All About Heart And Blood Vessels

Semaglutide for Heart Failure with Preserved Ejection Fraction and Obesity

Johnson Francis — Wed, 29 May 2024 14:17:27 +0000

Semaglutide is a glucagon-like peptide-1 receptor agonist which has been shown to reduce body weight and improve health status in patients with obesity related heart failure with preserved ejection fraction in the STEP-HFpEF Program [1]. Semaglutide was adminstered once weekly as subcutaneous injection. The medication has been approved for long term weight management and has been shown to produce major weight loss in overweight and obese persons. It has favourable effects on cardiometabolic risk. Semaglutide reduces C-Reactive Protein level, systolic blood pressure and NT-proBNP level in patients with obesity and heart failure with preserved ejection fraction.

Reference

Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovsky V, Merkely B, Núñez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084. doi: 10.1056/NEJMoa2306963. Epub 2023 Aug 25. PMID: 37622681.

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Lipoprotein(a), LDL on “on steroids”?

Johnson Francis — Sat, 25 May 2024 01:10:39 +0000

Some have called Lipoprotein(a), known in short as Lp(a) as low density lipoprotein particle on steroids, while others have called it the ‘ugly’ cholesterol where as LDL cholesterol is bad cholesterol and HDL cholesterol the good cholesterol. Reason is that extensive data suggest it as a causal factor for atherosclerotic cardiovascular disease [1]. Lp(a) levels above 50 mg/dL which is present in about a fifth of the global adult population is thought to increase risk and need intensification of therapies reducing risk of atherosclerotic cardiovascular disease like statins. Now we have a real-world registry data of patients with Lp(a) levels collected during routine clinical practice [2].

A retrospective cohort of patients with Lp(a) measured at two medical centres from 2000 to 2019 were studied. Association of Lp(a) with major adverse cardiovascular events – nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or cardiovascular mortality was evaluated. Nearly sixteen and a half thousand people were analysed and had a mean follow up period of 11.9 years. Nearly ten thousand had baseline atherosclerotic cardiovascular disease. Among these persons, those in the 71st to 90th percentile of Lp(a) levels (112-215 nmol/L) had 21% increased hazard of major adverse cardiovascular events. This was similar to those in the 91st to 100th percentile group. The risk was particularly for myocardial infarction and coronary revascularization.

A little over six thousand two hundred did not have atherosclerotic cardiovascular disease at baseline. Among them, there was a continuously higher hazard of MACE with increasing Lp(a) levels. Those in the 91st to 100th Lp(a) percentile group had the highest relative risk of 1.93.

References

Wong ND. Lipoprotein(a): Ready for Prime Time? J Am Coll Cardiol. 2024 Mar 5;83(9):887-889. doi: 10.1016/j.jacc.2024.01.004. PMID: 38418001.
Berman AN, Biery DW, Besser SA, Singh A, Shiyovich A, Weber BN, Huck DM, Divakaran S, Hainer J, Kaur G, Blaha MJ, Cannon CP, Plutzky J, Januzzi JL, Booth JN 3rd, López JAG, Kent ST, Nasir K, Di Carli MF, Bhatt DL, Blankstein R. Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2024 Mar 5;83(9):873-886. doi: 10.1016/j.jacc.2023.12.031. PMID: 38418000.

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Severe Hypertriglyceridemia and Multiorgan Disease

Johnson Francis — Thu, 23 May 2024 10:46:55 +0000

It is well known that severe hypertriglyceridemia with serum triglyceride levels 500 mg/dL or more is an important risk factor for acute pancreatitis. Severe hypertriglyceridemia is also a risk factor for atherosclerotic cardiovascular disease [1]. New targets for treatment of severe hypertriglyceridemia are inhibition of apolipoprotein C-III, angiopoietin-like protein 3, angiopoietin-like protein 4, and fibroblast growth factor-21. A research letter published in JACC Advances estimated the prevalence of chronic conditions and multiorgan disease among adults in the United States of America with severe hypertriglyceridemia [2]. They pooled data from Nutrition Examination Survey of 1999-2000 and 2017-2020 cycles with severe hypertriglyceridemia.

