GeroScience (2018) 40:485–496
https://doi.org/10.1007/s11357-018-0044-9

ORIGINAL ARTICLE

Repeated Valsalva maneuvers promote symptomatic
manifestations of cerebral microhemorrhages: implications
for the pathogenesis of vascular cognitive impairment in older
adults
Zoltan Ungvari & Andriy Yabluchanskiy & Stefano Tarantini & Peter Toth &
Angelia C. Kirkpatrick & Anna Csiszar & Calin I. Prodan

Received: 28 August 2018 / Accepted: 25 September 2018 / Published online: 4 October 2018
# American Aging Association 2018

Abstract Multifocal cerebral microhemorrhages
(CMHs, also known as Bcerebral microbleeds^), which
are associated with rupture of small intracerebral
Z. Ungvari : A. Yabluchanskiy : S. Tarantini : P. Toth :
A. Csiszar
Vascular Cognitive Impairment Program, Reynolds Oklahoma
Center on Aging, University of Oklahoma Health Sciences Center,
Oklahoma City, OK, USA
Z. Ungvari : A. Yabluchanskiy : S. Tarantini : P. Toth :
A. Csiszar
Translational Geroscience Laboratory, Department of Geriatric
Medicine, University of Oklahoma Health Sciences Center,
Oklahoma City, OK, USA
Z. Ungvari : P. Toth
Institute for Translational Medicine, University of Pecs Medical
School, Pecs, Hungary
P. Toth
Cerebrovascular Laboratory, Department of Neurosurgery and
Szentagothai Research Center, University of Pecs Medical School,
Pecs, Hungary
A. C. Kirkpatrick : C. I. Prodan
Veterans Affairs Medical Center, Oklahoma City, OK, USA
A. C. Kirkpatrick
Department of Medicine, University of Oklahoma Health Sciences
Center, Oklahoma City, OK, USA
C. I. Prodan (*)
Department of Neurology, University of Oklahoma Health
Sciences Center, 920 S. L. Young Blvd Suite 2040, Oklahoma
City 73104 OK, USA
e-mail: calin-prodan@ouhsc.edu

vessels, have been recognized as an important cause
for cognitive decline in older adults. Although recent
studies demonstrate that CMHs are highly prevalent in
patients 65 and older, many aspects of the pathogenesis
and clinical significance of CMHs remain obscure. In
this longitudinal observational study, a case of a 77year-old man with multifocal CMHs is described, in
whom the rupture of intracerebral vessels could be
linked to repeatedly performing extended Valsalva maneuvers. This patient was initially seen with acute aphasia after performing a prolonged Valsalva maneuver
during underwater swimming. T2-weighted magnetic
resonance imaging revealed a left acute frontal intracerebral hemorrhage (ICH) with multiple CMHs. The
aphasia was resolved and no cognitive impairment was
present. Two years later, he developed unsteadiness and
confusion after performing two prolonged Valsalva maneuvers during underwater swimming separated by
about 12 days. Repeat brain imaging revealed an acute
right and a subacute left ICH, with a marked interval
increase in the number of CMHs. The patient also
exhibited manifest memory loss after the second admission and was diagnosed with dementia. These observations suggest that prolonged Valsalva maneuver is potentially a common precipitating cause of both CMHs
and symptomatic ICHs. The Valsalva maneuver both
increases the systolic arterial pressure and gives rise to
a venous pressure wave transmitted to the brain in the
absence of the competent antireflux jugular vein valves.
This pressure increase is superimposed on existing hypertension and/or increases in blood pressure due to

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exercise and increased venous return due to immersion
of the body in water. We advocate that further studies are
needed to distinguish between CMHs with arterial and
venous origins and their potential to lead to ICH induced
by Valsalva maneuver as well as to determine whether
these lesions have a predilection for a particular
location.
Keywords Vascular contributors to cognitive
impairment and dementia . VCID . Vascular cognitive
impairment . VCI . Vascular aging . Cerebrovascular .
Cerebromicrovascular . Stroke . Transient ischemic
attack

