Young Adult Survivors of Preterm Birth Are at Increased Risk of Stroke: The Missing Link

 Unless you can time travel back to your birth and prevent your preterm birth this gives no preventative measures on preventing these early strokes.

Young Adult Survivors of Preterm Birth Are at Increased Risk of Stroke: The Missing Link

Nomazulu Dlamini

,

Lori C. Jordan

Originally published17 Jun 2021https://doi.org/10.1161/STROKEAHA.121.035283Stroke. 2021;52:2618–2620

• This article is a commentary on the following

See related article, p 2609

Adult survivors of prematurity are at increased risk of hypertension, diabetes, lipid disorders, and ischemic heart disease.^1–4 Crump et al⁵ used data from the Swedish Birth Register and Swedish Death Register to investigate stroke risk in premature infants. This national retrospective cohort study included 95% of all singleton births in Sweden from 1973 to 1994 who survived to 18 years of age, were still living in Sweden, and had gestational age information in the birth register for a total of 2 140 866 individuals. Participants were followed up for first-time stroke (identified via the International Classification of Disease codes) through 2015, allowing 28 million years of follow-up. People with stroke at <18 years of age were excluded, and thus ages at the time of stroke were 18 to 43 years for a total of 4861 strokes (0.2%). Cox regression was used to examine stroke risks associated with gestational age at birth. Participants were grouped as follows: early preterm (22–33 weeks), late preterm (34–36 weeks), early term (37–38 weeks), full term (39–41 weeks), which was the reference group, and post-term (42 weeks). In addition, the first 2 groups were combined to provide summary estimates for preterm birth (<37 weeks). Importantly, preterm infants were also compared with full-term siblings, in the 1.7 million with siblings, to reduce confounding familial, genetic, or environmental risk factors for stroke unrelated to preterm birth. Low gestational age (22–33 weeks) was the highest risk group for any stroke; adjusted hazard ratio (1.42 [95% CI, 1.11–1.81]) and estimates were similar for ischemic or hemorrhagic stroke. Of note, stroke risk increased by 3% for each week of lower gestation, that is, the greater the degree of prematurity, the greater the stroke risk. After comparison to full-term siblings, termed co-sibling analysis, the hazard ratios attenuated slightly but still suggested increased risk of stroke. The age of the study cohort ranged from 25 to 43 years at the time of the study. Thus, the current cohort reports on stroke risk in young adults rather than all adults. While this is a weakness in one sense, factors contributing to stroke risk in young adults are of high interest.The incidence of stroke is changing over time, but the changes vary by age. While the incidence is decreasing in people over 65 years of age, it is increasing in young adults.⁶ This increase in young adult stroke is occurring on the backdrop of improved outcomes and increased life expectancy in children with critical or chronic medical conditions such as prematurity.⁷ Crump et al highlighted the high incidence of known adult stroke risk factors and elevated stroke risk in adult survivors of preterm birth. However, the mechanisms that underpin these observations are not well understood. To date, multiple mechanisms have been proposed including arterial stiffness, impairment in arterial vasodilatation, and tissue developmental arrest. A plausible unifying process, and potentially the missing link that explains the association between prematurity and young adult stroke risk, is vascular endothelial dysfunction at the microcirculatory level of the tissue capillary bed. Acute and chronic disturbances in oxygenation, altered hemodynamics, inflammation, and infection activate signaling molecules such as bradykinin and vascular endothelial growth factor and the production of NO through numerous pathways. Sustained NO activation, reduced NO bioavailability, and overproduction of reactive oxygen signaling results in oxidative stress and the tipping of normal vascular endothelial function into that of dysfunction. This results in disrupted vascular homeostasis, abnormal vasomotor tone and vascular reactivity, vascular remodeling, and a prothrombotic state.⁸ Vascular endothelial dysfunction is shown to begin early in childhood and is recognized as an early pathophysiological process in atherogenesis—the subclinical precursor of arteriosclerosis or arterial stiffness.⁹ This may result in accelerated vascular aging, which then eventually contributes to increased ischemic risk.

The reported relationship between gestational age and stroke risk is also striking as it points to critical developmentally determined periods of vulnerability. This is in-keeping with theories of selective vulnerability whereby the brain injury mostly reflects the specific cell lines maturing at the time of injury.¹⁰ It is notable that collagen content within the vascular wall is known to increase between the 12th and 25th weeks of fetal life.¹¹ From the 25th to 42nd week of gestation, there is an increase in elastin production triggered by the release of endothelial factors such as platelet-derived growth factor and insulin-like growth factors. This is a critical period of vascular remodeling in which the elastin/collagen ratio plays a major role in the development of arterial compliance. Much of this work has been in systemic arteries necessitating further studies within the blood vessels of the brain.¹¹ However, these observations of a lower elastin/collagen ratio in preterm compared with term infants and arterial stiffness provide a likely pathological basis for the association between gestation and stroke risk.

