Tag: Stroke

Posted on by

Gout flares associated with subsequent cardiovascular events

Gout flares associated with subsequent cardiovascular events

Experts at the University of Nottingham, in collaboration with experts at Keele University, have found that the risk of heart attacks and strokes temporarily increases in the four months after a gout flare.

The research showed that gout patients who suffered from a heart attack or stroke were twice as likely to have had a gout flare in the 60 days prior to the event, and one and a half times more likely to have a gout flare in the 61-120 days prior.

The results of the study, led by Professor Abhishek in the School of Medicine at the University of Nottingham, are published in the journal JAMA.

Gout is a common form of arthritis that affects one in 40 adults in the UK. It is caused by high levels of uric acid, a chemical produced by breakdown of tissues in the body and present in certain foods and drinks.

At high levels, uric acid is deposited in and around joints as needle shaped urate crystals. Once released from their deposits, these crystals cause severe inflammation manifesting as joint pain, swelling, redness, and tenderness that often lasts for 1-2 weeks. These episodes, called gout flares, often recur. Inflammation is also a risk factor for heart attack and stroke.

People with gout tend to have more cardiovascular risk factors, although there have been no previous studies about whether gout flares are linked with an increased risk of heart attack and stroke. In this study, the experts examined whether there was a temporary increase in risk of heart attack or stroke after a gout flare.

The team used anonymized data from 62,574 patients with gout treated in the National Health Service in the UK. Of these, 10,475 experienced heart attack or stroke after the diagnosis of gout, while others of similar age, sex, and duration of gout, did not experience such events. They evaluated the association between heart attacks or strokes and recent gout flares and adjusted these results for comorbidities, socioeconomic deprivation, lifestyle factors and prescribed medications among other things. They found that gout patients who suffered a heart attack or stroke were twice as likely to have had a gout flare in the 60 days prior to the event, and one and a half times more likely to have a gout flare in the preceding 61-120 days.

They found a similar high rate of heart attack or stroke in the 0-60 and 61-120 days after gout flares compared with other time periods, when they used information from only patients who consulted for a gout flare and also experienced either heart attack or stroke. This further strengthened the finding that gout flares are associated with a transient increase in cardiovascular events following flares. The increased odds and rates persisted when people with pre-existing heart disease or stroke before their gout diagnosis were excluded, and when shorter exposure periods such as 0-15 and 16-30 days prior to heart attack or stroke, were considered.

Gout patients who died from a heart attack or stroke had over four times the odds of experiencing a gout flare in the preceding 0-60 days and over twice the odds of gout flare in the preceding 61-120 days.

This is the first study of its kind to examine whether there is an association between recent gout flares and heart attacks and strokes.


The results show that among patients with gout, patients who experienced a heart attack or stroke had significantly increased odds of a gout flare during the preceding 120-days compared with patients who did not experience such events. These findings suggest that gout flares are associated with a transient increase in cardiovascular events following flares.


People with recurrent gout flares should be considered for long-term treatment with urate lowering treatments such as allopurinol. This is a reliable way of removing urate crystal deposits and providing freedom from gout flares. Patients should also be considered for concurrent treatment with anti-inflammatory medicines such as colchicine for the first few months because urate lowering treatments may trigger gout flares in the short term.


People with gout should be encouraged to adopt a healthy lifestyle with appropriate treatment of conditions such as high blood pressure, high cholesterol, obesity and diabetes to minimise their background risk of heart attack and stroke”


Professor Abhishek, lead author on the study

Source:

Journal reference:

Cipolletta, E., et al. (2022) Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout. JAMA. doi.org/10.1001/jama.2022.11390.

Posted on by

Step Up for Stroke Event – GlobalNews Events

Step Up for Stroke Event - GlobalNews Events

62,000 people across Canada have a stroke every year. It changes lives, and no one should go through that alone.

That’s why March of Dimes Canada is calling on everyone to Step Up for Stroke.

Anyone, anywhere, can get involved in this exciting national fundraiser. Here’s how:

  • Choose an activity you enjoy and set a goal for the month of June – bike 62 kms, walk 62,000 steps, cook 62 meals, swim 62 laps – anything you can safely and comfortably do.
  • Register on stepupforstroke.ca.
  • Invite people you know to step up and donate.

All the money raised will go directly towards March of Dimes Canada’s After Stroke program, which provides personalized support to stroke survivors and their caregivers.

“Identifying and accessing community supports and services can be difficult and overwhelming for many people discharged from hospital following a stroke,” says Christina Sperling, Director of Community Programs and After Stroke. “The After Stroke program fills this critical gap and provides participants with a true sense of community and inclusion, helping them feel supported and see real progress in their recovery.”

Here in Halifax, a Step Up for Stroke event is taking place on Saturday, June 25th at 1 pm at the Emera Oval. “We’re very excited to be able to host an in-person event again,” says Rebecca Bourbonnais, Regional Manager at March of Dimes Canada. “Especially for such an important cause, we encourage everyone impacted by stroke to come and hear more about our program at our inaugural event sponsored by Lawtons.

“The kind, considerate encouragement received from the After Stroke Coordinator helped us see a path forward in our post stroke recovery. The support allowed us to ask questions, to shift perceptions and to truly understand that this is a journey and that everything takes time. The reminder that ‘it has only been a few months’ and ‘people continue to recover from stroke years later’ gave us confidence for the future. We are beyond thankful and grateful for the support that the After Stroke program has given us.” says a Halifax couple enrolled in the program.

Posted on by

Analysis finds little proof that testosterone treatment increases the risk of cardiovascular events

Analysis finds little proof that testosterone treatment increases the risk of cardiovascular events

Testosterone replacement therapy appears safe in the short-to-medium term to treat a condition caused by deficiency of the male sex hormone, according to the most comprehensive analysis of the treatment to date, published in The Lancet Healthy Longevity journal.

The findings suggest that men given testosterone to treat hypogonadism are at no greater risk of heart attack, stroke, and other cardiovascular events in the short-to-medium term than men who do not receive testosterone treatment.