Introduction
In recent years, continued advances in MRI technology
have allowed for the increased detection of small chronic intracerebral hemorrhages (< 5 to 10 mm in diameter)
termed cerebral microhemorrhages (CMHs; also described as microbleeds) (Ungvari et al., 2017a). CMHs
appear as small, round, or oval hypointense lesions
corresponding to focal hemosiderin depositions
surrounded by essentially normal brain tissue, which
can be best detected using T2*-weighted gradientrecall echo (T2*-GRE) MRI sequences and are typically
not seen on CT. Because paramagnetic hemosiderin
remains present for a long time at the location of previous bleedings, these imaging technologies enable the
sensitive assessment of cumulative CMH burden.
There is growing evidence that CMHs are clinically not
silent and contribute significantly to cognitive
decline(Ungvari et al., 2017a). It has now also become
clear that CMHs frequently occur in combination with
larger intracerebral hemorrhages (ICHs) suggesting shared
pathomechanisms(Ungvari et al., 2017a). Despite recent
advances in our understanding the cellular and molecular
mechanisms that promote microvascular fragility in the
aging(Ungvari et al., 2017a), several critical aspects of
the pathogenesis of CMHs remain elusive.
In this longitudinal observational study, a case of a
77-year-old man with multifocal CMHs is described, in
whom the rupture of intracerebral vessels could be
linked to repeatedly performing prolonged Valsalva maneuvers during underwater swimming. This unique clinical observation allowed us to formulate a novel hypothesis considering the potential causal role of the Valsalva

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maneuver and, in particular, the impact of increased
venous pressure in the pathophysiology of CMHs.

Case presentation
A 77-year-old right-handed man was admitted to the hospital with complaints of acute onset of difficulty finding
words. This developed immediately after performing a
prolonged Valsalva maneuver as part of an extended underwater swimming where he remained submerged for
more than half of the length of an Olympic-size pool. He
has been an avid swimmer throughout most of his adult
life, and he described the underwater swimming described
above as likely the longest in terms of length and duration.
Past medical history included gout, aortic stenosis, and
chronic atrial fibrillation. Although a prior diagnosis of
hypertension was recorded, he was never on antihypertensive medications and managed to control his blood pressure with diet and exercise. His medications included
allopurinol and warfarin. Initial examination found only
decreased word production with naming errors and mild
paraphasia. Magnetic resonance imaging of the brain revealed an acute left frontal intracerebral hemorrhage (ICH)
measuring approximately 5 cc with an additional 22 small
areas of signal loss on gradient echo T2-weighted images
in both hemispheres consistent with CMHs (Fig. 1). The
vast majority of the CMHs (18/22) were in a lobar distribution (temporal, parietal, and occipital) with the remaining 4 in the basal ganglia and cerebellum. Laboratory data,
including complete blood count, hepatic and renal function
tests, electrolytes, lipid profile, urine analysis, fasting glucose, C-reactive protein, ANA, ESR, and uric acid were
normal. Initial INR (international normalized ratio) was
1.8, and it was rapidly reversed with subsequent INR at
0.9. Of note, prior INR was never above 2.5. Additional
investigations include echocardiogram and ultrasound of
carotid arteries, which failed to reveal any significant
pathology. His language improved during the admission,
and at the time of discharge, he was very close to baseline.
Cognitive screening performed with the Montreal cognitive assessment (MoCA) was 26 at the time of hospital
discharge, with minimal impact noted from his language
deficit. He was discharged with a diagnosis of intracerebral
hemorrhage and amyloid angiopathy. After extensive review of risks and benefits with the medical team, he was
not placed on anticoagulation or antiplatelet therapy. At
2 months post-discharge, outpatient clinic evaluation
found complete recovery of language occurred within