A major strength of this work was the co-sibling analysis, which demonstrated that the increased risk in ischemic and hemorrhagic stroke was partially explained by familial (genetic or environmental) factors. Modifiable environmental and lifestyle factors such as smoking and exercise are known to be important for the maintenance of vascular health and are, therefore, tangible interventions that target many of the proposed mechanisms of ischemic injury in adults. Crump et al also highlight the importance and impact of maternal health on fetal health and future adult stroke risk. Many of these modifiable environmental and lifestyle factors relate to social determinants of health and are also associated with preterm birth.¹²

Noninvasive cranial ultrasound and novel applications of functional magnetic resonance imaging provide tools for future research in this field. Hemodynamic disturbance and abnormal oxygenation are known to cause microstructural alterations in white matter and the secretion of toxic factors that impair myelination.¹³ Of note, abnormalities commonly seen on brain magnetic resonance imaging of preterm infants are similar to those associated with vascular endothelial dysfunction in the brain. Magnetic resonance angiography assessment of vessel wall macrostructure that uses black-blood imaging techniques represents an area of major advancement in noncontrast-based vessel wall imaging in children and an additional modality for the measurement of macrostructural changes in the circulatory system.^14,15 However, much more work must be done to understand the pathophysiology.

Weaknesses in this work are those inherent to large administrative data studies including lack of complete clinical records particularly those to assess later-in-life risk factors and reliance on the International Classification of Disease codes. Other weaknesses include that improvements in care over time may result in survivor bias for preterm infants surviving early in the study and that Sweden is a country with a fairly homogeneous population. Additional geographic, racial, and ethnic diversity is needed in future work.

We have made great strides in caring for premature infants such that survivors of prematurity from the 1970s may be different than those from the 1990s. Today our neonatal intensive care units save incredibly sick premature infants, thus it is not surprising that Crump et al found that associations between premature birth and stroke risk are slightly stronger in more recent births. Follow-up programs track these former premature infants throughout childhood, but this study suggests the need for attention to medical conditions and stroke and cardiovascular risk factors is lifelong. Overall, this work, in combination with additional discussed literature, suggests that illness early in life may lead to premature vascular aging, particularly if hemodynamics and oxygenation are altered.

Disclosures Dr Jordan has served as a consultant for bluebird bio and Global Blood Therapeutics. The other author reports no conflicts.

Footnotes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Disclosures, see page 2619.

Correspondence to: Nomazulu Dlamini, MD, PhD, Division of Neurology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. Email nomazulu.dlamini@sickkids.ca

 

Is a Bradykinin Storm Brewing in COVID-19?

 No clue.

Is a Bradykinin Storm Brewing in COVID-19?

Excess of the inflammatory molecule bradykinin may explain the fluid build-up in the lungs of patients with coronavirus infections. Clinical trials of inhibitors are putting this hypothesis to the test.

Alakananda Dasgupta

ABOVE: A hyperactive bradykinin system permits fluid, shown in yellow, to leak out of a blood vessel and allows immune cells, shown in purple, to squeeze out as well.
JASON SMITH/ORNL, US DEPARTMENT OF ENERGY

On a Sunday afternoon in mid-April this year, Daniel Jacobson, a computational systems biologist at Oak Ridge National Laboratory in Tennessee, was looking at gene expression data from the lung fluid of COVID-19 patients on his computer screen when he spotted something striking—the expression of genes for key enzymes in the renin-angiotensin system (RAS), involved in blood pressure regulation and fluid balance, was askew.

Jacobson followed this abnormal RAS in the lung fluid samples to the kinin cascade, an inflammatory pathway that is tightly regulated by the RAS. He found that the kinin system—in which a key peptide, bradykinin, causes blood vessels to leak and fluid to accumulate in tissues and organs—was thrown out of balance as well in COVID-19 patients. Infected individuals showed heightened expression of genes for the bradykinin receptors, as well as for enzymes called kallikreins that activate the kinin pathway, compared with controls.

The results, published July 7 in eLife, could perhaps explain the abnormal accumulation of fluid in the lungs that is so common in COVID-19 patients, the authors say.

Unbeknownst to Jacobson, Frank van de Veerdonk, an infectious disease specialist at the Radboud University Medical Center in the Netherlands, was heading down the same molecular pathway in mid-March. He had noticed two features in COVID-19 patients in his clinic—fluid in the lungs and inflammation. Because other labs had pegged angiotensin-converting enzyme-2 (ACE2), a key enzyme in the RAS, as being the SARS-CoV-2 receptor, and because he knew that ACE2 regulates the kinin system, van de Veerdonk began connecting the dots. In April, he and his group hypothesized that a dysregulated bradykinin system was leading to leaky blood vessels in the lungs and perhaps causing excess fluid to build up.

See “Receptors for SARS-CoV-2 Present in Wide Variety of Human Cells”

Josef Penninger, director of the Life Sciences Institute at the University of British Columbia in Vancouver who discovered that ACE2 is the essential in vivo receptor for SARS, tells The Scientist that he is convinced that bradykinin plays a role in COVID-19 pathogenesis. “It does make a lot of sense.”

