critical biofluid flow choking index and in vivo demonstration of flow choking in the stenosis artery of the animal with air embolism
Cite as: Phys. Fluids 34, 101302 (2022); https://doi.org/10.1063/5.0105407
Submitted: 23 June 2022 • Accepted: 20 August 2022 • Published Online: 19 October 2022 V. R. Sanal Kumar, Bharath Rajaghatta Sundararam, Pradeep Kumar Radhakrishnan, et al.
ARTICLES YOU MAY BE INTERESTED IN
Universal benchmark data of the three-dimensional boundary layer blockage and average friction coefficient for in silico code verification
Physics of Fluids 34, 041301 (2022); https://doi.org/10.1063/5.0086638
Influence of morphological parameters on hemodynamics in internal carotid artery bifurcation aneurysms
Physics of Fluids 34, 101901 (2022); https://doi.org/10.1063/5.0117879 Special issue on the lattice Boltzmann method
Physics of Fluids 34, 100401 (2022); https://doi.org/10.1063/5.0127725
In vitro prediction of the lower/upper-critical biofluid flow choking index and in vivo
demonstration of flow choking in the stenosis artery of the animal with air embolism
Cite as: Phys. Fluids34, 101302 (2022);doi: 10.1063/5.0105407 Submitted: 23 June 2022
.
Accepted: 20 August 2022.
Published Online: 19 October 2022
V. R.Sanal Kumar,1,2,a) Bharath RajaghattaSundararam,2 Pradeep KumarRadhakrishnan,3
NichithChandrasekaran,2,4 Shiv KumarChoudhary,5 VigneshwaranSankar,2,6 AjithSukumaran,4 VigneshwaranRajendran,4 Sulthan Ariff Rahman MohamedRafic,2,4 DhruvPanchal,7,8 YashRaj,7,8 SrajanShrivastava,7,8 CharlieOommen,2 AnbuJayaraman,9 DeveswaranRajamanickam,9
and BharathSrinivasan9 AFFILIATIONS
1Vikram Sarabhai Space Centre, Indian Space Research Organisation, Trivandrum, Kerala 695022, India
2Aerospace Engineering, Indian Institute of Science, Bangalore, Karnataka 560012, India
3Innovations and Translational Research Stem Cell Therapeutics, Visakhapatnam, Andhra Pradesh 530045, India
4Aeronautical Engineering, Kumaraguru College of Technology, Coimbatore, Tamil Nadu 641049, India
5Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, New Delhi 110608, India
6Aerospace Engineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh 208016, India
7Amity Institute of Aerospace Engineering, Amity University, Noida, Uttar Pradesh 201313, India
8Computational Fluid Dynamics Group, Dhruv Aerospace, Ahmedabad, Gujarat 382481, India
9Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bangalore, Karnataka 560054, India
a)Author to whom correspondence should be addressed:[email protected].Tel.:þ91-8754200501
ABSTRACT
Diagnostic investigations ofaneurysm,hemorrhagic stroke, and other asymptomatic cardiovascular diseases and neurological disorders due to the flow choking (biofluid/boundary layer blockage persuaded flow choking) phenomenon in the circulatory system of humans and animals on the Earth and in the human spaceflight are active research topics of topical interest {Kumaret al., “boundary layer blockage persuaded flow choking leads to hemorrhagic stroke and other neurological disorders in earth and human spaceflight,”Paper presented at the Basic Cardiovascular Sciences Conference,23–25 August 2021(American Stroke Association, 2021) [Circ. Res.129, AP422 (2021)] and “Lopsided blood-thinning drug increases the risk of internal flow choking and shock wave generation causing asymptomatic stroke,” inInternational Stroke Conference,19–20 March 2021(American Stroke Association, 2021) [Stroke52, AP804 (2021)]}. The theoretical concept of flow choking [Kumaret al., “Lopsided blood-thinning drug increases the risk of internal flow choking leading to shock wave generation causing asymptomatic cardiovascular disease,”
Global Challenges5, 2000076 (2021); “Discovery of nanoscale boundary layer blockage persuaded flow choking in cardiovascular system—Exact prediction of the 3D boundary-layer-blockage factor in nanotubes,” Sci. Rep.11, 15429 (2021); and “The theoretical prediction of the boundary layer blockage and external flow choking at moving aircraft in ground effects,” Phys. Fluids33(3), 036108 (2021)] in the cardiovascular system (CVS) due to gas embolism is established herein through analytical,in vitro(Kumaret al., “Nanoscale flow choking and spaceflight effects on cardiovascular risk of astronauts—A new perspective,” AIAA Paper No. 2021-0357, 2021),in silico(Kumaret al., “Boundary layer blockage, Venturi effect and cavitation causing aerodynamic choking and shock waves in human artery leading to hemorrhage and massive heart attack—A new perspective,” AIAA Paper No. 2018-3962, 2018), andin vivoanimal methodology [Jayaramanet al., “Animalin vivo: The proof of flow choking and bulging of the downstream region of the stenosis artery due to air embolism,”Paper presented at the Basic Cardiovascular Sciences Conference, 25–28 July 2022(American Heart Association, 2022)]. The boundary layer blockage persuaded flow choking phenomenon is a compressible viscous flow effect, and it arises at a critical pressure ratio in continuum/non-continuum real-worldyoctotoyottascale flow systems and beyond [Kumaret al., “Universal benchmark data of the three-dimensional boundary layer blockage and average friction coefficient forin
