Commentary based on Bianchettin RG, Lavie CJ, Lopez-Jimenez F. Challenges in cardiovascular evaluation and management of obese patients. J Am Coll Cardiol 2023;81:490-504.¹

Introduction

Obesity is a multifaceted disease that is directly and indirectly implicated in atherosclerotic cardiovascular disease (CVD), heart failure (HF), atrial fibrillation (AF), and multiple CVD risk factors, including dyslipidemia, hypertension, type 2 diabetes mellitus (DM), and sleep disorders. The World Health Organization (WHO) defines obesity as body mass index (BMI) ≥30 kg/m². Although BMI is strongly correlated with body fat percentage, there are limitations in its predictive ability, with variation by sex, age, and race/ethnicity.² A range of anthropometric measurements of central adiposity, such as waist circumference, provide better means of characterizing body composition and assessing associated CVD risk.

Discussion

Imaging/Diagnostics in Obesity

Morphological changes due to obesity can negatively affect the diagnostic performance of electrocardiography (ECG) because of excessive chest wall subcutaneous fat tissue, which may result in low QRS voltage in these patients. This phenomenon may reduce the sensitivity for detection of ischemic ECG changes, including during stress testing. Obesity can also cause cardiac hypertrophy from increased cardiac workload and a leftward shift in the ECG axis because of displacement of the heart by an elevated diaphragm.

Transthoracic echocardiography and stress (pharmacological or exercise) echocardiography findings can be limited by poor acoustic windows because thicker subcutaneous fat tissue increases the depth needed to identify structures, with resultant decrease in spatial resolution. This limitation might affect detection of regional wall motion abnormalities during stress testing, although this can be mitigated by the use of ultrasound contrast.³ Differentiation between epicardial fat tissue and pericardial effusion can be challenging.

Single-photon emission computed tomography (CT) myocardial perfusion imaging (MPI) use may be limited by supplier-designated table weights (typically <136-181 kg), and radioisotope dosing may exceed maximal dosing, which is calculated on the basis of weight. Positron emission tomography MPI is often the recommended stress imaging modality for patients with BMI >40 kg/m² because it is minimally affected by BMI.

CT coronary angiography image quality is adversely affected by rising BMI; although this effect can be overcome by changing the CT parameters, it often results in increased radiation dose. Such testing may not be feasible in patients with BMI >40 kg/m² or when weight is above the CT table limit (usually 204 kg). Cardiac magnetic resonance imaging is less affected by obesity than is CT, but technical factors such as equipment bore size can be restrictive in patients with excess weight.

Pharmacology in Obesity

Obesity presents challenges in pharmacological treatment because of the pharmacokinetic and pharmacodynamic alterations with increased adipose tissue and volume of distribution. Physiological changes associated with weight gain such as greater cardiac output and increased blood flow to the liver and kidneys may elevate clearance of the medications. Conversely, patients with nonalcoholic fatty liver disease, which is commonly associated with obesity, will have reduced elimination rates of hepatically cleared medications.⁴ Lipophilic medications often need higher dosages on the basis of total body weight because they are usually deposited in the adipose tissue.

Direct oral anticoagulants (DOACs) present challenges in terms of appropriate dosing in patients with elevated BMI. Each DOAC has different pharmacokinetic considerations, and patients with obesity may be at risk of underdosing from reduced drug concentration. DOAC treatments may be unsuitable for patients with BMI >40 kg/m², and warfarin treatment may be preferable in this population. In addition, beta-blockers are associated with poorer exercise tolerance and fatigue, which may hinder efforts at weight loss.⁵

Interventional Cardiology/Surgery and Obesity

Patients with obesity may have increased challenges with vascular access while undergoing percutaneous interventions; however, BMI is not a predictor of 5-year mortality or CVD mortality in people undergoing coronary intervention. The "obesity paradox" has been noted among patients undergoing arterial revascularization, whereby obesity is associated with a neutral or beneficial effect on mortality following intervention in observational studies.

