A systematic review of present and future pharmaco-structural therapies for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are ubiquitous, they are limited by a lack of solid evidence, are often inadequate, poorly tolerated, and do not alter the natural disease course. As such, there has long been a need for effective, evidence-based, and targeted disease-modifying therapies for HCM. In this review, we redefine HCM as a treatable condition, evaluate current strategies for therapeutic intervention, and discuss novel myosin inhibitors. The majority of patients with HCM have elevated left ventricular outflow tract gradients, which predicts worse symptoms and adverse outcomes. Conventional pharmacological therapies for symptomatic HCM can help improve symptoms but are often inadequate and poorly tolerated. Septal reduction therapies (surgical myectomy and alcohol septal ablation) can safely and effectively reduce refractory symptoms and improve outcomes in patients with obstructive HCM. However, they require expertise that is not universally available and are not without risks. Currently, available therapies do not alter the disease course or the progressive cardiac remodeling that ensues, nor subsequent heart failure and arrhythmias. This has been regarded as an unmet need in the care of HCM patients. Novel targeted pharmacotherapies, namely cardiac myosin inhibitors, have emerged to reverse key pathophysiological changes and alter disease course. Their favorable outcomes led to the early Food and Drug Administration approval of mavacamten, a first-in-class myosin modulator, changing the paradigm for the pharmacological treatment of HCM.

An unusual presentation of non-infectious ascending aortitis: a case report of an asymptomatic murmur.

BACKGROUND: Aortitis refers to pathologic inflammation of the aortic wall and is broadly categorized into inflammatory (or non-infectious) and infectious aortitis. While rare, isolated non-infectious ascending aortitis (I-NIAA) is a clinical entity that is becoming increasingly recognized but remains poorly understood. CASE SUMMARY: A 72-year-old man presented with an asymptomatic murmur and was found to have severe aortic insufficiency second to a large ascending aortic aneurysm. He underwent surgical repair and pathology revealed isolated non-infectious ascending aortitis. Following successful surgical repair, he developed joint pains which were successfully treated with glucocorticoids. DISCUSSION: Isolated non-infectious aortitis is a rare entity that warrants further investigation. This case highlights the importance of sending surgical specimens for histopathologic evaluation even when a systemic process is not evident at the time of surgical repair. The development of systemic symptoms following surgical repair in this patient emphasizes the importance of thorough rheumatologic evaluation in patients found to have I-NIAA. Isolated non-infectious ascending aortitis remains poorly understood, and further study is needed to evaluate both its existence as a distinct clinical entity and the role of immunosuppressive therapy.

Hypertension management in older adults.

Vascular aging leads to arterial hypertension, which is the leading cause of cardiovascular mortality and morbidity in older adults. Blood pressure reduction is effective in reducing the cardiovascular risk and is safe in ambulatory older adults. It is important to note that blood pressure control in this group of patients is challenging because of comorbidities, polypharmacy, and frailty. Choice of pharmacotherapy is not simple and should be individualized.

Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase.

Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.

Lipoprotein abnormalities in South Asians and its association with cardiovascular disease: Current state and future directions.

South Asians have a high prevalence of coronary heart disease (CHD) and suffer from early-onset CHD compared to other ethnic groups. Conventional risk factors may not fully explain this increased CHD risk in this population. Indeed, South Asians have a unique lipid profile which may predispose them to premature CHD. Dyslipidemia in this patient population seems to be an important contributor to the high incidence of coronary atherosclerosis. The dyslipidemia in South Asians is characterized by elevated levels of triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, elevated lipoprotein(a) levels, and a higher atherogenic particle burden despite comparable low-density lipoprotein cholesterol levels compared with other ethnic subgroups. HDL particles also appear to be smaller, dysfunctional, and proatherogenic in South Asians. Despite the rapid expansion of the current literature with better understanding of the specific lipid abnormalities in this patient population, studies with adequate sample sizes are needed to assess the significance and contribution of a given lipid parameter on overall cardiovascular risk in this population. Specific management goals and treatment thresholds do not exist for South Asians because of paucity of data. Current treatment recommendations are mostly extrapolated from Western guidelines. Lastly, large, prospective studies with outcomes data are needed to assess cardiovascular benefit associated with various lipid-lowering therapies (including combination therapy) in this patient population.

Genetic Testing in Hyperlipidemia.

Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia.

Genetic testing in hyperlipidemia.

Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia.

Use of purified fibrinogen concentrate for dysfibrinogenemia and importance of laboratory fibrinogen activity measurement.

We report a patient with dysfibrinogenemia treated with purified fibrinogen concentrate who had discrepant post-treatment laboratory values. The patient had mild bleeding symptoms and was diagnosed with dysfibrinogenemia based on fibrinogen activity of 51 mg/dl and antigen of 240 mg/dl. He was treated for an adenoidectomy with purified fibrinogen concentrate (RiaSTAP®) at a dose of 70 mg/kg. A discrepancy in post-treatment fibrinogen activity was observed between the hospital and reference laboratories. Investigation revealed differences in laboratory assay and calibration methods. Fibrinogen concentrate may be a treatment option for patients with dysfibrinogenemia, but accurate laboratory technique is critical for fibrinogen measurement.

Severe thrombotic and bleeding complications in a baby with heterozygous factor V Leiden and acquired von Willebrand disease on ECMO.

We aim to present the case of a 5-week-old girl with severe respiratory failure placed on veno-venous extracorporeal membrane oxygenation (ECMO) that was then switched to veno-arterial ECMO. She required up to 60 units/kg/hr of heparin to keep her heparin level within the target range at .3-.7 units/mL. During the ECMO course, substantial thrombus formation was observed within the venous site of the ECMO cannula, which led to two circuit changes on ECMO day 9 and day 20. On ECMO day 15, she was noticed to have purpuric lesions on her chest and her right hand with no obvious arterial or venous clot detected by Doppler ultrasound. She was also noted to have remarkable hemolysis as the plasma free hemoglobin levels were substantially elevated up to 700 mg/dL. She was noted to have continuous oozing from the catheter insertion sites despite adequate underlying coagulation status. Her subsequent platelet function analysis, the thromboelastography, and thromboelastography platelet mapping suggested substantial platelet dysfunction. Her von Willebrand panel revealed absence of high molecular weight multimers. Further coagulation workup was prompted which revealed heterozygosity for factor V Leiden. The patient developed severe pulmonary hemorrhages and ECMO was discontinued on day 40.

Evaluation of heparin assay for coagulation management in newborns undergoing ECMO.

The objective was to identify the usefulness of heparin level by anti-factor Xa (anti-Xa) assay vs activated partial thromboplastin time (PTT) or activated clotting time (ACT) in neonates undergoing extracorporeal membrane oxygenation (ECMO). A retrospective record review of 21 patients in the neonatal intensive care unit (mean ECMO initiation age, 2 days; range, 0-4 days; male/female ratio, 1:1) undergoing ECMO from 2006 to 2008 was performed. Linear regression correlations between anti-Xa, PTT, and ACT were determined by extrapolating PTT and ACT therapeutic ranges that corresponded with the ECMO heparin target range of 0.3 to 0.6 U/mL. Pearson correlation coefficients between heparin levels and PTT (-0.903 to 0.984), PTT less than 40 seconds after correction using PTT-heparinase (-0.903 to 1.000), and ACT (-0.951 to 0.891) in this patient population were widely variable. Inconsistency of PTT and ACT therapeutic ranges corresponding to heparin levels of 0.3 to 0.6 U/mL prompts a multifactorial approach to ECMO management because no single laboratory test can be used to determine appropriate anticoagulation management.