silicocode verification,” Phys. Fluids34(4), 041301 (2022)]. The closed-form analytical models, capable of predicting the flow choking in CVS, developed from the well-established compressible viscous flow theory are reviewed and presented herein. The lower-critical flow-choking index of the healthy subject (human being/animal) is predicted through the speciation analysis of blood. The upper-critical flow-choking index is predicted from the specific heat of blood at constant pressure (Cp) and constant volume (Cv), estimated using the Differential Scanning Calorimeter. These flow-choking indexes, highlighted in terms of systolic-to-diastolic blood pressure ratio (SBP/DBP), are exclusively controlled by the biofluid/blood heat capacity ratio (BHCR¼Cp/Cv). Anin vitrostudy shows that nitrogen (N2), oxygen (O2), and carbon dioxide (CO2) gases are predominant in fresh-blood samples of the healthy humans andGuinea pigsat a temperature range of 37–40C (98.6–104F) causing gas embolism.In silicoresults demonstrated the existence of the biofluid/boundary layer blockage persuaded flow choking, stream tube flow choking, shock wave generation, and pressure overshoot in the downstream region of simulated arteries (with and without stenosis), at a critical pressure ratio, due to gas embolism. The flow choking followed by aneurysm (i.e.,bulging of the downstream region of the stenosis artery due to shock wave generation) due to air embolism is demonstrated through small animalin vivostudies. We could corroborate herein, with the animal in vivoand three-dimensionalin silicostudies, that flow-choking followed by shock wave generation and pressure overshoot occurs in arteries with stenosis due to air embolism at a critical pressure ratio. Analytical models reveal that flow-choking occurs at relatively high and low blood viscosities in CVS at a critical blood pressure ratio (BPR), which leads tomemory effect(stroke history/arterial stiffness) and asymptomatic car- diovascular diseases [Kumaret al., “Lopsided blood-thinning drug increases the risk of internal flow choking leading to shock wave generation causing asymptomatic cardiovascular disease,” Global Challenges5, 2000076 (2021)]. We concluded that an overdose of drug for reducing the blood viscosity enhances the risk of flow choking (biofluid/boundary layer blockage persuaded flow choking) due to an enhanced boundary layer blockage (BLB) factor because of the rise in Reynolds number (Re) and turbulence. An analytical model establishes that an increase inRe due to the individual or the joint effects of fluid density, fluid viscosity, fluid velocity, and the hydraulic diameter of the vessel creates high tur- bulence level in CVS instigating an escalated BLB factor heading to a rapid adverse flow choking. Therefore, prescribing the exact blood- thinning course of therapy is crucial for achieving the anticipated curative value and further annulling adverse flow choking (biofluid/boundary layer blockage persuaded flow choking) in CVS. We could conclude authoritatively herein, with the animalin vivostudies, that flow choking occurs in the artery with stenosis due to air embolism at a critical BPR (i.e., SBP/DBP¼1.892 9), which is regulated by the heat capacity ratio of air. The cardiovascular risk due to boundary layer blockage persuaded flow choking could be diminished by concurrently reducing the viscosity of biofluid/blood and flow-turbulence. This comprehensive review is a pointer toward achieving relentless unchoked flow conditions (i.e., flow Mach number<1) in the CVS for prohibiting asymptomatic cardiovascular diseases and neurological disorders associated with flow choking and shock wave generation followed by pressure overshoot causing arterial stiffness. The unchoked flow condition can be achieved in every sub- ject (human/animal) by suitably increasing the thermal-tolerance-level in terms of BHCR and/or by reducing the BPR within the pathophysio- logical range of individual subjects through the new drug discovery, the new companion drug with the conventional blood thinners and/or proper health care management for increasing the healthy-life span of one and all in the universe.