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2 months, and repeat MoCA at the time was 28. He had no
new neurological sign or symptoms and remained fully
independent. He also resumed his active lifestyle, including swimming, although he did not perform any underwater swimming similar to the length and duration that preceded his initial admission.
Two years later, he presented again to the hospital
complaining of sudden onset of unsteadiness and confusion, after performing two separate prolonged Valsalva
maneuvers during underwater swimming of similar length
and duration to the one that preceded his initial admission,
separated by about 12 days. Both instances were witnessed
by his wife, and she indicated that he developed difficulty
finding words immediately after the first maneuver, yet
declined to seek medical evaluation. As he developed
confusion and unsteadiness following the second maneuver, 12 days later, he finally agreed to undergo medical
evaluation. On examination, his vital signs were normal,
including blood pressure. He had mild paraphasia and
mildly impaired repetition and comprehension, but no
other focal deficits were noted. Repeat brain MRI
(Fig. 1) revealed an acute right parietal ICH (3.8 cc) and
subacute left temporal ICH (4.6 cc), with a marked
increase in the number of CMHs from 22 to 35. Most of
the CMHs developed between the two scans were in a
lobar distribution, but we noted also two additional deep
CMHs. The patient also exhibited manifest memory loss
after the second admission, with a repeat MoCA score of
19, and was diagnosed with dementia. Repeat laboratory
tests, including INR and additional investigations
including electroencephalogram, were normal. He
remained stable over the next 6 months after discharge,
with improvement noted in his language but no change in
his cognitive score. He has since quit swimming.
We consider the left frontal and temporal lesions
responsible for the language deficits noted on both
admissions, while the confusion and confusion and
overt memory loss reaching the severity of dementia
are most probably related to the bilateral hemispheric
ICHs and very large number of CMHs in a predominantly lobar distribution.

Discussion
A unique case of a patient is reported, who developed
multiple acute ICHs and significant increase in the number of CMHs during the performance of Valsalva maneuvers on repeated occasions, which resulted in

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clinically significant cognitive decline reaching the severity of dementia. The swimming style of our patient
involved performing regular underwater swimming,
which would include Valsalva maneuvers. However,
we noted a very close temporal relationship between
the performing unusually prolonged Valsalva maneuvers and the acutely symptomatic hemorrhages
(Fig. 2). Below, we discuss the similarities between the
pathologies of CMHs and larger ICHs, highlight the
synergistic role of aging and elevated blood pressure
in the pathogenesis of CMHs, discuss the contributions
of CMHs in cognitive decline, and present a mechanistic
hypothesis explaining the role of the Valsalva maneuver
in the generation of CMHs.
Association of CMHs and larger strokes
Clinical studies demonstrate that the presence of CMHs
predicts subsequent ICHs in elderly patients(Tsushima
et al., 2003), or in patients with ischemic stroke (Fan
et al., 2003; Nighoghossian et al., 2002). It is significant
that the patient presented here developed simultaneously larger ICHs and multiple CMHs in response to the
same challenges. These associations suggest that similar
cellular and molecular mechanisms promote vascular
fragility at different levels of the cerebral circulation
leading both to CMHs and larger ICHs.
Risk factors for CMHs
The patient presented here was at significant risk for
CMHs. There is strong evidence that age is the most
significant independent risk factor for CMHs (Ungvari
et al., 2017a; Chai et al., 2016; Jeerakathil et al., 2004;
Caunca et al., 2016). Prevalence of CMHs is low in
younger adults and significantly increases with advanced age (Poels et al., 2010; Romero et al., 2014).
The current evidence shows that the prevalence of
CMHs is between 24 and 56% in elderly patients
(Poels et al., 2010; Hilal et al., 2014; Poels et al.,
2011; Yang et al., 2015; Takashima et al., 2011; Lee
et al., 2004; Wiegman et al., 2014). However, due to
rapid development and increased availability of advanced imaging methods, this figure is expected to
significantly increase in the foreseeable future(Werring,
2011). Approximately half of the patients present with
multiple CMHs (Hilal et al., 2014), similar to the patient
presented here.