The chronic conditions included central obesity, diabetes mellitus, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and history of atherosclerotic cardiovascular disease. As per the data, 2.3 million US adults had severe hypertriglyceridemia. Among those with severe hypertriglyceridemia, 70.3% had central obesity, 32.7% had diabetes, 21.6% had chronic kidney disease, 67% had metabolic dysfunction-associated steatotic liver disease and 10.6% had atherosclerotic cardiovascular disease. Prevalence ratio of chronic conditions was almost three times compared to those with serum triglyceride level below 200 mg/dL.

References

Malick WA, Do R, Rosenson RS. Severe hypertriglyceridemia: Existing and emerging therapies. Pharmacol Ther. 2023 Nov;251:108544. doi: 10.1016/j.pharmthera.2023.108544. Epub 2023 Oct 15. PMID: 37848164.
Chen Gurevitz, Ligong Chen, Paul Muntner, and Robert S. Rosenson. Hypertriglyceridemia and Multiorgan Disease Among U.S. Adults. JACC Adv. 2024 May, 3 (5) 100932.

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Cardiovascular Risk of ADHD Treatment

Johnson Francis — Wed, 22 May 2024 14:40:34 +0000

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common behavioral disorder and treatment can ameliorate symptoms and improve quality of life. But most ADHD treatments can increase heart rate and blood pressure by stimulating the sympathetic nervous system and potentially increase cardiovascular risk. A recent study published in the Journal of American College of Cardiology checked association between long-term use of medications for ADHD and cardiovascular outcomes [1]. Adult patients started on ADHD treatment for the first time between 1998 and 2020 were identified using nation wide registers from Denmark. Outcomes evaluated in the study were acute coronary syndromes, stroke, heart failure and a composite of these. Over seventy three thousand adult first time users were identified. Those who discontinued treatment within 180 days were categorized as prior users and was about 36% of the initial number. Persons still on treatment were more likely to be concomitantly treated with non steroidal anti-inflammatory agents, antipsychotics, antidepressants and sedative hypnotics.

In the final analysis, associations between ADHD treatment and elevated 10-year risk of stroke, heart failure and composite cardiovascular outcome were found. A dose response relationship with higher dose was noted. Notably, there was no association with increased risk of acute coronary syndromes. Higher absolute risk of heart failure and stroke was noted in those on concomitant psychopharmaceutical and NSAID treatment. Ten year absolute risk was much higher in older age group. Relative risk of heart failure seemed to be most signifigantly influenced by increasing dosage and years of exposure. This is reasonable because the increase in number of years with increased sympathetic tone elevating heart rate and blood pressure could lead to heart failure. With all potential limitations of a register analysis, these data should be taken as hypothesis generating and followed up with randomized controlled clinical trials.

Reference

Holt A, Strange JE, Rasmussen PV, Nouhravesh N, Nielsen SK, Sindet-Pedersen C, Fosbøl EL, Køber L, Torp-Pedersen C, Gislason GH, McGettigan P, Schou M, Lamberts M. Long-Term Cardiovascular Risk Associated With Treatment of Attention-Deficit/Hyperactivity Disorder in Adults. J Am Coll Cardiol. 2024 May 14;83(19):1870-1882. doi: 10.1016/j.jacc.2024.03.375. PMID: 38719367.

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Intake of ultraprocessed food increases cardiometabolic risk in children

Johnson Francis — Tue, 21 May 2024 03:55:50 +0000

It is already known that high intake of ultraprocessed food is associated with higher cardimetabolic risk in adults. A new study published in the Journal of American Medical Association Network Open found that higher consumption of ultraprocessed food increased body mass index, waist circumference, fat mass index, fasting plasma glucose and decreased the levels of the protective high density lipoprotein (HDL) cholesterol concentrations [1]. That was a cross-sectional study of 1426 children in the Childhood Obesity Risk Assessment Longitudinal Study (CORALS). The study recruited preschool children aged 3 to 6 years from schools and centers in 7 cities of Spain, with informed consent from parents or caregivers. Findings of the study highlighted the need for public health initiatives to promote the replacement of ultraprocessed food with unprocessed or minimally processed foods.