Published under an exclusive license by AIP Publishing.https://doi.org/10.1063/5.0105407
NOMENCLATURE Ar Argon
Av Vessel cross-sectional area ablood Velocity of sound in blood medium BHCR Biofluid/blood heat capacity ratio (U)
BLB Boundary layer blockage BP Blood pressure
BPR Blood pressure ratio CD Convergent–divergent CG Composite/compound gas CO2 Carbon dioxide
CPR Critical pressure ratio CVS Cardiovascular system
Cp Specific heat at constant-pressure Cv Specific heat at constant-volume DBP Diastolic blood pressure DGE Dominant gases evolved
DSC Differential scanning calorimeter dA Differential port area
dV Differential velocity
dH Hydraulic-diameter of the vessel EDTA Ethylenediamine tetraacetic acid
HCR Heat capacity ratio
LCFI Lower critical flow choking index LCHI Lower critical hemorrhage index
M Mach number N2 Nitrogen O2 Oxygen
Re Reynolds number SBP Systolic blood pressure
SCAD Spontaneous coronary artery dissection UCFI Upper critical flow choking index UCHI Upper critical hemorrhage index
V Local velocity
VBR Highest velocity at the blockage region/choked flow region Vb Local velocity of blood/biofluid
U Biofluid/blood heat capacity ratio (BHCR) l Dynamic viscosity
b Kinematic viscosity of biofluid/blood qb Density of biofluid/blood-density
X Ejection-fraction in terms of biofluid/blood flow rate Subscript
BR Blockage region b Blood
l Local
m Minimum (lowest) I. INTRODUCTION
Proofs are intensifying on various cardiovascular diseases and dis- orders1–13associated with the boundary layer persuaded flow choking and/or biofluid flow choking (stenosis persuaded flow choking) fol- lowed by shock wave generation in nanoscale and large scale vessels of human circulatory system functioning on the Earth and in the human spaceflight.14–29The human circulatory system consists of a network of arteries, veins, and capillaries with the heart pumping blood through it.
Although various interdisciplinary studies have progressed substan- tially over the last few decades to understand the flow physics and chemistry of continuum/non-continuum/nanoscale fluid flows in the cardiovascular system (CVS), there are numerous unanswered research questions in medical sciences8–13,30–39pertaining toaneurysm,arrhyth- mia, hemorrhagic stroke, and other asymptomatic cardiovascular dis- eases and neurological disorders.13,28 Very recently, a few research questions of topical interest are received from various scientific com- munities across the globe pertaining to the effect of fluid flow choking in emerging diseases such as aneurysm, hemorrhagic stroke, and the acute-heart-failure.1–29This review paper aims for a plausible judgment on the diagnosis, prognosis, prevention, and treatment of various asymptomatic cardiovascular diseases and neurological disorders due to flow choking, in vessels with and without stenosis,14–31developing at different seasons across the globe.32–59Figures 1(a)–1(n)show various physical situations of biofluid/boundary layer blockage persuaded flow choking in the cardiovascular system (CVS).