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Fig. 1 Performing a prolonged
Valsalva maneuver during
extended underwater swimming
induced intracerebral
hemorrhages on two separate
occasions. CT (A) versus T2*GRE MRI (B) showing left
hemispheric hemorrhage (arrow)
at the time of initial admission in
2015 after first Valsalva
maneuver-related incident during
underwater swimming. CT (C)
versus T2*-GRE MRI (D)
showing right hemispheric acute
bleed (arrow) and left
hemispheric subacute bleed (star)
at the time of second admission in
2017 after two Valsalva
maneuvers performed during
underwater swimming separated
by about 2 weeks. Note that the
CT and MRI images have
different imaging angles. MR
images were obtained on a 1.5 T
field strength scanner (GE
medical systems)

High blood pressure is another important risk factor
for CMHs (Jeerakathil et al., 2004; Romero et al., 2014;
Cordonnier et al., 2007; Roob et al., 1999;
Sveinbjornsdottir et al., 2008; Vernooij et al., 2008).
The critical role of the synergistic interaction of aging
and high blood pressure in the pathogenesis of CMHs is
suggested by the observations that hypertension almost
exclusively promotes CMHs in older adults and rodent
models of aging (Ungvari et al., 2017a; Tarantini et al.,
2017a; Toth et al., 2015).
Cerebral amyloid angiopathy and Alzheimer’s disease (AD) are also important risk factors for CMHs
(Ungvari et al., 2017a; Yates et al., 2011; Pettersen
et al., 2008; Yates et al., 2014; Benedictus et al.,
2013). AD patients often exhibit multiple CMHs with
a cortical/subcortical localization (Yates et al., 2011; Ni
et al., 2015; Gorelick et al., 2011), which are thought to
exacerbate cognitive decline (Pettersen et al., 2008;
Goos et al., 2009). In AD patients, cerebral amyloid

angiopathy (CAA), which is manifested as deposition
of amyloid β protein and other protein aggregates in
intracerebral vessels, exhibits a similar distribution profile (Vinters & Gilbert, 1983; Biffi & Greenberg, 2011),
and it is likely that majority of CMHs in AD patients
develop in vessels affected by CAA. This concept is
supported by the observation that animal models of
CAA also exhibit multifocal CMHs (Fisher et al.,
2011). Importantly, CAA can also be present in the brain
of older adults even in the absence of manifest dementia
(prevalence of severe CAA is > 21% in individuals aged
> 85 (Lancet, 2001)), suggesting that amyloid deposition in the wall of microvessels may also play a significant role in microvascular fragility and the pathogenesis
of CMHs in older patients not diagnosed with AD.
There is also strong evidence supporting a critical role
of CAA in the pathogenesis of larger ICHs as well (Biffi
& Greenberg, 2011).

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489

Fig. 2 Increased number of
cerebral microhemorrhages
visible on T2*-GRE MRI
sequences after performance of
extended Valsalva maneuvers
during prolonged underwater
swimming. A, C Cerebral
microhemorrhages (please see
white arrowheads) at the time of
initial admission in 2015 after first
Valsalva maneuver-related
incident during underwater
swimming. B, D Increased
number of cerebral
microhemorrhages (white
arrowheads indicate new CMHs)
at the time of second admission in
2017 after two Valsalva
maneuvers performed during
underwater swimming separated
by about 2 weeks. Note also the
right hemispheric acute bleed
(arrow) and left hemispheric
subacute bleed (star) in panel B. A
significant memory loss was
noted after the second Valsalvarelated incident. At the time of the
hospital admission in 2017, the
patient had a MoCA score of 19/
30 and was diagnosed with
dementia. MRI images were
obtained on a 1.5 T field strength
scanner (GE medical systems)

Molecular mechanisms contributing to the increased
microvascular fragility associated with aging
Studies in preclinical animal models have recently revealed important cellular and molecular mechanisms
responsible for the dramatic age-related increases in
the susceptibility of older adults to CMHs (Ungvari
et al., 2017a; Tarantini et al., 2017a; Toth et al., 2015).
Age-related changes in extracellular matrix homeostasis
and consequential changes in to the tensile strength of
the vascular wall are critical factors in the increased
propensity for development of CMHs in aging(Ungvari
et al., 2017a). Studies in laboratory mice suggest that a
critical mechanisms by which aging facilitates development of CMHs involve exacerbation of hypertensioninduced oxidative stress (by upregulation of NADPH
oxidases and mitochondrial production of reactive oxygen species) and redox-sensitive activation of matrix
metalloproteinases (MMPs), which degrade collagen
and elastin and other components of the basal lamina