The underlying explanation is unknown, and this finding does not indicate causality but may be related to weight loss or cachexia resulting from more severe CVD in the normal BMI group or to earlier screening and medical management of patients with obesity. Nevertheless, the paradox is diminished with longer follow-up and increasing severity of obesity, with the highest CVD mortality seen in patients with BMI ≥35 kg/m² following coronary artery bypass graft surgery. Higher BMI is also associated with greater rates of postoperative AF and surgical wound complications.^6,7

Weight loss is recommended for patients with BMI ≥35 kg/m² before heart transplantation listing because of worse outcomes postoperatively, including increased frequency of high-grade rejection and short time to high-grade acute rejection.⁸

Management of Obesity

Body fat reduction and maintenance of healthier weight necessitates commitment to dietary and activity lifestyle adjustments. Medical nutrition therapy (MNT) and physical activity form the foundation for obesity management. MNT can produce modest weight reduction and should be tailored to patient preferences to develop a sustainable plan for reducing caloric intake below caloric expenditure. Guidelines recommend ≥30 min of physical activity, 5-7 days per week, to prevent weight gain and improve cardiovascular (CV) health. This activity can be more challenging in patients with osteoarthritis (OA), in whom activity can be limited, and for those with depression or DM because prescribed medications may contribute to weight gain (e.g., antidepressants, insulin use). Of course, MNT and increased physical activity are the foundation of obesity management.

Orlistat (a reversible inhibitor of gastric and pancreatic lipases) can be effective in promoting weight loss but is associated with significant adverse effects. Glucagon-like peptide-1 receptor agonists (GLP1RAs; e.g., semaglutide) and GLP1RAs/gastric inhibitory peptide (GIP) receptor agonists (e.g., tirzepatide) have been very effective, with associated weight loss of >15% and >20% of body weight, respectively, over 1 year on the target dose of therapy. The novel "triple-G" (GLP1RA, GIP receptor agonist, and the glucagon receptor agonist retatrutide) has demonstrated even greater efficacy, with 24% mean weight loss at 48 weeks in a recent phase 2 trial, offering another promising option in the future.⁹ As of December 2023, both semaglutide and tirzepatide had received Food and Drug Administration (FDA) approval for treatment of obesity.

The CV benefits of GLP1RAs were further demonstrated by the recently published SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial data, which demonstrated that therapy with high-dose semaglutide for patients with CVD and overweight or obesity without DM decreased major adverse CV events by 20%. The early separation in CVD outcomes between the semaglutide and placebo groups, before substantial weight loss was achieved, suggests potential direct cardioprotective benefits of GLP1RAs beyond their weight-loss effects.

Ongoing trials of other agents may yield further insights. Bariatric surgery results in loss of 20-35% of body weight and has been associated with lower risk of mortality, new-onset HF and myocardial infarction, and recurrent CVD events, and should be considered to reduce CVD risk in patients with BMI ≥35 kg/m² despite lifestyle and pharmacologic therapy.¹⁰

Conclusions

Obesity commonly presents with comorbid CVD and has implications for diagnostic testing and for pharmacological, procedural, and lifestyle interventions. Optimal prescribing practices can be more nuanced in those with obesity, and underdosing or overdosing may occur with therapies such as DOACs. Common comorbidities such as DM, depression, and OA can make weight loss challenging, and recently approved pharmacological interventions and bariatric surgery present additional opportunities for reducing weight and CVD risk in patients with obesity.

References

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8. Mehra MR, Canter CE, Hannan MM, et al.; International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases Council, International Society for Heart Lung Transplantation (ISHLT) Pediatric Transplantation Council, International Society for Heart Lung Transplantation (ISHLT) Heart Failure and Transplantation Council. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant 2016;35:1-23.
9. Jastreboff AM, Kaplan LM, Frías JP, et al.; Retatrutide Phase 2 Obesity Trial Investigators. Triple–hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med 2023;389:514-26.
10. van Veldhuisen SL, Gorter TM, van Woerden G, et al. Bariatric surgery and cardiovascular disease: a systematic review and meta-analysis. Eur Heart J 2022;43:1955-69.