Packer60categorically reported that acute heart failure is an event rather than a disease and placed a cogent plea for a radical change in thinking and in therapeutic drug development through multidisciplin- ary research.61Kumaret al.14–29,116,117reported in a series of publica- tions that such an event causing acute heart failure is due to the biofluid choking [due to the plaque induced converging–diverging (CD) nozzle flow effect or due to stenosis] and/or the boundary layer blockage persuaded flow choking (due to the boundary layer blockage persuaded CD nozzle flow effect). The discovery of biofluid/boundary layer blockage persuaded flow choking17and stream tube flow chok- ing14in the CVS calls for multidisciplinary and universal actions to propose novel therapies and to develop new drugs to reduce the risk of flow choking.14–31
Kumar et al.15 reported that as the pressure of the nanoscale fluid/non-continuum-flows rises, the fluid viscosity increases and the average-mean-free-path diminishes. As a result, the Knudsen number lowers and a zero-slip wall-boundary condition will persist in the com- pressible flow regime. It increases the risk of boundary layer blockage persuaded flow choking in biological systems causing asymptomatic cardiovascular diseases and neurological disorders.14–29The boundary layer persuaded flow choking (boundary layer blockage persuaded flow choking) condition in real-world flows (flow with the transfer of heat, i.e., diabatic flow) is certainly the unique scientific discovery in the domain of physics of fluids for solving various unresolved flow problems in the circulatory system,14–29 because it is an infallible mathematic model that satisfies all the conservation laws of nature.17 Therefore, we are prudently invoked the boundary layer blockage per- suaded flow choking condition herein for establishing cardiovascular risk factors in terms of the lower critical flow choking index (LCFI)
and the upper critical flow choking index (UCFI). The leading gas with the lowest heat capacity ratio (HCR) evolved or accumulated in the upstream region of the artery with blockage (boundary layer induced and/or plaque/stenosis) dictates the lower critical hemorrhage index (LCHI).19The upper critical hemorrhage index (UCHI)19is pre- dicted from the estimated values of Cp(specific heat of blood at con- stant pressure) and Cv(specific heat of blood at constant volume) of blood samples of healthy subjects. These hemorrhage indexes are cor- ollaries of flow choking indexes derived from the compressible viscous flow theory,31which are presented in Sec.III A.
The undesirable flow choking can be negated by creating an unchoked fluid flow condition in CVS. More specifically, the Mach number (M) must always be less than one throughout the cardiovascu- lar system for retaining the unchoked flow condition for prohibiting the shock wave generation causing arterial stiffness and leading to asymptomatic diseases and disorders. The Mach number is a dimen- sionless quantity representing the ratio of the highest flow velocity (V) and the local speed of sound (a) in the medium (i.e., M¼V/a). Over the centuries, the risk for hemorrhagic stroke and the acute-heart-fail- ure have been correlated with blood pressure (BP) levels but there was no clear demarcation in the critical blood pressure level of any individ- ual subject.40–42,62,63 Note that asymptomatic vascular diseases have been reported for both hypertension and hypotension subjects.
Therefore, the actual risk factors for hemorrhagic stroke and the acute-heart-failure reported for hypertension and hypotension sub- jects, presumably due to flow choking, were unknown until the dis- semination of our connected research articles.14–29The fact is that the risk factor for flow choking leading to asymptomatic cardiovascular diseases and disorders is not the blood pressure but the critical blood pressure (BP) ratio (CPR).19–23 The blood pressure ratio (BPR) is defined [see Eq.(1)in Sec.III] as the ratio of systolic BP to diastolic BP (i.e., BPR ¼SBP/DBP), which is regulated by the biofluid/blood heat capacity ratio (BHCR). Note that BHCR (denoted herein asU) is defined as the ratio of Cpand Cvof the corresponding fluid (gas or liq- uid) in the artery (i.e.,U¼Cp/Cv). It corroborates that flow choking leading to hemorrhagic stroke and the acute-heart-failure would occur in both hypertension and hypotension subjects. Therefore, in vitro estimation of BHCR is a meaningful objective for predicting the car- diovascular risk factors in terms of LCHI [see Eq.(3)in Sec.III] and UCHI [see Eq.(4)in Sec.III], which we have reviewed and presented herein in Sec.III B.