and extracellular matrix, in the cerebral vasculature(Toth
et al., 2015; Springo et al., 2015a). Amyloid deposition
can also significantly weaken the wall of the cerebral
vessels, compromising vascular resilience to high pressure, leading to both CMHs and lobar ICHs (Biffi &
Greenberg, 2011).
Age-related functional alterations that increase
the likelihood of CMHs in older adults
Aging is associated with increased aortic stiffness,
which compromises the Windkessel function increasing
systolic pressure and pressure pulsatility in older adults
(Diaz-Otero et al., 2016; Phan et al., 2016). There is
strong evidence linking cerebromicrovascular injury
and development of CMHs to the transmission of pulsatile high pressure waves into the thin-walled distal
portion of the brain microcirculation in older individuals. Excessive backward propagation of the reflected
arterial pressure waves from the periphery to the brain

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may augment pressure pulsatility transmitted to the
brain microcirculation in older adults. The available data
suggest that age-related dysfunction of cerebral
autoregulatory mechanisms, including impaired myogenic constriction and functional maladaptation of proximal resistance arteries to hypertension (Springo et al.,
2015b), allows the pressure waves penetrate the cerebral
circulation without significant attenuation and reaches
the fragile cerebral microvessels, increasing the likelihood of pressure-induced CMHs.
Role of CMHs in cognitive decline
The Montreal cognitive assessment (MoCA) is a sensitive screening instrument recommended to identify patients with vascular cognitive impairment. The MoCA
assesses several cognitive domains, including visuospatial abilities, multiple aspects of executive functions,
short-term memory recall, phonemic fluency, verbal
abstraction, attention, concentration, working memory,
language, and orientation. In our case, we noted a clear
temporal association between interval development of
CMHs, and also ICHs, and cognitive impairment. This
observation supports the need for larger populationbased cross-sectional studies showing that patients with
CMHs have higher incidence of cognitive dysfunction
(Chai et al., 2016; Hilal et al., 2014; Wu et al., 2014; van
Norden et al., 2011; Poels et al., 2012; Werring et al.,
2004; Werring et al., 2010; Yakushiji et al., 2015;
Yakushiji, 2016), followed by longitudinal studies examining the impact of additional CMHs on cognitive
status. Evidence from the literature suggests that that
increased CMH burden predicts the severity of cognitive
dysfunction (Wu et al., 2014). The behavioral/cognitive
consequences of CMHs evidently depend on their
locations(van Norden et al., 2011). The patient presented here had CMHs with a lobar distribution involving
temporal, parietal, and occipital areas with additional
presence of several deep, non-lobar, CMHs. The results
of a recent meta-analysis demonstrate that CMHs in the
deep brain regions, lobar regions, basal ganglia, and
thalamus are associated with significant cognitive
decline(Wu et al., 2014). CMHs located in the temporal
lobe associate with memory and attention impairment,
whereas frontal lobe CMHs were reported to result in
impairment of memory, concept shifting, psychomotor
speed, and attention(van Norden et al., 2011). CMHs in
the deep and lobar regions were shown to associate with
attention/executive and fluency domains(Valenti et al.,