Ultraprocessed foods are those which undergo extensive industrial processing and often containing multiple ingredients, additives and preservatives which make them ready to eat, palatable and appealing. They are typically rich in saturated fats, sugars, sodium and other additives and lower in essential nutrients, which increase the cardiometabolic risk. As they have high availablitiy and affordability, with wide marketing to children, they are more often used by children and adolescent along with their families, especially those who are more prone for obesity due to socioeconomic and educational reasons. As the habits established during early childhood are often followed in adulthood this compounds the risk of cardiovascular disease and other noncommunicable diseases.

Reference

Khoury N, Martínez MÁ, Garcidueñas-Fimbres TE, Pastor-Villaescusa B, Leis R, de Las Heras-Delgado S, Miguel-Berges ML, Navas-Carretero S, Portoles O, Pérez-Vega KA, Jurado-Castro JM, Vázquez-Cobela R, Mimbrero G, Andía Horno R, Martínez JA, Flores-Rojas K, Picáns-Leis R, Luque V, Moreno LA, Castro-Collado C, Gil-Campos M, Salas-Salvadó J, Babio N. Ultraprocessed Food Consumption and Cardiometabolic Risk Factors in Children. JAMA Netw Open. 2024 May 1;7(5):e2411852. doi: 10.1001/jamanetworkopen.2024.11852. PMID: 38758555; PMCID: PMC11102022.

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Aficamten: A New Cardiac Myosin Inhibitor for Hypertrophic Obstructive Cardiomyopathy

Johnson Francis — Wed, 15 May 2024 12:27:45 +0000

After the approval of mavacamten, a novel cardiac myosin inhibitor for symptomatic hypertrophic obstructive cardiomyopathy, a new medication in the same group is getting ready. Hypertrophic obstructive cardiomyopathy is a genetically determined disease of the heart muscle in which gross thickening of the wall between the two lower chambers of the heart obstructs outflow of blood from the left sided chamber known as left ventricle. This can cause breathlessness and giddiness on exertion and sometimes chest pain. It has also the potential to cause sudden death due to life threatening heart rhythm disorders. Mavacamten and aficamten decreases the contractile force of the heart muscle and thereby reduces the chance of obstruction to outflow of blood from the left ventricle. A recent clinical trial published in the leading medical journal New England Journal of Medicine has documented the beneficial effects of aficamten.

Compared to mavacamten, aficamten has lesser potential for drug-drug interactions. Half-life of aficamten in blood is lower so that dose titration is possible within shorter periods than mavacamten, to individualize the dose schedule. The suppressive effect of aficamten on the pumping action of the heart is lower by design so that there is less chance of development of heart failure due to reduced pump function while increasing the dose. In the recent study report there was no loss of benefit in those who were on another group of medications for hypertrophic cardiomyopathy known as beta blockers. It was there in studies on mavacamten earlier.

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Novel Gene Editing for Sickle Cell Disease and β-Thalassemia

Johnson Francis — Mon, 13 May 2024 00:46:57 +0000

Novel gene editing treatment with exa-cel has been recently approved for treatment of severe sickle cell disease and transfusion-dependent β-thalassemia [1]. It was six decades back that it was noticed that patients with hereditary persistence of fetal hemoglobin had a milder course of β-thalassemia and it was postulated that stimulation of production of fetal hemoglobin might provide benefits to adults with sickle cell disease and severe β-thalassemia. Later it was also shown that higher levels of fetal hemoglobin was associated with prolonged survival in these conditions [2]. Two articles published in the New England Journal of Medicine have evaluated the role of Exagamglogene autotemcel (exa-cel) in the treatment of severe sickle cell disease and transfusion-dependent β-thalassemia [3,4]. Autologous cellular therapy exagamglogene autotemcel is generated by editing an erythroid-specific enhancer of BCL11A. That is why it needs autologous bone marrow transplantation and hence quite cumbersome and expensive, with limited availability.