Over the decades,32–51,64–72 most of the previous researchers assumed that the human blood is an incompressible fluid and its Cp
and Cv are identical. This assumption is patently not true as the human blood specific volume (or density) does change with tempera- ture and/or pressure. Note that the specific heat capacity depends on the number of degrees of freedom and each independent degree of freedom permits the particles to store thermal energy; as a result, the biofluid/blood heat capacity ratio (U¼Cp/Cv) will be always greater than one.14–29In the previous connected paper, we have conclusively reported (Ref.14) that the specific heat at the constant pressure (Cp) of real-world flows is always higher than its specific heat at the constant-volume (Cv). It entails that according to the first law of ther- modynamics, all flowing fluids in nature are compressible with differ- ent degrees of compressibility percentage, as the enthalpy is always higher than the internal energy. On this rationale, the physical situa- tion of boundary layer blockage persuaded flow choking and/or
FIG. 1.(a)-(n) Manifestation of different physical situations of flow choking in CVS.15,16,19,30(a) The physical situation of biofluid/ nanoscale boundary layer blockage persuaded flow choking in arteries with atherosclerosis in the cerebral circulation.15[Reproduced with permission from Kumaret al., Sci. Rep.11, 15429 (2021). Copyright 2021 Authors licensed under a Creative Commons Attribution (CC BY) License]. (b) Biofluid/boundary layer blockage persuaded flow choking in arteries with three different physical situations, viz., stenosis, artery with stent implant, and with plaque deposit.16,19[Reproduced with permission from Kumaret al., Global Challenges5, 2000076 (2021). Copyright 2021 Authors licensed under a Creative Commons Attribution (CC BY) License]. (c) Demonstration of flow choking in the artery with and without plaque. (d) Demonstration of flow chok- ing in a stenosis artery. (e) Demonstration of boundary layer blockage persuaded flow choking in the artery with bifurcation. (f) Highlighting flow choking and the high-risk regions in the artery with bifurcation. (g) boundary layer blockage persuaded flow choking and the high-risk regions in the artery with bifurcation. (h) Biofluid flow choking and the high-risk regions in the artery with plaque and bifurcation. (i) A partially blocked artery creating a situation of biofluid flow choking. (j) Highlighting nanoscale biofluid flow choking in a blocked artery. (k) A partially blocked artery with a stent creating a situation of boundary layer blockage persuaded flow choking. (l) Highlighting flow choking and the high-risk regions in CVS. (m) Highlighting flow choking and the high-risk regions in the artery. (n) Highlighting flow choking and the high-risk regions in a T-shaped artery.
biofluid flow choking in CVS at a critical blood pressure ratio (CPR) is reaffirmed. Additionally, we could corroborate within vitro studies (the first in the World116,117) conducted (28 September–16 November 2018) in the National Center for Combustion Research and Developments (NCCRD) at the Indian Institute of Science (IISc), Bangalore, in collaboration with the All India Institute of Medical Sciences (AIIMS), New Delhi, that Cpof human blood of the healthy subject is higher than Cv.14–29Thein vitromethodologies invoked for estimating the LCHI and UCHI are critically reviewed herein and pre- sented in Sec.III B. We have conclusively reported in a series of publi- cations the possibilities of the existence of the phenomenon of flow choking (biofluid/boundary layer blockage persuaded flow choking/
stream tube flow choking14–29) in continuum/non-continuum real- world flow systems leading to shock wave generation and transient pressure overshoot. To demonstrate the transient sharp pressure spike due to flow choking and shock wave generation causing memory effect (stroke history/arterial stiffness) due to air and/or gas embolism, we have carried outin silicostudies in simulated arteries with and without stenosis and presented in Sec.III C.
After obtaining the ethics committee approval and as per the pro- tocol, the first animalin vivostudy (6 December 2021) on flow chok- ing was carried out successfully at the Faculty of Pharmacy in M.S.
Ramaiah University of Applied Sciences, Bangalore, India (Ref.29), for conclusively establishing the phenomenon of flow choking in a ste- nosis artery of a small animal (rat model) at a critical blood pressure ratio (BPR). The animalin vivomethodology is reviewed and pre- sented in Sec.III D.
II. FLOW CHOKING IN THE CARDIOVASCULAR SYSTEM Clinical reports from across the globe reveal that proofs are intensifying on various cardiovascular diseases and neurological dis- orders in all age groups allied with the COVID-19 pandemic and oth- erwise in healthy subjects1–13 as a result of the flow-choking (boundary layer blockage persuaded flow choking/biofluid choking) due to air and/or gas embolism.14–29The risk is more severe in elderly people with comorbidities.1 The flow-choking (biofluid/boundary layer blockage persuaded flow choking) occurs in the cardiovascular system (CVS) at relatively high and low blood viscosity.14–29It is well known in medical sciences that air or gas embolisms can cause seri- ous and potentially fatal conditions, such as stroke or heart attack.
The amplified incidence of brain infarction and the large vessel stroke in several sites have been testified in patients with COVID-19.4–9 These are presumably because of the undesirable flow choking (bio- fluid choking/boundary layer blockage persuaded flow choking/
stream tube flow choking) followed by the generation of shock waves at the multiple sites. Note thatflow chokingis a compressible viscous flow effect, and it occurs at a critical BPR in any blood vessel with uniform and/or non-uniform port geometry under gravity and microgravity conditions.14–29A literature review reveals that astro- nauts/cosmonauts suffered neurological disorders during human spaceflight and thereafter due to high BPR.18,27,28The risk of bound- ary layer blockage persuaded flow choking is more serious in micro- gravity conditions if the downstream region of the vessel is having divergence and/or bifurcation port because it creates shock waves.