Testosterone replacement therapy is the standard treatment for hypogonadism, which can cause sexual dysfunction, weakening of bones and muscles, and reduced quality of life. Risk factors for the condition include aging (as testosterone levels decline with age), obesity (BMI of 30 kg/m2 or above), and diabetes.

Despite being widely used, the cardiovascular safety of testosterone treatment has until now remained unclear due to inconsistent findings. This is because most previous clinical studies have relied on aggregate data, rather than individual participant data and have not published details of individual adverse events.

Prescribing of testosterone for hypogonadism is increasing globally, but conflicting messages about its safety may have led to many patients not receiving the treatment. Ongoing studies should help to determine the longer-term safety of testosterone but, in the meantime, our results provide much-needed reassurance about its short-to-medium term safety. Our findings could have important implications for the treatment of men with hypogonadism worldwide.”


Jemma Hudson, Study Lead Author, University of Aberdeen

The authors conducted a systematic review identifying 35 eligible clinical trials published since 1992, of which 17 provided individual participant data. A blinded analysis by two independent clinicians enabled the classification of every cardiovascular event, allowing for a more robust analysis of the cardiovascular safety of testosterone treatment.

A meta-analysis using individual participant data from 17 studies and a further meta-analysis integrating these data with the aggregate data provided by the 18 trials that did not provide individual participant data were performed.

Among the 17 trials with individual patient data, 1,750 participants received testosterone and 1,681 were given a placebo. The average length of testosterone treatment was 9.5 months. The average age of participants was 65 years, and most were white and did not smoke. Participants’ average BMI was 30 kg/m2, which is considered obese.

A meta-analysis showed there were 120/1,601 (7.5%) cardiovascular events in the testosterone group and 110/1,519 (7.2%) in the placebo group across 13 trials that provided this information. Patient age, smoking or diabetes status did not affect cardiovascular risk. Similarly, there was no significant difference in mortality rate between the testosterone group (6/1,621 deaths, 0.4%) and the placebo group (12/1,537 deaths, 0.8%) across the 14 trials that provided individual patient data on mortality, but only limited data were available.

The researchers also found that testosterone significantly reduced serum total cholesterol, high-density lipoprotein (HDL), and triglycerides compared with placebo. However, there were no significant differences in serum low-density lipoprotein (LDL), blood pressure, glycaemic parameters, diabetes incidence, and prostate adverse outcomes between the testosterone and placebo groups.

The meta-analysis that integrated individual participant data with aggregate data showed similar results.

The authors acknowledge some limitations to their study. There was little available data evaluating the cardiovascular safety of testosterone treatment beyond 12 months, and the very small number of deaths recorded during testosterone trials hampered the authors’ ability to analyze why they occurred.

However, the longer-term safety of testosterone treatment is currently being investigated in another clinical trial. While the meta-analysis of aggregate data showed similar results to the one involving individual patient data only, it cannot be ruled out with certainty that a high number of unreported cardiovascular events in the trials that did not provide individual participant data could alter the current conclusions.

Source:

Journal reference:

Hudson, J., et al. (2022) Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. The Lancet Healthy Longevity. doi.org/10.1016/S2666-7568(22)00096-4

Posted on by

Clopidogrel monotherapy linked with reduced risk of net adverse clinical events, study finds

Clopidogrel monotherapy linked with reduced risk of net adverse clinical events, study finds

Results from a real-world study investigating safety and effectiveness of clopidogrel versus aspirin monotherapy beyond 12 months after PCI in high-risk patients during the chronic maintenance period. This study found that clopidogrel monotherapy was associated with reduced risk of net adverse clinical events (NACE; all-cause death, MI, stent thrombosis, stroke, or BARC type 2, 3, or 5 bleeding) and MACCE (death, MI, stent thrombosis, stroke), and a numerical decrease in major or clinically relevant nonmajor bleeding (BARC type 2, 3, or 5 bleeding), compared with aspirin monotherapy. The findings were presented today as late-breaking clinical research at the Society for Cardiovascular Angiography & Interventions (SCAI) 2022 Scientific Sessions.

P2Y12 inhibitor monotherapy reduces bleeding risk without increasing the risk of ischemic events compared with dual antiplatelet therapy (DAPT), especially in the first 12 months following percutaneous coronary intervention (PCI). Recent research showed that among patients who were event free for six to 18 months post-PCI and successfully received the intended duration of DAPT, clopidogrel monotherapy was superior compared with aspirin monotherapy in terms of NACE. However, optimal antiplatelet monotherapy during the chronic maintenance period beyond 12 months after PCI with drug-eluting stents in high-risk patients in real-world settings is previously unknown.

In total, 8,377 consecutive patients at high risk for both bleeding and thrombosis were identified from the prospective Fuwai PCI Registry if they satisfied one clinical and one angiographic criterion. Patients who received antiplatelet (aspirin or clopidogrel) monotherapy longer than 12 months and were free from ischemic and bleeding events at 12-month post-PCI without extended duration of DAPT were included. The primary endpoint was net adverse clinical events (NACE) from 12 to 30 months. The key secondary endpoints were major adverse cardiac or cerebral events (MACCE) and major or clinically relevant nonmajor bleeding (BARC type 2, 3 or 5).

“These findings show for the first time clopidogrel monotherapy is associated with reduced risk of long-term NACE and MACCE,” said Hao-Yu Wang, Cardiometabolic Medicine Center, Coronary Heart Disease Center, Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. “Our results may have important practical implications for determining the optimal treatment for patients requiring a single antiplatelet drug, either aspirin or clopidogrel, for secondary prevention of ischemic events in high-risk PCI population.”

Of 7,392 high-risk patients that were event-free after the first year and adherent to DAPT, 5,664 patients who received antiplatelet monotherapy (clopidogrel monotherapy: n=1,974 and aspirin monotherapy: n=3690) were included in the present analysis. Researchers found that between 12 and 30 months, the net adverse clinical events were lower with clopidogrel monotherapy compared to aspirin monotherapy (Kaplan-Meier estimate: 2.5% vs. 5.0%; adjusted HR:0.566, 95% CI: 0.403-0.795). Clopidogrel monotherapy was associated with lower risk for MACCE (Kaplan-Meier estimate: 1.0% vs. 3.1%, log-rank p = 0.001 ), as well as lower incidence rates of all-cause death, MI, and stroke. The difference in risk between the groups was statistically similar for major or clinically relevant nonmajor bleeding (Kaplan-Meier estimate: 1.5% vs. 2.1%, log-rank p = 0.199).