Exagamglogene autotemcel is designed to reactivate fetal hemoglobin synthesis by ex vivo gene editing using CRISPR–Cas9 (CRISPR-associated protein 9), the novel gene editing tool which has been recognized by a Nobel Prize. CRISPR stands for clustered regularly interspaced short palindromic repeats. Gene editing is done for autologous CD34+ hematopoietic stem and progenitor cells at the erythroid-specific enhancer region of BCL11A. BCL11A gene encodes B-cell lymphoma/leukemia 11A protein. BCL11A plays a role in the switch from γ- to β-globin expression during the transition from fetal to adult erythropoiesis. Exa-cel treatment eliminated painful vaso-occulsive crises in 97% of patients with sickle cell disease for a period of one year or more [3]. Similarly, treatment with exa-cel preceded by myeloablation resulted in transfusion independence in 91% of transfusion-dependent β-thalassemia patients [4]. Specificity of exa-cel in avoiding unintentional editing of other sites or off-target editing has been checked by another study published in the same issue of NEJM [5].

References

Daley GQ. Welcoming the Era of Gene Editing in Medicine. N Engl J Med. 2024 May 9;390(18):1642-1645. doi: 10.1056/NEJMp2314279. Epub 2024 Apr 24. PMID: 38657270.
McCune JM, Kiem HP. Extending Gene Medicines to All in Need. N Engl J Med. 2024 May 9;390(18):1721-1722. doi: 10.1056/NEJMe2403104. Epub 2024 Apr 24. PMID: 38657269.
Frangoul H, Locatelli F, Sharma A, Bhatia M, Mapara M, Molinari L, Wall D, Liem RI, Telfer P, Shah AJ, Cavazzana M, Corbacioglu S, Rondelli D, Meisel R, Dedeken L, Lobitz S, de Montalembert M, Steinberg MH, Walters MC, Eckrich MJ, Imren S, Bower L, Simard C, Zhou W, Xuan F, Morrow PK, Hobbs WE, Grupp SA; CLIMB SCD-121 Study Group. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med. 2024 May 9;390(18):1649-1662. doi: 10.1056/NEJMoa2309676. Epub 2024 Apr 24. PMID: 38661449.
Locatelli F, Lang P, Wall D, Meisel R, Corbacioglu S, Li AM, de la Fuente J, Shah AJ, Carpenter B, Kwiatkowski JL, Mapara M, Liem RI, Cappellini MD, Algeri M, Kattamis A, Sheth S, Grupp S, Handgretinger R, Kohli P, Shi D, Ross L, Bobruff Y, Simard C, Zhang L, Morrow PK, Hobbs WE, Frangoul H; CLIMB THAL-111 Study Group. Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. N Engl J Med. 2024 May 9;390(18):1663-1676. doi: 10.1056/NEJMoa2309673. Epub 2024 Apr 24. PMID: 38657265.
Yen A, Zappala Z, Fine RS, Majarian TD, Sripakdeevong P, Altshuler D. Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel. N Engl J Med. 2024 May 9;390(18):1723-1725. doi: 10.1056/NEJMc2313119. Epub 2024 Apr 24. PMID: 38657268.

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New Guidelines Favouring Exercise in Hypertrophic Cardiomyopathy

Johnson Francis — Fri, 10 May 2024 11:09:53 +0000

Hypertrophic cardiomyopathy, a disease with thickening of heart muscle, is an important cause of sudden cardiac death in athletes. But the 2024 Guidelines for Management of Hypertrophic Cardiomyopathy, which is now available online with free access at Journal of American College of Cardiology website seems to encourage exercise for persons with hypertrophic cardiomyopathy. They mention that recent evidence demonstrates benefits outweigh risks in many patients with appropriate assessment. Of course, the wording ‘with appropriate assessment’ is of topmost importance.