We have already reported that flow choking is more prone to micro- gravity than under gravity condition due to enhanced BPR, blood vis- cosity, and turbulence.18,20,23,27 It is well known that under the
microgravity condition, plasma volume decreases and hematocrit increases related to the condition on the earth’s surface. It enhances the relative viscosity of blood causing an early flow-choking (flow/
biofluid choking). Our theoretical findings lead us to conclude that for healthy life, all subjects (human being/animals) on the Earth and in outer space with relatively high BPR inevitably have sufficiently high BHCR for reducing the risk of flow choking. It leads one to con- vey that for healthy life all subjects with relatively high-BPR certainly have reasonably high-BHCR for negating the risk of the flow-choking causing asymptomatic cardiovascular diseases and disorders.
It is a well-established scientific fact that the phenomenon of flow choking (biofluid choking/boundary layer blockage persuaded flow choking/stream tube flow choking) leads to supersonic flow develop- ment in the downstream region of any choked vessel with a divergent port. Note that any minor disturbance to the supersonic flow in CVS creates shock waves and it will be followed by the transient pressure- overshoot if the vessel geometry is having divergence, bifurcation, ste- nosis, and/or occlusion regions.14–29The wall movement of the visco- elastic vessel and/or the pulsatile flow of the biofluid/blood or any environmental effect such as high level acoustics can certainly disturb the supersonic flow in any vessel creating normal/oblique shock waves.
This is an interesting research topic for finding solutions to health haz- ards on Earth and as well as on outer space for implementing success- fully the future human spaceflight and space tourism projects of various space agencies. These are succinctly reported in our connected publications.14–29Admittedly, the magnitude of BPR and BHCR is influenced by the multitude of risk factors, which are identified by var- ious researchers on asymptomatic cardiovascular disease and disorders over the centuries.1–29It includes psychological73and pathophysiologi- cal risk factors,74,75 seasonal effects,76 lifestyles,77 and local effects (high noise,78heat stroke, etc.79). All these narrations lead to establish that examining the fundamental cause(s) of the altered variations of BPR and BHCR of the individual subject on earth and microgravity environment is a significant research topic worldwide for the future health care management. In this regard, further studies are envisaged in biological sciences and space medicine for finding solutions and/or discovering the drug for prohibiting flow choking and associated asymptomatic diseases and neurological disorders experienced in all subjects including astronaut/cosmonauts due to the undesirable shock wave generation.14–29
Hypertension is a major risk factor of post-stroke cognitive impairment (PSCI),10,11 vascular dementia,10 Alzheimer’s,12 and Fibrinoid necrosis.11–13Therefore, critical examination of the possibili- ties of the flow choking and the subsequent shock wave generation in CVS helps the physicians in the diagnosis and prognosis of various asymptomatic diseases and neurological disorders. Although the out- come gathered from the prevailing clinical and non-clinical studies adds to the comprehension developed on intracerebral hemorrhage (ICH) and several asymptomatic diseases and disorders, the funda- mental cause ofaneurysm,hemorrhagic stroke, and other neurological disorders on earth and in human spaceflight was unknown to the sci- entific community.15It is well known that blood pressure (BP) varia- tions are non-linear in stroke patients. The exact causes of such BP variations are still unknown. Note that the fundamental cause of the asymptomatic cardiovascular disease (CVD) has come to the fore- ground after the theoretical discovery of the boundary layer blockage persuaded flow choking phenomenon.17Of late, the discovery of the
boundary layer blockage persuaded flow choking and the stream tube- flow-choking got incredible significance in biological sciences for pre- dicting risk factors of the aneurysm, arrhythmia, hemorrhagic stroke, and myocardial infarction on earth and in human spaceflight.14–29The boundary layer blockage persuaded flow choking model reveals that the possibilities of the occurrence of hemorrhagic stroke in hyperten- sion or hypotension patients are high owing to the fact that the govern- ing parameter of this episode is the critical blood pressure ratio (CPR).