Researchers recommended that their findings should be further investigated through a randomized clinical trial.

Source:

Society for Cardiovascular Angiography and Interventions

Posted on by

Takotsubo Syndrome Also Linked to Happy Life Events

Takotsubo Syndrome Also Linked to Happy Life Events

Takotsubo syndrome, a condition that’s also been called “broken heart syndrome,” can be triggered by both positive and negative life stressors, especially in men, a new study suggests.

The findings show that although Takotsubo syndrome, a type of acute heart failure related to atypical patterns of transient left ventricular contraction abnormalities, is often triggered by negative emotional stressors, it can also stem from positive life events, something the researchers are calling “happy heart syndrome.”

In this registry study, males were more likely to experience Takotsubo syndrome from a positive life event, as were those with atypical, nonapical ballooning, report Thomas Stiermaier, MD, of the University Hospital Schleswig-Holstein in Lübeck, Germany, and colleagues.

Patients with negative and positive emotional triggers experienced similar short- and long-term outcomes, they found.

The results were published online May 4 in the JACC: Heart Failure.

Previous studies have shown that Takotsubo syndrome can be related to negative emotional triggers, physical triggers such as heavy physical activity or medical procedures (or, in some cases, neither of these), or even a combination of emotional and physical triggers, the authors say. Research shows that physical triggers are most often linked to poor outcomes.

A vast number of clinical scenarios may lead up to Takotsubo syndrome, noted Jason H. Rogers, MD, a professor of cardiovascular medicine at the University of California, Davis, Medical Center, commenting on these findings.

“Examples would include other medical illness, such as infection or recent surgery, having a heated argument with someone, running to catch a flight at the airport, and even being awakened suddenly by a sick pet,” Rogers told theheart.org | Medscape Cardiology.

But not all patients experience unhappy life stressors before these events occur, he added. “It is possible for patients to have happy life stressors that can lead to Takotsubo syndrome also.”

For this analysis, the research team evaluated 2482 patients using data from the multicenter GErman-Italian-Spanish Takotsubo (GEIST) Registry, one of the largest of its kind. Of these patients, 910 experienced an emotional trigger; of these, 873 had negative preceding events, and 37 had pleasant preceding events. The mean age was about 70 years in both groups.

The study team then compared patients with negative emotional triggers to those with positive emotional triggers, which included weddings, the birth of grandchildren, birthday parties, or anticipation of a trip or Christmas.

There was a 1.5% incidence of pleasant emotional triggers among all Takotsubo syndrome patients.

Among patients with positive prior triggers, there was a higher incidence of atypical ballooning (27.0% vs 12.5%; P = .01), and a higher percentage of these patients were male (18.9% vs 5.0%; P < .01) in comparison with those with negative events prior to Takotsubo syndrome.

Long-term death rates (8.8% vs 2.7%; P = .20) and rates of in-hospital complication outcomes, including cardiogenic shock, stroke, death, or pulmonary edema (12.3% vs 8.1%; P = .45), were similar for patients with negative preceding events and for those with positive preceding events.

Study limitations include that it cannot provide insight into the specific mechanisms of Takotsubo syndrome, it was observational, the sample size of patients in the positive events group was small, and the contributing research facilities assessed cardiac biomarker levels differently.

“Additional research efforts are needed to explore whether numerically lower cardiac-related event rates in patients with happy heart syndrome would be statistically significant in a larger sample size,” the researchers conclude.

Stiermaier reports no relevant financial relations.

JACC Heart Fail. Published online May 4, 2022. Full text

Ashley Lyles is an award-winning medical journalist. She is a graduate of New York University’s Science, Health, and Environmental Reporting Program. Previously, she studied professional writing at Michigan State University, where she also took premedical classes. Her work has taken her to Honduras, Cambodia, France, and Ghana and has appeared in outlets such as The New York Times Daily 360, PBS NewsHour, The Huffington Post, Undark, The Root, Psychology Today, Insider, and Tonic (Health by Vice), among other publications.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Posted on by

Leakage after left atrial appendage occlusion associated with higher risk of adverse events

Leakage after left atrial appendage occlusion associated with higher risk of adverse events

Patients who had leakage to the left atrial appendage due to incomplete device sealing after left atrial appendage occlusion (LAAO) experienced more clotting and bleeding events within a year following their procedure compared with patients who had no leaking, according to a study presented at the American College of Cardiology’s 71st Annual Scientific Session.

The study, which included data from more than 50,000 patients, is by far the largest to date to assess how leaking after LAAO affects the likelihood of adverse health outcomes. The results suggest that even small leaks are associated with a 10%-15% higher risk of adverse events.

Our study shows that any leak matters, and we should find ways to optimize the procedure to minimize the proportion of patients who end up with leaks. Because this is a preventative procedure, it is important to find ways to master this and prevent leaks from happening. Fortunately, there are indications that leaking might be less common with newer devices and improved techniques.”


Mohamad Alkhouli, MD, professor of medicine at Mayo Clinic and study’s lead author

Stroke is a major concern in patients with atrial fibrillation (AFib), the most common heart rhythm disorder. Blood thinners are the primary medical option for reducing the risk of strokes, which are caused when a blood clot blocks an artery in the brain; however, blood thinners are not suitable for many patients due to drug interactions, bleeding complications, cost, frequent blood checks with warfarin or other reasons. The WATCHMAN device, approved by the U.S. Food and Drug Administration in 2015, is designed to help prevent strokes by sealing off the heart’s left atrial appendage where blood can pool and clot. It is now widely used to reduce the risk of stroke in patients with AFib who cannot tolerate long-term use of blood thinners.

