on chronotropic incompetence and exercise tolerance in patients with advanced heart failure.

BACKGROUND: Chronotropic incompetence is defined as the inability to reach 80% of heart rate (HR) reserve or 80% of the maximally predicted HR during exercise. The presence of chronotropic incompetence is associated with reduced peak oxygen consumption, and rate-responsive pacing therapy is under investigation to improve exercise capacity in heart failure (HF). However, uncertainty exists about whether chronotropic incompetence and reduced exercise tolerance in HF are attributable to ß-blockade. METHODS AND RESULTS: Subjects with HF and receiving long-term ß-blocker therapy underwent cardiopulmonary exercise tolerance testing under 2 conditions in random sequence: (1) after a 27-hour washout period (Off-BB) and (2) 3 hours after ß-blocker ingestion (On-BB). Norepinephrine levels were drawn at rest and at peak exercise. ß1-response to norepinephrine was assessed using the chronotropic responsiveness index: ΔHR/Δlog norepinephrine. Nineteen patients with systolic HF (left ventricular ejection fraction, 22.8±7.7%) were enrolled. Mean age was 49.4±12.3 years. Average carvedilol equivalent dose was 29.1±17.0 mg daily. Peak HR off/on ß-blockers was 62.7±18.7% and 51.4±18.2% HR reserve (P<0.01) and 79.1±11.0% and 70.3±12.3% maximally predicted HR (P<0.01). For the Off-BB and On-BB conditions, the respiratory exchange ratios were 1.05±0.06 and 1.05±0.10 (P=0.77), respectively, confirming maximal and near identical effort in both conditions. The peak oxygen consumption was 16.6±3.34 and 15.9±3.31 mL/kg/min (P=0.03), and the chronotropic responsiveness index was 19.3±7.2 and 16.2±7.1 (P=0.18). CONCLUSIONS: Acute ß-blocker cessation does not normalize the chronotropic response to exercise in patients with advanced HF and chronotropic incompetence.

Metabolic abnormalities in adults with cystic fibrosis.

BACKGROUND AND OBJECTIVE: Survival of patients with cystic fibrosis (CF) has improved, resulting in increased exposure of patients to cardiovascular risk factors. Diabetes mellitus is common in patients with CF; however, less is known about lipid abnormalities in this population. In this study, the prevalence of lipid abnormalities was investigated in a contemporary population of adults with CF. METHODS: Clinical and laboratory data on 221 adult patients with CF were collected retrospectively. Fasting serum glucose levels and lipid profiles were recorded. The age-specific values for healthy individuals, as reported by the National Health and Nutrition Examination Surveys, were used for comparison. RESULTS: The mean age of the patients was 30 +/- 10 years, 55.1% were men and the mean FEV(1)% was 68 +/- 25%. Sixty-nine patients (31.2%) had CF-related diabetes mellitus and 52 (23.5%) were receiving insulin therapy. In addition, 36 patients (16.3%) had impaired glucose tolerance. Triglyceride levels were similar to those of historical control subjects (mean +/- SEM, 1.37 +/- 0.05 and 1.39 +/- 0.02 mmol/L, respectively, P = 0.75). However, in the 30-39 years age group of CF patients, triglyceride levels were increased relative to those of their control counterparts (1.79 +/- 0.14 vs 1.38 +/- 0.04 mmol/L, P = 0.006). Total cholesterol levels were lower in the CF patients compared with control subjects, across all age groups. CONCLUSIONS: Abnormalities of glucose metabolism are highly prevalent in CF patients, and are accompanied by hypertriglyceridaemia in the 30-39 years age group. Prospective studies are required to confirm lipid abnormalities and investigate possible cardiovascular complications in patients with CF.

beta-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors.

In the embryonic kidney, progenitors in the metanephric mesenchyme differentiate into specialized renal epithelia in a defined sequence characterized by the formation of cellular aggregates, conversion into polarized epithelia and segmentation along a proximal-distal axis. This sequence is reiterated throughout renal development to generate nephrons. Here, we identify global transcriptional programs associated with epithelial differentiation utilizing an organ culture model of rat metanephric mesenchymal differentiation, which recapitulates the hallmarks of epithelialization in vivo in a synchronized rather than reiterative fashion. We observe activation of multiple putative targets of beta-catenin/TCF/Lef-dependent transcription coinciding with epithelial differentiation. We show in cultured explants that isolated activation of beta-catenin signaling in epithelial progenitors induces, in a TCF/Lef-dependent manner, a subset of the transcripts associated with epithelialization, including Pax8, cyclin D1 (Ccnd1) and Emx2. This is associated with anti-apoptotic and proliferative effects in epithelial progenitors, whereas cells with impaired TCF/Lef-dependent transcription are progressively depleted from the epithelial lineage. In vivo, TCF/Lef-responsive genes comprise a conserved transcriptional program in differentiating renal epithelial progenitors and beta-catenin-containing transcriptional complexes directly bind to their promoter regions. Thus, beta-catenin/TCF/Lef-mediated transcriptional events control a subset of the differentiation-associated transcriptional program and thereby participate in maintenance, expansion and stage progression of the epithelial lineage.

Dissecting stages of mesenchymal-to-epithelial conversion during kidney development.

During embryonic development, the structures of the nephron from the glomerulus to distal tubule derive from the metanephric mesenchyme. The mesenchymal cells change their cell type and produce highly organized epithelia under the influence of signals from the ureteric bud. The morphological sequence of this conversion includes the formation of a corona of mesenchymal cells surrounding the tips of the ureteric bud, followed by the development of a pre-tubular aggregate, which evolves into preliminary forms of the segmented nephron. Currently, these stages are largely based on histomorphologic criteria and expression of marker molecules. However, to dissect the effects of inductive signals from the ureteric bud in more detail, a sophisticated readout of stages in the conversion process is required, based on the onset of epithelial polarity and the occurrence of vectorial transport. In this review, we discuss some of the new approaches in establishing the staging of the conversion process.