In the Journals

Obesity causally linked to aortic valve stenosis, replacement

Børge G. Nordestgaard

Patients with a genetic predisposition for obesity may have an increased risk for aortic valve stenosis and valve replacement, according to research published in the Journal of the American College of Cardiology.

Using a Mendelian randomization design to assess the genetic and observational association between obesity and aortic valve stenosis, researchers found that patients with allele scores between 4 and 10 experienced an increased risk for aortic valve stenosis compared with patients with an allele score of 0 to 3 (P for trend = 9105).

Compared with scores between 0 and 3, the adjusted HRs for aortic valve stenosis and replacement were:

  • 1.3 (95% CI, 1-1.7) for an allele score of 4;
  • 1.4 (95% CI, 1.1-1.8) for a score of 5 to 6; and
  • 1.6 (95% CI, 1.3-2.1) for a score of 7 to 10.

“We wondered whether a previously reported association between high body mass index and increased risk of aortic valve stenosis is causal — or if obesity is only just a marker of disease risk,” Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen and chief physician of the department of clinical biochemistry at Copenhagen University Hospital, Denmark, told Healio. “The findings that genes increasing the risk of being overweight also increase the risk of aortic valve stenosis indicate that the relationship between obesity and aortic valve stenosis is causal.”

“The mechanism behind obesity causing aortic valve stenosis may be due to either structural changes of the heart or metabolic changes of the obese body,” Morten Kaltoft, MD, of the department of clinical biochemistry at the Herlev and Gentofte Hospital of Copenhagen University Hospital, Denmark, and colleagues wrote. “Structurally, obesity causes higher blood pressure, increasing stress on the heart, which could lead to geometric changes of the left ventricle and aortic valve, and high blood pressure could initiate atherosclerosis through endothelial injury. Metabolically, obesity causes increased levels of atherogenic lipoproteins that are deposited on the leaflet wall of the aortic valve.”

BMI and aortic valve stenosis

In other findings, compared with an allele score of 0 to 3, individuals with an allele score of 7 to 10 had a mean increase in BMI of 0.87 kg/m2. Observationally, a 1 kg/m2 increase in BMI was associated with a greater risk for aortic valve stenosis (aHR = 1.06; 95% CI, 1.05-1.08) and valve replacement (aHR = 1.06; 95% CI, 1.03-1.08), according to the study.

“Our study showed that risk of aortic valve stenosis is higher in individuals with both high body mass index and high waist-hip ratio or waist circumference,” the researchers wrote. “However, whether the waist-hip ratio-associated single nucleotide polymorphisms have an effect on the incidence of aortic valve stenosis and replacement is unclear from our data, as is the question of whether overall and abdominal obesity would differentially influence aortic valve stenosis and replacement.”

Researchers used data from the Copenhagen General Population Study to assess BMI, waist-hip ratio, waist circumference and information on five genetic variants associated with obesity. In conjunction with the Mendelian randomization design, investigators were able to determine the associations of obesity with aortic valve stenosis and replacement for a median follow-up period of 8.7 years.

Regarding future research, “We need to understand how obesity leads to aortic valve stenosis,” Nordestgaard said in an interview. “We need to know whether weight loss in individuals with obesity will reduce aortic valve stenosis progression or severity.”

Related editorial

“A major limitation of Mendelian randomization relates to possible pleiotropic effects of the genetic variants used, ie, single genetic variants can affect multiple phenotypic traits, which means that this approach may not necessarily provide a proof of causality,” Cécile Oury, PhD, research director at the National Fund for Scientific Research, Belgium, and colleagues wrote in a related editorial. “In the study by Kaltoft et al, the use of allele scoring contributes to overcome this potential bias, which greatly strengthens their findings.” – by Scott Buzby

Disclosures: The research was supported in part by a grant from the Novo Nordisk Foundation. The authors and Oury report no relevant financial disclosures.

Børge G. Nordestgaard

Patients with a genetic predisposition for obesity may have an increased risk for aortic valve stenosis and valve replacement, according to research published in the Journal of the American College of Cardiology.

Using a Mendelian randomization design to assess the genetic and observational association between obesity and aortic valve stenosis, researchers found that patients with allele scores between 4 and 10 experienced an increased risk for aortic valve stenosis compared with patients with an allele score of 0 to 3 (P for trend = 9105).

Compared with scores between 0 and 3, the adjusted HRs for aortic valve stenosis and replacement were:

  • 1.3 (95% CI, 1-1.7) for an allele score of 4;
  • 1.4 (95% CI, 1.1-1.8) for a score of 5 to 6; and
  • 1.6 (95% CI, 1.3-2.1) for a score of 7 to 10.

“We wondered whether a previously reported association between high body mass index and increased risk of aortic valve stenosis is causal — or if obesity is only just a marker of disease risk,” Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen and chief physician of the department of clinical biochemistry at Copenhagen University Hospital, Denmark, told Healio. “The findings that genes increasing the risk of being overweight also increase the risk of aortic valve stenosis indicate that the relationship between obesity and aortic valve stenosis is causal.”

“The mechanism behind obesity causing aortic valve stenosis may be due to either structural changes of the heart or metabolic changes of the obese body,” Morten Kaltoft, MD, of the department of clinical biochemistry at the Herlev and Gentofte Hospital of Copenhagen University Hospital, Denmark, and colleagues wrote. “Structurally, obesity causes higher blood pressure, increasing stress on the heart, which could lead to geometric changes of the left ventricle and aortic valve, and high blood pressure could initiate atherosclerosis through endothelial injury. Metabolically, obesity causes increased levels of atherogenic lipoproteins that are deposited on the leaflet wall of the aortic valve.”

BMI and aortic valve stenosis

In other findings, compared with an allele score of 0 to 3, individuals with an allele score of 7 to 10 had a mean increase in BMI of 0.87 kg/m2. Observationally, a 1 kg/m2 increase in BMI was associated with a greater risk for aortic valve stenosis (aHR = 1.06; 95% CI, 1.05-1.08) and valve replacement (aHR = 1.06; 95% CI, 1.03-1.08), according to the study.

“Our study showed that risk of aortic valve stenosis is higher in individuals with both high body mass index and high waist-hip ratio or waist circumference,” the researchers wrote. “However, whether the waist-hip ratio-associated single nucleotide polymorphisms have an effect on the incidence of aortic valve stenosis and replacement is unclear from our data, as is the question of whether overall and abdominal obesity would differentially influence aortic valve stenosis and replacement.”

Researchers used data from the Copenhagen General Population Study to assess BMI, waist-hip ratio, waist circumference and information on five genetic variants associated with obesity. In conjunction with the Mendelian randomization design, investigators were able to determine the associations of obesity with aortic valve stenosis and replacement for a median follow-up period of 8.7 years.

Regarding future research, “We need to understand how obesity leads to aortic valve stenosis,” Nordestgaard said in an interview. “We need to know whether weight loss in individuals with obesity will reduce aortic valve stenosis progression or severity.”

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Related editorial

“A major limitation of Mendelian randomization relates to possible pleiotropic effects of the genetic variants used, ie, single genetic variants can affect multiple phenotypic traits, which means that this approach may not necessarily provide a proof of causality,” Cécile Oury, PhD, research director at the National Fund for Scientific Research, Belgium, and colleagues wrote in a related editorial. “In the study by Kaltoft et al, the use of allele scoring contributes to overcome this potential bias, which greatly strengthens their findings.” – by Scott Buzby

Disclosures: The research was supported in part by a grant from the Novo Nordisk Foundation. The authors and Oury report no relevant financial disclosures.