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Trimethylamine N ‐ Oxide and Mortality Risk in Patients With Peripheral Artery Disease

View Article: PubMed Central - PubMed

ABSTRACT

Background: Production of the proatherogenic metabolite, trimethylamine N‐oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis development in animal models and is associated with atherosclerotic coronary artery disease in humans. The utility of studying plasma levels of TMAO to risk stratify in patients with peripheral artery disease (PAD) has not been reported.

Methods and results: We examined the relationship between fasting plasma TMAO and all‐cause mortality (5‐year), stratified by subtypes of PAD and presence of coronary artery disease in 935 patients with PAD who underwent elective angiography for cardiac evaluation at a tertiary care hospital. Median plasma TMAO was 4.8 μmol/L (interquartile range, 2.9–8.0 μmol/L). Elevated TMAO levels were associated with 2.7‐fold increased mortality risk (fourth versus first quartiles, hazard ratio 2.86, 95% CI 1.82–3.97, P<0.001). Following adjustments for traditional risk factors, inflammatory biomarkers, and history of coronary artery disease, the highest TMAO quartile remained predictive of 5‐year mortality (adjusted hazard ratio 2.06, 95% CI 1.36–3.11, P<0.001). Similar prognostic value for elevated TMAO was seen for subjects with carotid artery, non–carotid artery, or lower extremity PAD. TMAO provided incremental prognostic value for all‐cause mortality (net reclassification index, 40.22%; P<0.001) and improvement in area under receiver operator characteristic curve (65.7% versus 69.4%; P=0.013).

Conclusions: TMAO, a pro‐atherogenic metabolite formed by gut microbes, predicts long‐term adverse event risk and incremental prognostic value in patients with PAD. These findings point to the potential for TMAO to help improve selection of high‐risk PAD patients with or without significant coronary artery disease, who likely need more aggressive and specific dietary and pharmacologic therapy.

No MeSH data available.


Related in: MedlinePlus

Relationship between plasma trimethylamine‐N‐oxide (TMAO) concentration and mortality risk stratified according to baseline characteristics. Forest plot of hazard ratio (squares) of 5‐year all‐cause mortality comparing first and fourth quartiles of plasma TMAO levels. Bars represent 95% CI. The wide confidence intervals in some subgroups are in part due to their small sample sizes and event rate. ApoA1 indicates apolipoprotein A1; ApoB, apolipoprotein B; eGFR, estimated glomerular filtration rate; hsCRP, high‐sensitivity C‐reactive protein; LDL, low‐density lipoprotein; LEAD, lower extremity peripheral artery disease; MPO, myeloperoxidase.
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jah31807-fig-0004: Relationship between plasma trimethylamine‐N‐oxide (TMAO) concentration and mortality risk stratified according to baseline characteristics. Forest plot of hazard ratio (squares) of 5‐year all‐cause mortality comparing first and fourth quartiles of plasma TMAO levels. Bars represent 95% CI. The wide confidence intervals in some subgroups are in part due to their small sample sizes and event rate. ApoA1 indicates apolipoprotein A1; ApoB, apolipoprotein B; eGFR, estimated glomerular filtration rate; hsCRP, high‐sensitivity C‐reactive protein; LDL, low‐density lipoprotein; LEAD, lower extremity peripheral artery disease; MPO, myeloperoxidase.

Mentions: Over the 5‐year follow‐up, 222 (27%) deaths occurred in our cohort. Nineteen patients (19/821=2%) were not reached at 5‐year follow‐up. As illustrated in the Kaplan–Meier analyses shown in Figure 3, a graded increase in risk for all‐cause mortality was observed with increasing plasma levels of TMAO. Elevated plasma TMAO levels were associated with a 2.7‐fold increased risk for all‐cause mortality (unadjusted HR=2.69, 95% CI 1.82–3.97, P<0.001) (Table 3). Following adjustments for traditional risk factors, history of CAD, statin use, and inflammatory marker including log‐transformed myeloperoxidase, log‐transformed hsCRP and apolipoprotein A‐1 and apolipoprotein B,, elevated plasma TMAO levels remained a significant predictor of the risk of 5‐year all‐cause mortality (adjusted HR 1.88, 95% CI 1.21–2.92, P=0.002), as well as after adjusting for traditional risk factor, log‐transformed hsCRP, and log‐transformed eGFR (adjusted HR 1.59, 95% CI 1.03–2.45, P=0.038) (Table 3). A similar graded increase in risk was observed when levels of TMAO were analyzed as a continuous variable in increments of 1 SD (unadjusted HR 1.53, 95% CI 1.35–1.74, P<0.001) and remained significant after adjusting for traditional risk factor, log‐transformed hsCRP and log‐transformed eGFR (adjusted HR 1.26, 95% CI 1.03–1.53, P=0.016). The inclusion of TMAO as a covariate resulted in a significant improvement in risk estimation over traditional risk factors (net reclassification improvement, 40.22%, [P<0.001]; Integrated Discrimination Improvement, 10.0%, [P<0.001]; and differences in area under the receiver‐operating characteristic curve 65.69 versus 69.42, P=0.013). Interestingly, mortality risks were similar between PAD diagnosis subgroups (between CAS, non‐CAS, and LEAD), as well as other clinical and laboratory subgroups that might be affected for mortality risks (Figure 4).