For the study, researchers analyzed data from 51,333 patients who underwent LAAO procedures with the WATCHMAN device between 2016-2019 as recorded in the ACC’s LAAO Registry, a database that includes nearly all LAAO procedures conducted in the U.S. and is part of the College’s NCDR registries. Echocardiograms were used to classify the size of any leaks around the device an average of 45 days after a LAAO procedure, a standard part of the clinical follow-up for this procedure. Registry data also included information about subsequent adverse health events occurring in the years after the procedure.

Overall, researchers found that 73.4% of patients had no leaks, 25.8% had small leaks (greater than zero but less than 5 millimeters across) and 0.7% had large leaks (greater than 5 millimeters)—proportions similar to those reported in previous registry studies and clinical trials.

While relatively few patients—roughly 2%-3%—experienced adverse events in the year following their LAAO procedure, the researchers found that the relative risk of these events varied significantly between patients with and without leaks. Compared to patients who had no leaking, those with small leaks had a 10% higher relative risk of suffering any major adverse events, an 11% higher relative risk of major bleeding complications, and a 15% higher relative risk of clotting-related events, including stroke, systemic embolization and transient ischemic attacks.

The study revealed no significant differences in the rate of adverse events between patients with large leaks and those with small or no leaks, which Alkhouli said is likely due to the use of anticoagulants in these patients. Instructions for the WATCHMAN device indicate that patients who have residual leaks greater than 5 millimeters across should be considered to have a failed procedure, and they are generally treated with anticoagulants.

Alkhouli said leaking is relatively common with LAAO procedures because the size and shape of the left atrial appendage varies widely from person to person, which can make it difficult for operators to position the device in a way that completely seals off the appendage. He noted that the shape of the appendage portion where the leaked blood flows into could affect the associated risks. More recent technologies, such as the use of CT scans to image the appendage and software that allows users to practice the procedure virtually before operating on a patient, could help operators place the WATCHMAN device in a more optimal position. Alkhouli said newer generation WATCHMAN device designs, which were introduced in 2021, could also help to reduce the risk in some patients.

The study was based on registry data reflecting real-world practices, meaning variations in the measurement of leaks could exist and may impact the results of the study, Alkhouli said. He added that future studies could help clarify whether using blood thinners in some patients with leaks smaller than 5 millimeters would be helpful in reducing stroke risk.

This study was simultaneously published online in the JACC: Clinical Electrophysiology at the time of presentation. The study was funded by Boston Scientific, maker of the WATCHMAN device.

Alkhouli will present the study, “Residual Leaks Post Left Atrial Appendage Occlusion,” on Sunday, April 3, at 12:15 p.m. ET / 16:15 UTC in the Main Tent, Hall D.

Source:

American College of Cardiology

Posted on by

Heart complications after a stroke increase the risk of future cardiovascular events

Heart complications after a stroke increase the risk of future cardiovascular events
stroke
A blood clot forming in the carotid artery. Credit: copyright American Heart Association

People who survive an ischemic stroke are much more likely to develop major heart complications during the first month after their stroke, and, as a result, they also have an increased risk of death, heart attack or another stroke within five years, compared to people who don’t develop heart problems soon after a stroke, according to new research published today in Stroke.

Ischemic stroke is the most common type of stroke—accounting for 87% of all strokes—and occurs when blood flow to the brain is blocked. After a stroke, people often have cardiovascular complications, known as stroke-heart syndrome. Heart complications include acute coronary syndrome, angina (chest pain), heart rhythm issues such as atrial fibrillation, arrhythmia and ventricular fibrillation; heart attack; heart failure or Takotsubo syndrome (broken heart syndrome), a type of stress-induced temporary enlargement of a part of the heart that impacts its ability to pump effectively. These conditions increase the risk of disability or death in the short term, yet the long-term consequences for people with stroke-heart syndrome is unknown.

“We know heart disease and stroke share similar risk factors, and there’s a two-way relationship between the risk of stroke and heart disease. For example, heart conditions such as atrial fibrillation increase the risk of stroke, and stroke also increases the risk of heart conditions,” said Benjamin J.R. Buckley, Ph.D., lead author of the study and a postdoctoral research fellow in preventive cardiology at the Liverpool Centre for Cardiovascular Science, University of Liverpool in the United Kingdom. “We wanted to know how common newly diagnosed heart complications are after a stroke and, importantly, whether stroke-heart syndrome is associated with increased risk of long-term major adverse events.”

Researchers analyzed the medical records of more than 365,000 adults treated for ischemic stroke at more than 50 health care sites predominantly in the United States, between 2002 and 2021. People who were diagnosed with stroke-heart complications within four weeks after a stroke were matched to an equal number of stroke survivors who did not have these heart complications within four weeks (the control group).

After adjusting for potential confounding factors, such as age, sex and race/ethnicity, and comparing the stroke survivors who had new heart complications to those who did not, the analysis found:

  • Overall, among all stroke survivors in the study, about 1 in 10 (11.1%) developed acute coronary syndrome, 8.8% were diagnosed with atrial fibrillation, 6.4% developed heart failure, 1.2% exhibited severe ventricular arrythmias and 0.1% developed ‘broken heart’ syndrome within four weeks after the stroke.
  • Risk of death within five years after a stroke significantly increased among the participants with new heart complications: 49% more likely if they had developed acute coronary syndrome; 45% more likely if they had developed atrial fibrillation/flutter; and 83% more likely if they developed heart failure. Severe ventricular arrhythmias doubled the risk of death.
  • Chance of hospitalization and heart attack within five years after a stroke was also significantly higher among those who developed heart complications within the one-month window.
  • Stroke survivors with Takotsubo syndrome were 89% more likely to have a major heart event within the five years after their stroke.
  • People who developed atrial fibrillation after stroke were 10% more likely to have a second stroke within five years after their stroke.
  • People with stroke and newly diagnosed cardiovascular complications were 50% more likely to have a recurrent stroke within five years after the first stroke.

“I was particularly surprised by how common stroke-heart syndrome was and the high rate of recurrent stroke in all subgroups of adults with stroke-heart syndrome” Buckley said. “This means that this is a high-risk population where we should focus more secondary prevention efforts.”