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2016). There are several limitations to establishing direct cognitive associations according to the location of
CMHs in the patient presented here, including the cooccurrence of larger ICHs and the higher educational
level of the patient that may affect his performance on
various tasks of the MoCA. The pathomechanisms by
which CMHs negatively impact cognitive function likely involve focal brain damage and consequential disruption of neuronal and astrocytic communication in the
neighboring cerebral regions(Heringa et al., 2014).
CMHs also likely promote focal inflammatory changes
and blood brain barrier disruption as well as microglia
activation(Rosidi et al., 2011).
Potential role of Valsalva maneuver in the pathogenesis
of arteriolar CMHs
In the patient presented here, we hypothesize that development of CMHs as well as larger ICHs was causally
linked to the repeated performance of Valsalva maneuvers during underwater swimming. The Valsalva maneuver (defined as a forced expiratory blow against a
closed glottis) that the patient performed likely lasted
well over 20 s. The Valsalva maneuver triggers a typical
sequence of complex hemodynamic events, resulting in
a significant transient arterial pressure increase that can
reach ~ 200 mmHg (Lee et al., 1954; Kroeker & Wood,
1956; Monge Garcia et al., 2009; Reyes et al., 1967).
Immersion in water also exposed the patient’s body to a
pressure gradient, which likely resulted in a redistribution of blood and consequential increases in cardiac
output contributing to the increased blood pressure. In
addition, the patient was exercising, which further elevated blood pressure. The Valsalva maneuver also has
documented effects on the autoregulation of cerebral
blood flow (Tiecks et al., 1995). The available evidence
suggests that increased systolic blood pressure wave
during the Valsalva maneuver reaches the brain and
imposes an unduly burden upon the distal, vulnerable
portion on the cerebral microcirculation, especially in
older patients with compromised autoregulatory mechanisms. On the basis of studies performed in preclinical
animal models of hypertension-induced CMHs
(Ungvari et al., 2017a; Tarantini et al., 2017a; Toth
et al., 2015), we hypothesize that increased penetration
of high pressure to the cerebral microcirculation combined with the increased fragility of the cerebral
microvessels contributed significantly to the genesis of
CMHs in the patient presented here. In that regard, it

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would be highly informative to assess cerebral autoregulation and pressure pulsatility in this patient in subsequent studies.
The Valsalva maneuver is fairly common in many
other everyday activities that involve moderate exertion,
including weight lifting, blowing air into inflatable devices or musical instruments (e.g., oboe), intense
coughing, vomiting, nose blowing, and strain during
defecation or sexual intercourse. Depending on the
levels of expiratory strain, intrathoracic pressure in these
conditions may increase well over > 150–200 mmHg
(Sharpey-Schafer, 1953), which is then transmitted to
the circulation and reaches the brain. It is likely that
when elderly patients’ microvascular pressure exceeds
the threshold for structural injury in weakened cerebral
microvessels, CMHs ensue.
Potential role of Valsalva maneuver in the pathogenesis
of venous CMHs?
During Valsalva maneuver, the increased intrathoracic
pressure is transmitted to the venous circulation,
resulting in significant increases in central venous
pressure(Wysoki et al., 2001). As a consequence, a
retrograde venous pressure wave may also reach the
vulnerable cerebral microcirculation contributing to the
pathogenesis of CMHs (Ungvari et al., 2017a). In the
internal jugular veins, valves are present, which have a
significant role in the prevention of venous reflux and
the penetration of backward venous pressure waves into
the cerebral venous system during the Valsalva maneuver (Chung et al., 2014; Zivadinov, 2013; Zivadinov &
Chung, 2013; Fisher et al., 1982). However, in aged
individuals, the internal jugular vein valves are often
incompetent enabling retrograde transmission of increased venous pressure. Although the role of CMHs
of venous origin is not well understood in the brain,
there is strong evidence that retinal hemorrhages of
venous origin can be generated by Valsalva maneuvers
(Al-Mujaini & Montana, 2008; Chapman-Davies &
Lazarevic, 2002). Our observations warrant further studies to establish the link between jugular vein valve
insufficiency and CMH incidence in older individuals.
Perspectives
In conclusion, this report illustrates that performing a
Valsalva maneuver may promote the development of
CMHs (Fig. 3) as well as trigger the emergence of larger,