Note that the Y-shaped vessels (i.e., blood vessels with diver- gence/bifurcation region), without any apparent blockage, in the car- diovascular system are more prone to boundary layer blockage persuaded flow choking, which may be related to asymptomatic car- diovascular diseases (seeFig. 1). Note that blood pressure ratio (BPR) and BHCR are the two apparent controlling parameters of the bound- ary layer blockage persuaded flow choking. After invoking the mathe- matical models,14–29Kumaret al.19presumed that Moyamoya disease occurs because of the undesirable flow-choking (flow/biofluid choking and/or stream tube flow choking) heading to the multiple-shock-wave generation resulted by transient pressure-spike leading to the cell death in several sites of the blood vessels. In summary, the novel concept of flow/biofluid choking and stream tube flow choking14in the cardio- vascular system imparts a physical insight into the diagnosis, progno- sis, treatment, and prevention of numerous kinds of cardiovascular diseases and disorders.14–29
Briefly, CPR governed by the BHCR is now believed as the preva- lent risk factor for flow choking leading to acute heart failure, aneu- rysm, hemorrhagic-stroke, and other asymptomatic cardiovascular diseases and neurological disorders. When BPR is equal to CPR, the flow choking occurs anywhere in the CVS. In this physical situation, velocity of sound in the blood medium will be equal to the local flow velocity of blood [i.e., Mach number (M) equal to one]. When BPR CPR, the flow choking followed by multiple shockwaves can occur in the downstream region at multiple sites (seein silicoresults in Sec.
III C) of the vessels having divergent or a bifurcation or stenosis regions [seeFigs. 1(a)–1(n)].
The clinical report from Iran8 corroborates that when BPR CPR, the risk of brain hemorrhage is high in COVID-19 patients.
The fact is that the risk of flow choking is likely to aggravate in COVID-19 patients and others leading to brain hemorrhage and other asymptomatic cardiovascular diseases due to the slight oscillation in blood pressure (BP) for bothhypertension andhypotensionsubjects because the controlling parameter of flow choking is the BP ratio (BPR).15–29It is crystal clear from the case report of Razaviet al.8that the COVID-19 patient suffers from gas embolism15 because the patient’s temperature exceeds 37.5C. In this review, a live clinical case report8 of the aforesaid COVID-19 patient from Mazandaran University of Medical Science, Sari, Iran, is reproduced in verbatim for corroborating the possibility of the occurrence of the phenomenon of flow choking due to gas embolism leading tointracerebral hemorrhage (ICH). Note that Razaviet al.8of Mazandaran University of Medical Science, Iran, presented “the case of a 79-year-old man with a history of fever and cough of three days’ duration referred to the emergency department with acute loss of consciousness. At admission, he was febrile (temperature 38.6C), with a fast heart rate (115 beats per minute)and rapid breathing(respiratory rate, 22 breaths per minute).
Blood pressure was 140/65 mm Hg. Partial pressure of oxygen was 51.8 mm Hg; partial pressure of carbon dioxide was 27.9 mm Hg; and
saturated oxygen was 86.6%. There was no history of hypertension or anticoagulation therapy. In addition to the loss of consciousness (Glasgow coma scale score¼7)and bilateral extensor plantar reflexes, physical examination revealed coarse rales in the left lower lobe of the lungs. Paraclinical findings revealed lymphopenia (590 cells/mm2), erythrocyte sedimentation rate of 85 mm/h, C-reactive protein of 10 mg/
l, creatinine of 1.4 mg/dl, platelets of 210109/l, prothrombin time of 12 s, international normalized ratio of 1 and partial thromboplastin time of 64 s, as well as normal liver function and other routine labora- tory tests. Lung computed tomography revealed a ground-glass opacity in the left lower lobe, and brain computed tomography revealed a mas- sive intracerebral hemorrhage(ICH)in the right hemisphere, accompa- nied by intraventricular and subarachnoid hemorrhage. Real-time PCR of oropharyngeal swab confirmed COVID-19 infection.” It is crystal clear from the above clinical report of Razaviet al.8that this COVID- 19 patient suffered gas embolism leading to flow choking and shock wave generation because his reported temperature was 38.6C and BPR was 2.153 846 (SBP/DBP: 140/65 mm Hg). More specifically, at this temperature, gases will evolve in the circulatory system. Under this condition, when BPR>LCHI, flow choking occurs. It is evident from the BP reading of this COVID-19 patient that his BPR exceeds LCHI. At this physical situation, flow choking leads to shock wave generation and pressure overshoot causing bulging and/or tearing of the downstream region of the choked blood vessels. This concept is established in this review through analytical, in vitro, in silico, and in vivomethodologies.