The study’s results build on the understanding of the two-way link between the brain and the heart and extend this understanding to long-term health outcomes. “We are working on additional research to determine how stroke-heart syndrome may be better predicted,” Buckley said.

“We also need to develop and implement treatments to improve outcomes for people with stroke-heart syndrome,” Buckley said. “For example, comprehensive exercise-based rehabilitation may be helpful after a stroke, so for people with stroke and newly developed heart complications, it should also be beneficial, maybe even more so. I think this is an interesting area for future research.”

Study limitations include that it is a retrospective analysis and knowing whether the heart complications diagnosed following an ischemic stroke were caused by stroke or rather contributed to the stroke, is unclear.

“This research underscores why it’s so important for neurologists and cardiologists to work hand-in-hand with their patients and each other to understand why the first stroke occurred and perform a comprehensive assessment to identify new risk factors for another stroke and for cardiovascular disease that may require initiation of prevention therapies,” said Lee H. Schwamm, M.D., volunteer chair of the American Stroke Association Advisory Committee and the C. Miller Fisher Chair in Vascular Neurology at Massachusetts General Hospital in Boston. “The American Stroke Association recommends a personalized secondary stroke prevention plan for every stroke survivor.”

Even with statins, high triglycerides may increase risk of second stroke

More information:
Stroke (2022). www.ahajournals.org/doi/STROKEAHA.121.037316

Provided by
American Heart Association


Citation:
Heart complications after a stroke increase the risk of future cardiovascular events (2022, March 31)
retrieved 31 March 2022
from https://medicalxpress.com/news/2022-03-heart-complications-future-cardiovascular-events.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.

Posted on by

People with elevated blood pressure upon standing more likely to have risk for cardiovascular events

People with elevated blood pressure upon standing more likely to have risk for cardiovascular events

Among young and middle-aged adults with high blood pressure, a substantial rise in blood pressure upon standing may identify those with a higher risk of serious cardiovascular events, such as heart attack and stroke, according to new research published today in the American Heart Association’s peer-reviewed journal Hypertension.

This finding may warrant starting blood-pressure-lowering treatment including medicines earlier in patients with exaggerated blood pressure response to standing.”


Paolo Palatini, M.D., lead author of the study and professor of internal medicine at the University of Padova in Padova, Italy

Nearly half of Americans and about 40% of people worldwide have high blood pressure, considered to be the world’s leading preventable cause of death. According to the American Heart Association’s 2022 heart disease statistics, people with hypertension in mid-life are five times more likely to have impaired cognitive function and twice as likely to experience reduced executive function, dementia and Alzheimer’s disease.

Typically, systolic (top number) blood pressure falls slightly upon standing up. In this study, researchers assessed whether the opposite response – a significant rise in systolic blood pressure upon standing – is a risk factor for heart attack and other serious cardiovascular events.

The investigators evaluated 1,207 people who were part of the HARVEST study, a prospective study that began in Italy in 1990 and included adults ages 18-45 years old with untreated stage 1 hypertension. Stage 1 hypertension was defined as systolic blood pressure of 140-159 mm Hg and/or diastolic BP 90-100 mm Hg. None had taken blood pressure-lowering medication prior to the study, and all were initially estimated at low risk for major cardiovascular events based on their lifestyle and medical history (no diabetes, renal impairment or other cardiovascular diseases). At enrollment, participants were an average age of 33 years, 72% were men, and all were white.

At enrollment, six blood pressure measurements for each participant were taken in various physical positions, including when lying down and after standing up. The 120 participants with the highest rise (top 10%) in blood pressure upon standing averaged an 11.4 mm Hg increase; all increases in this group were greater than 6.5 mm Hg. The remaining participants averaged a 3.8 mm Hg fall in systolic blood pressure upon standing.

The researchers compared heart disease risk factors, laboratory measures and the occurrence of major cardiovascular events (heart attack, heart-related chest pain, stroke, aneurysm of the aortic artery, clogged peripheral arteries) and chronic kidney disease among participants in the two groups. In some analyses, the development of atrial fibrillation, an arrhythmia that is a major risk factor for stroke, was also noted. Results were adjusted for age, gender, parental history of heart disease, and several lifestyle factors and measurements taken during study enrollment.

During an average 17-year follow-up 105 major cardiovascular events occurred. The most common were heart attack, heart-related chest pain and stroke.

People in the group with top 10% rise in blood pressure:

  • were almost twice as likely as other participants to experience a major cardiovascular event;

  • did not generally have a higher risk profile for cardiovascular events during their initial evaluation (outside of the exaggerated blood pressure response to standing);

  • were more likely to be smokers (32.1% vs. 19.9% in the non-rising group), yet physical activity levels were comparable, and they were not more likely to be overweight or obese, and no more likely to have a family history of cardiovascular events;

  • had more favorable cholesterol levels (lower total cholesterol and higher high-density-lipoprotein cholesterol);

  • had lower systolic blood pressure when lying down than the other group (140.5 mm Hg vs. 146.0 mm Hg, respectively), yet blood pressure measures were higher when taken over 24 hours.

After adjusting for average blood pressure taken over 24 hours, an exaggerated blood pressure response to standing remained an independent predictor of adverse heart events or stroke.

“The results of the study confirmed our initial hypothesis – a pronounced increase in blood pressure from lying to standing could be prognostically important in young people with high blood pressure. We were rather surprised that even a relatively small increase in standing blood pressure (6-7 mm Hg) was predictive of major cardiac events in the long run,” said Palatini.

In a subset of 630 participants who had stress hormones measured from 24-hour urine samples, the epinephrine/creatinine ratio was higher in the people with a rise in standing blood pressure compared to those whose standing blood pressure did not rise (118.4 nmol/mol vs. 77.0 nmol/mol, respectively).

“Epinephrine levels are an estimate of the global effect of stressful stimuli over the 24 hours. This suggests that those with the highest blood pressure when standing may have an increased sympathetic response [the fight-or-flight response] to stressors,” said Palatini. “Overall, this causes an increase in average blood pressure.”