Trimethylamine N ‐ Oxide and Mortality Risk in Patients With Peripheral Artery Disease
Relationship between plasma trimethylamine‐N‐oxide (TMAO) concentration and mortality risk stratified according to baseline characteristics. Forest plot of hazard ratio (squares) of 5‐year all‐cause mortality comparing first and fourth quartiles of plasma TMAO levels. Bars represent 95% CI. The wide confidence intervals in some subgroups are in part due to their small sample sizes and event rate. ApoA1 indicates apolipoprotein A1; ApoB, apolipoprotein B; eGFR, estimated glomerular filtration rate; hsCRP, high‐sensitivity C‐reactive protein; LDL, low‐density lipoprotein; LEAD, lower extremity peripheral artery disease; MPO, myeloperoxidase.
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jah31807-fig-0004: Relationship between plasma trimethylamine‐N‐oxide (TMAO) concentration and mortality risk stratified according to baseline characteristics. Forest plot of hazard ratio (squares) of 5‐year all‐cause mortality comparing first and fourth quartiles of plasma TMAO levels. Bars represent 95% CI. The wide confidence intervals in some subgroups are in part due to their small sample sizes and event rate. ApoA1 indicates apolipoprotein A1; ApoB, apolipoprotein B; eGFR, estimated glomerular filtration rate; hsCRP, high‐sensitivity C‐reactive protein; LDL, low‐density lipoprotein; LEAD, lower extremity peripheral artery disease; MPO, myeloperoxidase.
Mentions: Over the 5‐year follow‐up, 222 (27%) deaths occurred in our cohort. Nineteen patients (19/821=2%) were not reached at 5‐year follow‐up. As illustrated in the Kaplan–Meier analyses shown in Figure 3, a graded increase in risk for all‐cause mortality was observed with increasing plasma levels of TMAO. Elevated plasma TMAO levels were associated with a 2.7‐fold increased risk for all‐cause mortality (unadjusted HR=2.69, 95% CI 1.82–3.97, P<0.001) (Table 3). Following adjustments for traditional risk factors, history of CAD, statin use, and inflammatory marker including log‐transformed myeloperoxidase, log‐transformed hsCRP and apolipoprotein A‐1 and apolipoprotein B,, elevated plasma TMAO levels remained a significant predictor of the risk of 5‐year all‐cause mortality (adjusted HR 1.88, 95% CI 1.21–2.92, P=0.002), as well as after adjusting for traditional risk factor, log‐transformed hsCRP, and log‐transformed eGFR (adjusted HR 1.59, 95% CI 1.03–2.45, P=0.038) (Table 3). A similar graded increase in risk was observed when levels of TMAO were analyzed as a continuous variable in increments of 1 SD (unadjusted HR 1.53, 95% CI 1.35–1.74, P<0.001) and remained significant after adjusting for traditional risk factor, log‐transformed hsCRP and log‐transformed eGFR (adjusted HR 1.26, 95% CI 1.03–1.53, P=0.016). The inclusion of TMAO as a covariate resulted in a significant improvement in risk estimation over traditional risk factors (net reclassification improvement, 40.22%, [P<0.001]; Integrated Discrimination Improvement, 10.0%, [P<0.001]; and differences in area under the receiver‐operating characteristic curve 65.69 versus 69.42, P=0.013). Interestingly, mortality risks were similar between PAD diagnosis subgroups (between CAS, non‐CAS, and LEAD), as well as other clinical and laboratory subgroups that might be affected for mortality risks (Figure 4).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Production of the proatherogenic metabolite, trimethylamine N&#8208;oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis development in animal models and is associated with atherosclerotic coronary artery disease in humans. The utility of studying plasma levels of TMAO to risk stratify in patients with peripheral artery disease (PAD) has not been reported.

Methods and results: We examined the relationship between fasting plasma TMAO and all&#8208;cause mortality (5&#8208;year), stratified by subtypes of PAD and presence of coronary artery disease in 935 patients with PAD who underwent elective angiography for cardiac evaluation at a tertiary care hospital. Median plasma TMAO was 4.8&nbsp;&mu;mol/L (interquartile range, 2.9&ndash;8.0&nbsp;&mu;mol/L). Elevated TMAO levels were associated with 2.7&#8208;fold increased mortality risk (fourth versus first quartiles, hazard ratio 2.86, 95% CI 1.82&ndash;3.97, P&lt;0.001). Following adjustments for traditional risk factors, inflammatory biomarkers, and history of coronary artery disease, the highest TMAO quartile remained predictive of 5&#8208;year mortality (adjusted hazard ratio 2.06, 95% CI 1.36&ndash;3.11, P&lt;0.001). Similar prognostic value for elevated TMAO was seen for subjects with carotid artery, non&ndash;carotid artery, or lower extremity PAD. TMAO provided incremental prognostic value for all&#8208;cause mortality (net reclassification index, 40.22%; P&lt;0.001) and improvement in area under receiver operator characteristic curve (65.7% versus 69.4%; P=0.013).

Conclusions: TMAO, a pro&#8208;atherogenic metabolite formed by gut microbes, predicts long&#8208;term adverse event risk and incremental prognostic value in patients with PAD. These findings point to the potential for TMAO to help improve selection of high&#8208;risk PAD patients with or without significant coronary artery disease, who likely need more aggressive and specific dietary and pharmacologic therapy.

No MeSH data available.


Related in: MedlinePlus