491

acutely symptomatic, ICHs. Our findings are in agreement with the results of large cross-sectional studies that
increased CMH burden predicts cognitive decline. Despite recent advances in detection of CMHs and in our
understanding of their diagnostic and prognostic values,
a number of key questions related to their pathogenesis
remain to be clarified. Future studies both in humans
and in animal models should characterize what percentage of CMHs occurs in the arterioles, in the capillaries,
or in the venules and determine how this pattern is
affected by Valsalva maneuver. Longitudinal studies
on individuals who are frequently exposed to increased
intrathoracic pressure due to forced expiration (e.g.,
professional bass and woodwind instrument players)
would be quite informative in that regard. Preclinical
studies should provide additional proof-of-concept that
increases in central venous pressure indeed exacerbate
microvascular injury and increase CMH burden. There
is increasing evidence that aging promotes critical functional and structural alterations in the cerebral arterial
circulation (Toth et al., 2015; Springo et al., 2015a;
Springo et al., 2015b; Castillo-Carranza et al., 2017;
Toth et al., 2017; Toth et al., 2013; Tucsek et al.,
2014a; Tucsek et al., 2014b; Csiszar et al., 2017;
Tarantini et al., 2017b; Tarantini et al., 2017c; Tucsek
et al., 2017; Ungvari et al., 2017b; Ungvari et al.,
2017c). Further studies are warranted to better understand the pro-fragility effects of aging in the venous
circulation and capillaries as well. The role of novel
cellular mechanisms potentially involved in age-related
vascular pathologies and increased microvascular fragility, including neuroendocrine changes (Tarantini et al.,
2017a; Tarantini et al., 2016a; Tarantini et al., 2016b),
dysregulation of the extracellular matrix (Meschiari
et al., 2017), and non-conventional mechanisms of microvascular inflammation (e.g., persistent infection of
the vascular cells with cytomegalovirus (Aiello et al.,
2017; Jackson et al., 2017; Leng et al., 2017; NikolichZugich & van Lier, 2017; Souquette et al., 2017)),
should be explored. Studies on novel preclinical animal
models of aging (Ashpole et al., 2017; Fang et al., 2017;
Podlutsky et al., 2017; An et al., 2017; Bennis et al.,
2017; Deepa et al., 2017; Urfer et al., 2017) to understand pathogenesis of CMHs should also be encouraged.
In the clinical practice in addition to the importance of
blood pressure control, lifestyle interventions limiting
temporal blood pressure surges should be emphasized
for prevention of CMHs. Patients at risk should be
advised to avoid Valsalva maneuvers (e.g., no

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Fig. 3 Model depicting the mechanisms by which Valsalva maneuvers performed during underwater swimming may promote the
development of CMHs in older adults. The Valsalva maneuver
increases arterial pressure, which is transmitted to the vulnerable
downstream portion of the cerebral microcirculation due to impaired autoregulatory protection and stiffening of the conduit
arteries in older adults. In addition, both acute exercise and immersion in water (by causing redistribution of blood and

consequential increases in cardiac output) contribute to the increased blood pressure. Age-related MMP activation, oxidative
stress, and amyloid deposition in the vascular wall increase microvascular fragility predisposing older individuals to the development of CMHs. The Valsalva maneuver also significantly increases venous pressure, which is transmitted to the thin-walled
cerebral venules due to the age-related dysfunction of jugular vein
valves, promoting CMHs of venular and/or capillary origin

underwater swimming and weight lifting, promotion of
the consumption of stool-loosening foods, and
reconsidering exercise practices).

R01-NS100782 and R01-NS056218); a Pilot Grant from the Stephenson Cancer Center funded by the National Cancer Institute
Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center; the Oklahoma
Shared Clinical and Translational Resources (OSCTR) program
funded by the National Institute of General Medical Sciences
(U54GM104938 to AY); the Presbyterian Health Foundation (to
ZU, AC, AY, and CP); the European Union-funded grants EFOP3.6.1-16-2016-00008, 20765-3/2018/FEKUTSTRAT, EFOP3.6.2.-16-2017-00008, GINOP-2.3.2-15-2016-00048, and
GINOP-2.3.3-15-2016-00032; the National Research, Development and Innovation Office (NKFI-FK123798); and the

Funding information This work was supported by grants from
the American Heart Association (ST); the Oklahoma Center for
the Advancement of Science and Technology (to AC, AY, and
ZU); the National Center for Complementary and Alternative
Medicine (R01-AT006526 to ZU); the National Institute on Aging
(R01-AG055395, R01-AG047879, and R01-AG038747); the National Institute of Neurological Disorders and Stroke (NINDS;

GeroScience (2018) 40:485–496
Hungarian Academy of Sciences (Bolyai Research Scholarship
BO/00634/15 to PT). The authors acknowledge the support from
the NIA-funded Geroscience Training Program in Oklahoma
(T32AG052363).
Compliance with ethical standards
Disclaimer The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National Institutes of Health.

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