“The findings suggest that blood pressure upon standing should be measured in order to tailor treatment for patients with high blood pressure, and potentially, a more aggressive approach to lifestyle changes and blood-pressure-lowering therapy may be considered for people with an elevated [hyperreactor] blood pressure response to standing,” he said.

Results from this study may not be generalizable to people from other ethnic or racial groups since all study participants reported white race/ethnicity. In addition, there were not enough women in the sample to analyze whether the association between rising standing blood pressure and adverse heart events was different among men and women. Because of the relatively small number of major adverse cardiac events in this sample of young people, the results need to be confirmed in larger studies.

Source:

American Heart Association

Journal reference:

Palatini, P., et al. (2022) Blood Pressure Hyperreactivity to Standing: a Predictor of Adverse Outcome in Young Hypertensive Patients. Hypertension. doi.org/10.1161/HYPERTENSIONAHA121.18579.

Posted on by

Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diab | DMSO

Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diab | DMSO

Introduction

Type 2 diabetes has been considered a vital risk factor for promoting the occurrence and/or development of cardiovascular disease (CVD), such as stroke and coronary heart disease (CHD), and CVD mortality.1–3 Previous studies have shown that individuals with type 2 diabetes may have different severities of the disease, which depends on the presence of comorbidities or other risk factors.4 Well-understood risk heterogeneity and identifying individuals at long-term risk could help improve and personalize cardiovascular risk management for these individuals with type 2 diabetes.

Activation of the renin-angiotensin system (RAS) is a vital pathophysiological mechanism of CVD and renal insufficiency in diabetic patients.5 Many previous observational studies have demonstrated that inhibiting the RAS, which is currently the front-line treatment for diabetic nephropathy,5 could delay worsening renal function and reduce the risk of CVD morbidity and mortality in patients with diabetes.6–8 Importantly, although RAS inhibition has shown many beneficial effects, not all patients showed significant improvements in the prognosis of CVD complications. Hence, accurately estimating the active state of the intrarenal RAS might provide a good opportunity to help identify whether diabetic patients are at high risk of poor prognosis. The kidney has all parts of the RAS pathway that can produce angiotensinogen, which further promotes the production of angiotensin II (angII).9 AngII, produced by the kidney, has been reported to pose a key role in renal function and hemodynamics, affecting the development of cardiovascular pathology.10

Recently, several cross-sectional studies have reported that urinary angiotensinogen may be considered a potential biomarker of renal dysfunction in hypertensive patients.11,12 However, whether urinary and/or serum levels of angiotensinogen can be considered potential biomarkers for predicting stroke risk is still unclear. In this study, we measured urinary and serum levels of angiotensinogen in patients with type 2 diabetes. We aimed to assess whether angiotensinogen levels are associated with stroke prognosis.

Methods

Study Sample

We studied 488 hospitalized patients with type 2 diabetes from Tianjin Nankai Hospital in China between January 2009 and December 2015. None of the included patients had other serious chronic diseases, such as cancers, liver diseases, or respiratory diseases, before admission. After discharge, the patients with type 2 disease were contacted by telephone. A total of 21 patients with type 2 diabetes were excluded from this cohort study due to the diagnosis of serious chronic diseases within three months before admission, including neoplastic diseases (N=10), liver diseases (N=7) and other serious diseases (N=4). The diagnostic criteria for type 2 diabetes were determined by 3 endocrinologists.13 For the purposes of this study, during a mean follow-up of 5 years, ischemic or hemorrhagic stroke requiring hospitalization was defined as an endpoint event. The endpoint event was diagnosed by two neurologists. The Ethics Committee of Tianjin Nankai Hospital approved this study. This was a retrospective study, so this study applied for patients informed exemption according to the Declaration of Helsinki guidelines.

Follow-Up

The included diabetic patients were followed up by telephone and/or reviewing, until the occurrence of endpoint events. The endpoint events of this study were defined as ischemic stroke requiring rehospitalization, hemorrhagic stroke requiring rehospitalization and death caused by stroke. During the 5-year follow-up period, 7 patients with diabetes were lost to follow-up.

Measurement of Serum and Urinary Angiotensinogen Levels

Fasting venous blood samples were obtained from the diabetic patients in the first morning after inclusion. The concentrations of angiotensinogen in urine and serum samples were measured by using enzyme-linked immunosorbent assays (ELISA) at baseline.14 Angiotensinogen concentrations were tested three times in each patient, and the average value of the three results was used for statistical analysis. The interassay and intra-assay coefficients of variability for the serum and urine angiotensinogen assays were 6.5% and 4.5%, respectively.

The blood samples were also measured for serum albumin (ABL), glycosylated hemoglobin (HbA1c), hemoglobin (Hb), low density lipoprotein (LDL), high sensitivity C-reactive protein (hs-CRP) and high density lipoprotein (HDL) levels and were tested at the same time by using immunoassay on an ELECSYS2010 instrument (Roche Diagnostics, Germany). Serum levels of the estimated glomerular filtration rate (eGFR) were calculated by using the Chronic Kidney Disease (CKD) Epidemiology Collaboration equation.15 For research purposes, an eGFR<60 mL/min/1.73 m2 was considered renal insufficiency.

Statistical Analysis

All of the data were analyzed by using SPSS 22.0, and a P ≤ 0.05 was considered to be statistically significant. The Kolmogorov–Smirnov test was used to analyze the normality of the data. t-tests or chi-square tests were performed to compare the two groups (eGFR≥60 mL/min/1.73 m2 and eGFR<60 mL/min/1.73 m2). In the multivariate analysis, Cox regression analysis was performed to identify the independent values of serum and urinary angiotensinogen levels at baseline on predicting the risk of stroke events in patients with type 2 diabetes. To further evaluate the independent association, we further excluded the effect of “duration of diabetes” by sensitivity analysis. Moreover, we also analyzed the association between serum and urinary angiotensinogen levels at baseline and the risk of stroke events during the follow-up period using stratified analysis by adding “taking RAS inhibitors” and “an eGFR≥60 mL/min/1.73 m2”. Additionally, an endpoint (stroke event)-free curve was constructed by the Kaplan–Meier method, and the Log rank test was performed.