As you are aware, exercise is not for everyone with hypertrophic cardiomyopathy. Mild to moderate recreational exercise without competition is tagged green, vigorous recreational activities as yellow and competitive sports as orange, with Class I, IIa and IIb recommendations respectively. Class I is the most accepted recommendation. Class II is where there could be divided opinion among experts, with more agreement in Class IIa and less agreement in Class IIb. If it is deemed harmful, it is tagged red and Class III. There are certainly some persons with severe forms of hypertrophic cardiomyopathy in whom exercise could be harmful and hence Class III.

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Holt-Oram Syndrome

Johnson Francis — Tue, 05 Mar 2024 04:37:32 +0000

Holt-Oram Syndrome is a familial heart disease with skeletal malformations described by Mary Holt and Samuel Oram. Initial description was familial atrial septal defect associated with abnormalities of the radial aspect of the upper limb. Characteristic abnormality was the simian thumb which lies in the same plane as the other fingers and hence unable to oppose like a normal thumb. Holt-Oram Syndrome has also been called as atriodigital dysplasia, though ventricular septal defect and other cardiac abnormalities were reported later. The semial report had described associated conduction disturbances and arrhythmias as well.

Autosomal dominant inheritance has been associated with mutation in transcription factor gene TBX5 in Holt-Oram syndrome. Cardiac malformations are seen in 75% of affected family members. Carpal bone abnormalities are clinically silent and evident only radiologically. Due to the autosomal dominant pattern of inheritance, 50% of offspring can be affected. TBX5 mutations account for upto 70% of cases of Holt-Oram syndrome. Nearly 85% of cases of Holt-Oram Syndrome have de novo mutations.

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How bad is Lipoprotein(a)?

Johnson Francis — Thu, 29 Feb 2024 00:53:16 +0000

It is well known that lipoprotein(a) is associated with increased risk of cardiovascular disease, including calcific aortic valve disease. New treatment modalities are being investigated in clincal trials like Lp(a)HORIZON and OCEAN(a) which are expected to be completed within a year or two. A recent retrospective cohort study evaluated the incidence of major adverse cardiovascular events (MACE) among patients with and without baseline atherosclerotic cardiovascular disease and their association with lipoprotein(a) levels. MACE includes nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and cardiovascular mortality [1].

Nearly sixteen thousand and five hundred individuals were analyzed and had a median follow up of nearly 12 years. There were over six thousand and two hundred individuals without established atherosclerotic cardiovascular disease at baseline. A continuously higher hazard of MACE with increasing Lp(a) levels was noted in the study.

Lp(a) was considered as an unmodifiable cardiovascular risk factor. The clinical trials mentioned intially are investigating the effects of antisense oligonucleotides and small interfering RNAs in reducing the risk due to Lp(a). PCSK9 inhibitors have been shown to decrease Lp(a) levels by about 20%. FOURIER [2] and ODYSSEY [3] trials had shown that those with baseline elevated Lp(a) levels in addition to elevated LDL had the greatest cardiovascular benefit from PCSK9 inhibitors.

Reference

Adam N. Berman, David W. Biery, Stephanie A. Besser, Avinainder Singh, Arthur Shiyovich, Brittany N. Weber, Daniel M. Huck, Sanjay Divakaran, Jon Hainer, Gurleen Kaur, Michael J. Blaha, Christopher P. Cannon, Jorge Plutzky, James L. Januzzi, John N. Booth, J. Antonio G. López, Shia T. Kent, Khurram Nasir, Marcelo F. Di Carli, Deepak L. Bhatt, and Ron Blankstein. Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2024 Mar, 83 (9) 873–886.
O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Češka R, Ezhov MV, Jukema JW, Jensen HK, Tokgözoğlu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019 Mar 19;139(12):1483-1492. doi: 10.1161/CIRCULATIONAHA.118.037184. PMID: 30586750.
Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, Fras Z, Goodman SG, Halvorsen S, Hanotin C, Harrington RA, Jukema JW, Loizeau V, Moriarty PM, Moryusef A, Pordy R, Roe MT, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg PG, Schwartz GG; ODYSSEY OUTCOMES Committees and Investigators. Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. J Am Coll Cardiol. 2020 Jan 21;75(2):133-144. doi: 10.1016/j.jacc.2019.10.057. PMID: 31948641.

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