He adds that Jacobson’s study lends support to the hypothesis, but further confirmation is needed. “Gene expression signatures don’t tell us the whole story. I think it is very important to actually measure the proteins.”

van de Veerdonk recognizes that peptide levels need to be measured and is currently setting up mass spectrometry to measure kinins in the plasma, which have a half-life in plasma of just a few seconds.

In the meantime, Jacobson and his coauthors advocate in their paper for targeting the bradykinin pathway to counter the excess fluid present in the lungs of COVID-19 patients. As there are already a couple of approved drugs that can interfere with the kinin pathway, doctors have begun deploying them in a number of clinical trials.

Decoding the bradykinin inflammatory pathway in COVID-19

A common theme that underpins many of the disease manifestations of COVID-19, such as acute respiratory distress syndrome (ARDS), is inflammation and edema, or fluid build-up. An assorted cast of leaky blood vessels, immune cells (as well as the cytokines and other molecules produced by them), and plasma proteins such as clotting factors, bradykinin, and other kinins assume center stage in this spectacle of acute inflammation.

Activation of the kinin system in the context of blood clotting—which can be dysregulated in some COVID-19 patients—generates bradykinin and related peptides through two distinct pathways: the plasma kallikrein pathway (activated by a clotting factor called the Hageman factor) and the tissue kallikrein pathway (activated by tissue enzymes and plasmin, an enzyme in the fibrinolytic system that breaks down clots in the bloodstream). Bradykinin is then converted to des-Arg9-bradykinin (DABK). When bradykinin and DABK bind to their corresponding receptors, B₂R and B₁R, respectively, fluid begins to leak from blood vessels.

The leaky blood vessels and lung fluid build-up in some COVID-19 patients might be explained by the virus’s corruption of an inflammation safeguard, namely, ACE2’s degradation of DABK. Read the full description of the pathway here.

the scientist staff

The RAS pathway tightly controls the kinin system. ACE breaks down bradykinin, while ACE2 breaks down DABK. ACE and ACE2 therefore act as regulatory brakes in the kinin system. But because ACE2 combines with SARS and SARS-CoV-2 and is internalized into the cell during infection, extracellular levels of the enzyme might drop, and, according to van de Veerdonk’s hypothesis, the bradykinin cascade then goes into overdrive.

See “Could Curbing Runaway Immune Responses Curb COVID-19?”

“As part of the explanation of COVID pathophysiology, it makes perfect sense, but it’s one piece of a very large and complex puzzle and it only partly helps us explain and understand better a very difficult disease,” says David Fedson, a retired general internist who is interested in developing treatments for pathogens that cause pandemics. Now it’s up to physicians to connect the dots and ask, “how is that meaningful and what can I do about it?—which is the most important question.”

Penninger, who is the founder of a company that is testing ACE2 as a treatment for lung failure in a Phase 2 trial in COVID-19 patients, agrees. 

Targeting the bradykinin pathway in COVID

Currently, there are two approved drugs that target the kinin system: icatibant (a B₂R blocker) and the monoclonal antibody lanadelumab, which inhibits plasma kallikrein (there are no drugs yet approved that inhibit tissue kallikrein). van de Veerdonk contends that targeting the kinin system early in the disease, soon after a patient is hospitalized, and is hypoxic, but hasn’t yet developed ARDS, might be helpful.

That is what his group found in a small exploratory study published this month. COVID-19 patients taking icatibant showed marked improvement in oxygenation as evidenced by a substantial decrease in need for supplemental oxygen, compared to control patients.

Allen Kaplan, a professor at the Medical University of South Carolina and an expert on bradykinin who was not connected with the study, tells The Scientist that this preliminary observation supports the idea that icatibant might be helpful “and should therefore be studied in a double-blind placebo-controlled fashion [in COVID patients].”

Another multicenter randomized clinical trial in the US is testing icatibant in critically ill COVID-19 patients in the ICU.

A clinical trial in Cleveland is testing lanadelumab in COVID-19 patients with pneumonia.

van de Veerdonk’s group is also testing the plasma kallikrein inhibitor (which is being supplied by Takeda, a company that also manufactures icatibant) in a multicenter clinical trial in the Netherlands in hospitalized COVID-19 patients receiving supplemental oxygen, to see whether the drug decreases the need for oxygen.

If all goes well for van de Veerdonk and his team, lanadelumab will be integrated into the REMAP-CAP trial that is evaluating several drugs for community-acquired pneumonia in thousands of patients across several countries and includes COVID-19 patients in one arm.

Kaplan has his reservations, and notes that using the monoclonal antibody against plasma kallikrein in COVID-19 could be interesting, but if it turns out that tissue kallikrein is more important in the disease, it won’t work.

Clarification (August 27): The seventh paragraph initially indicated that van de Veerdonk is currently using mass spectrometry to measure kallikreins in the plasma of COVID-19 patients and that it was impossible to do the same for bradykinin, which has a half-life in plasma of just a few seconds. This has now been changed to clarify that van de Veerdonk is currently setting up mass spectrometry to measure kinins in the plasma, which have a very short half-life