Results

Clinical Characteristics of the 467 Patients with Type 2 Diabetes at Baseline

The clinical characteristics of the patients with type 2 diabetes at baseline are presented in Table 1. According to the median value of the eGFR (57 mL/min/1.73 m2), all the patients were divided into two groups. The patients with low eGFRs (<57 mL/min/1.73 m2) tended to have longer durations of diabetes, higher systolic and diastolic blood pressures, and higher rates of ever being a smoker, ever being a drinker, taking RAS inhibitors and having a CVD history, compared with patients with high eGFRs (≥57 mL/min/1.73 m2, all P<0.05). For laboratory measurements, the patients with low eGFRs had higher levels of urinary angiotensinogen, LDL, HbA1c and Hs-CRP and lower levels of ALB and Hb than those with high eGFRs (all P<0.05). Interestingly, serum angiotensinogen was not significantly different between the two groups (P>0.05).

Table 1 Clinical Characteristics in 467 Patients with Type 2 Diabetes at Baseline

Cox Proportional Hazard Analysis for the Associations Between Serum and Urinary Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes

All included patients were prospectively followed up for a median period of 5 years, and 47 patients had stroke events (including ischemic and hemorrhagic stroke). Kaplan–Meier analysis showed that patients with low eGFRs (<57 mL/min/1.73 m2) had a significantly higher rate of stroke events than those with high eGFRs (Figure 1, P=0.040). To further investigate the potential risk for stroke events, a multivariate Cox proportional hazard regression model was used. Urinary angiotensinogen levels (HR=2.78, 95% CI 1.54–5.94, P=<0.001) were associated with an increased risk of stroke events when adjustments for age, sex, BMI, ever smoking and ever drinking were made, which was similar to serum angiotensinogen levels (HR=1.54, 95% CI 1.10–3.27, P=0.037) in Model 1 (Table 2). The significant associations changed slightly after adding systolic and diastolic blood pressures and CVD history in Model 1. After continuing to add the laboratory measurements into Model 2, our results suggested that urinary angiotensinogen levels (HR=2.74, 95% CI 1.50–5.88, P=<0.001, Model 3) were an independent predictor for the risk of stroke events in patients with type 2 diabetes, but not serum angiotensinogen levels (HR=1.42, 95% CI 0.95–2.65, P=0.071, Model 3).

Table 2 Cox Proportional Hazard Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes

Figure 1 Kaplan–Meier analysis of the endpoint-free curve stratified into 2 groups by median level of the eGFR.

We performed an additional sensitivity analysis to evaluate the associations of urinary and serum angiotensinogen levels with the risk of stroke events in patients with type 2 diabetes by adding “duration of diabetes” as a covariate (Table 3). Similarly, the results also suggested that higher urinary angiotensinogen levels still contributed to an increased risk of stroke events (HR=2.71, 95% CI 1.48–5.82, P<0.001, Model 3), but not serum angiotensinogen levels (HR=1.37, 95% CI 0.89–2.21, P=0.104, Model 3), after adjusting for the confounding factors.

Table 3 Sensitivity Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes

Stratified Analysis of the Associations Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes by “Taking RAS Inhibitors” and “an eGFR≥60 mL/Min/1.73 M2”

Stratified analysis was performed by adding “taking RAS inhibitors” and “an eGFR≥60 mL/min/1.73 m2” as covariates. Our results still showed that the association between urinary angiotensinogen levels and the risk of stroke events in patients with type 2 diabetes was significant (HR=2.64, 95% CI 1.45–5.78, P<0.001, Model 3) and was not affected by “taking RAS inhibitors”, as shown in Table 4. Importantly, the significant association was affected by “an eGFR≥60 mL/min/1.73 m2”, as shown in Table 5. We found that a significant association existed only in patients with eGFRs<60 mL/min/1.73 m2 (HR=2.78, 95% CI 1.59–6.30, P<0.001, Model 3) and not in patients with eGFRs≥60 mL/min/1.73 m2 (HR=1.39, 95% CI 0.95–3.53, P=0.054, Model 3). In addition, serum angiotensinogen levels still had no association with the risk of stroke events in the stratified analysis.

Table 4 Stratified Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes by “Taking RAS Inhibitors”

Table 5 Stratified Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes by “Egfr≥60 mL/Min/1.73 M2”

Discussion

In the present study, our baseline data suggested that patients with higher urinary levels of angiotensinogen had lower eGFRs. However, serum levels of angiotensinogen were not associated with the eGFR. Moreover, Cox regression analysis suggested that diabetic patients with high levels of urinary angiotensinogen had a high rate of stroke events. Our results documented that increasing urinary angiotensinogen levels were associated with a higher risk for stroke events in diabetic patients. Furthermore, the significant relationship of urinary angiotensinogen levels with stroke risk can be affected by renal function.

Although previous studies have documented that angiotensinogen can be produced and secreted from both the liver and kidneys,10 serum and urinary levels of angiotensinogen originating from different sources pose different impacts on renal function.16,17 Existing evidence suggests that human angiotensinogen cannot be detected in urine obtained from hypertensive and nonhypertensive rats that were injected with human angiotensinogen, which may be explained by the limited glomerular permeability of circulating angiotensinogen and/or degrading angiotensinogen in tubules.18 Under normal renal structure and function, it has been reported that angiotensinogen is expressed in proximal tubular cells and released into the ureter.10 However, in the case of hyperglycemia, the expression of angiotensinogen is significantly increased in proximal tubular cells.19,20 Furthermore, some clinical investigations have reported that diabetic patients have higher urinary angiotensinogen levels,21 whereas there was no difference in serum angiotensinogen levels between diabetic patients and control individuals.21 This previous evidence may suggest that blood angiotensinogen is not a direct source of urinary angiotensinogen. Consistently, our results also suggested that urinary angiotensinogen originates locally from the kidney instead of serum.

Increased angiotensinogen expression in tubules can promote the activation of the intrarenal RAS. Consistent with our study, diabetic patients with low eGFRs had a greater increase in urinary angiotensinogen levels than serum angiotensinogen levels. One similar finding showed that CKD patients with low eGFRs documented higher urinary angiotensinogen levels, suggesting a negative relationship between urinary angiotensinogen levels and renal function.22 Studies have long confirmed the correlation between abnormal renal function and CVDs.23 Our multivariate correlational analysis reported that elevated levels of urinary angiotensinogen contributed to high stroke risk. Hence, the increased levels of urinary angiotensinogen might contribute to the pathological development of stroke, which may be explained by renal dysfunction and/or the incidence of CVD caused by diabetes mellitus.

Our results have several obvious strengths. On the one hand, in the first morning after admission, blood and urinary tests can better reflect the levels of serum and urinary angiotensinogen in diabetic patients. We are the first to find that urinary angiotensinogen can be considered a valuable predictor for endpoints (stroke events requiring rehospitalization) in diabetic patients. On the other hand, our study confirmed complete follow-up and standardized adjudication of the endpoint, so our results are very reliable. Certainly, this study also has several limitations, including a small sample size in a single center. First, although many various confounding factors, including renal function, were adjusted in our study, which may be the most important factor influencing urinary angiotensinogen levels, some other potential confounding factors were not eliminated due to other unknown determinants of urinary angiotensinogen levels. Second, because urinary levels of angiotensinogen were measured in the first morning after admission, the time-dependent variables after discharge were not assessed, which might cause survivorship biases. Third, using many covariates in our Cox regression analysis may have caused overfitting of the model, leading to bias in the results. Finally, we did not further investigate the mechanisms underlying the association of urinary angiotensinogen levels with stroke. Additionally, our study only included the Asian race and limits the generalizability of our results to other races, such as white and black races. In summary, these limitations should be considered in future studies to elaborate on this work.

Conclusions

Our results suggested that elevated urinary levels of angiotensinogen contributed to higher stroke risk in diabetic patients. Reducing urinary levels of angiotensinogen might be a new biomarker to reduce stroke risk.

Funding

There is no funding to report.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18–e209. doi:10.1161/CIR.0b013e3182009701

2. Selvin E, Juraschek SP, Coresh J. Kidney disease in people with diabetes: the expanding epidemic. Am J Kidney Dis. 2012;59(3):340–342. doi:10.1053/j.ajkd.2011.11.016

3. Foster MC, Rawlings AM, Marrett E, et al. Cardiovascular risk factor burden, treatment, and control among adults with chronic kidney disease in the United States. Am Heart J. 2013;166(1):150–156. doi:10.1016/j.ahj.2013.03.016

4. Di Angelantonio E, Kaptoge S, Wormser D, et al.; Emerging Risk Factors Collaboration. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314(1):52–60. doi:10.1001/jama.2015.7008

5. Koya D, Araki S, Haneda M. Therapeutic management of diabetic kidney disease. J Diabetes Investig. 2011;2(4):248–254. doi:10.1111/j.2040-1124.2011.00112.x

6. Lewis EJ, Hunsicker LG, Clarke WR, et al.; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860. doi:10.1056/NEJMoa011303

7. Brenner BM, Cooper ME, de Zeeuw D, et al.; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–869. doi:10.1056/NEJMoa011161

8. Fried LF, Emanuele N, Zhang JH, et al.; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–1903. doi:10.1056/NEJMoa1303154

9. Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ. In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest. 1990;85(2):417–423. doi:10.1172/JCI114454

10. Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007;59(3):251–287. doi:10.1124/pr.59.3.3

11. Kobori H, Alper AB Jr, Shenava R, et al. Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients. Hypertension. 2009;53(2):344–350. doi:10.1161/HYPERTENSIONAHA.108.123802

12. Kobori H, Ohashi N, Katsurada A, et al. Urinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases. J Am Soc Hypertens. 2008;2(5):349–354. doi:10.1016/j.jash.2008.04.008

13. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017;389(10085):2239–2251. doi:10.1016/S0140-6736(17)30058-2

14. Katsurada A, Hagiwara Y, Miyashita K, et al. Novel sandwich ELISA for human angiotensinogen. Am J Physiol Renal Physiol. 2007;293(3):F956–60. doi:10.1152/ajprenal.00090.2007

15. Krogh J, Benros ME, Martin Balslev J, et al. The association between depressive symptoms, cognitive function, and inflammation in major depression[J]. Brain Behav Immun. 2014;35(1):70–76. doi:10.1016/j.bbi.2013.08.014

16. Sawaguchi M, Araki SI, Kobori H, et al. Association between urinary angiotensinogen levels and renal and cardiovascular prognoses in patients with type 2 diabetes mellitus. J Diabetes Investig. 2012;3(3):318–324. doi:10.1111/j.2040-1124.2011.00172.x

17. Yasue S, Masuzaki H, Okada S, et al. Adipose tissue-specific regulation of angiotensinogen in obese humans and mice: impact of nutritional status and adipocyte hypertrophy. Am J Hypertens. 2010;23(4):425–431. doi:10.1038/ajh.2009.263

18. Kobori H, Nishiyama A, Harrison-Bernard LM, Navar LG. Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension. Hypertension. 2003;41(1):42–49. doi:10.1161/01.HYP.0000050102.90932.CF

19. Ohashi N, Urushihara M, Satou R, Kobori H. Glomerular angiotensinogen is induced in mesangial cells in diabetic rats via reactive oxygen species–ERK/JNK pathways. Hypertens Res. 2010;33(11):1174–1181. doi:10.1038/hr.2010.143

20. Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS. High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology. 2002;143(8):2975–2985. doi:10.1210/endo.143.8.8931

21. Saito T, Urushihara M, Kotani Y, Kagami S, Kobori H. Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes. Am J Med Sci. 2009;338(6):478–480. doi:10.1097/MAJ.0b013e3181b90c25

22. Yamamoto T, Nakagawa T, Suzuki H, et al. Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol. 2007;18(5):1558–1565. doi:10.1681/ASN.2006060554

23. Annon CP, Perkovic V, Agarwal R, et al. Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c <7%: results from the credence trial. Circulation. 2020;141(5):407–410. doi:10.1161/CIRCULATIONAHA.119.044359