III. GAS EMBOLISM AND FLOW CHOKING—PROOF OF CONCEPT
The concepts offlow choking14(biofluid/boundary layer blockage persuaded flow choking) are well connected herein with the prevailing concepts in the biological sciences for discovering possible methods for negating the risk offlow chokingheading to asymptomatic cardio- vascular diseases and neurological disorders. Note that flow choking could occur in CVS without prejudice to thepercutaneous coronary intervention(PCI). It is a proven scientific fact that the flow choking (biofluid/boundary layer blockage persuaded flow choking) occurs in any vessel at a critical total-to-static pressure ratio (i.e., critical BPR herein). The critical pressure ratio (CPR) for flow choking is uniquely regulated by the heat-capacity-ratio (HCR) of the fluid (blood/bio- fluid/gas). Note that flow choking in any vessel leads to supersonic flow development if the downstream of the choked location of the ves- sel is having sudden expansion/divergence/ bifurcation region.
Furthermore, vessels with vasospasm, stenosis, and/or occlusion regions are more prone to flow choking and supersonic flow develop- ment [see Figs. 1(a)–1(n)]. Admittedly, any minor disturbance to supersonic flow leads to the transient shock wave generation.
Shockwave is a type of transmitting disturbance that travels faster than the local speed of sound in the medium. Shockwave carries energy and is characterized by an abrupt, nearly discontinuous, change in pres- sure, temperature, and density of the medium. The strength of the shock wave depends on the local supersonic flow Mach number. Note that under the unchoked flow condition (i.e., BPR<CPR), the super- sonic flow vanishes and the risk of shock wave causing artery stiffness and other cardiovascular risk will be annulled.
It has been established that the boundary layer blockage per- suaded flow choking phenomenon occurs, in the real-world flows
(continuum and non-continuum) due to the compressible viscous flow effect, in the form of asonic-fluid-throat effect because of the boundary layer blockage (BLB) factor.14,15Mathematical models dis- close that the reasonably high and low blood viscosity are risk factors of asymptomatic cardiovascular disease.19–21Note that altered varia- tions of blood viscosity and high turbulence lead to flow choking in CVS. It leads to cavitation, shock wave generation, and transient pres- sure-spike.
Our aim was to establish the proof of the concept of the flow chok- ing in the cardiovascular system (CVS) causing asymptomatic cardio- vascular diseases and neurological disorders bycorrelating multitude of parameters,viz.,the blood pressure ratio (BPR), biofluid/blood-heat- capacity-ratio (BHCR), biofluid/blood viscosity, biofluid/blood density, stenosis (in terms of the vessel cross-sectional area and/or the hydraulic diameter of the vessel), and ejection fraction in terms of fluid flow rate (X). In this regard, an infallible closed-form analytical model was devel- oped and presented herein. We have correlated multitude of variables for setting unchoked flow conditions in CVS for negating the undesir- able flow choking causing asymptomatic cardiovascular diseases and neurological disorders. We have reviewed and presented analytical, in vitro,in silico,and small animalin vivostudies for conclusively estab- lishing the proof of the concept of flow choking in CVS. The methodol- ogy used in these studies are given in Secs.III A–III D.
A. Analytical methodology
Using the compressible flow theory, the following closed-form analytical models [see Eqs. (1)–(5)] have been developed for correlating the BHCR (U), BPR, biofluid/blood-kinematic-viscosity (b), biofluid/blood-density (qb), diastolic-blood-pressure (DBP), hydraulic-diameter of the vessel (dH), the vessel cross-sectional area (Av), highest blood/biofluid velocity (Vb), Reynolds number (Re), Mach number (M), boundary-layer-blockage (BLB), and ejection- fraction in terms of the biofluid/blood flow rate (X) for predicting the risk of flow-choking in the cardiovascular system (CVS),
BPR¼SBP
DBP< Uþ1 2 U=U1
; (1)
M<1; (2a)
Reb dH
qb UðDBPÞ 1=2
<1; (2b)
XlVl
UmðDBPÞAvÞl
" #1=2
<1; (2c)
LCFI¼LCHI¼ Umþ1 2 Um1Um
; (3)
UCFI¼UCHI¼ Ubþ1 2 UUb
b1
: (4)
Equations(1)and(2)are two independent and complementing conditions for maintaining the unchoked flow condition in the CVS.
Note that the flow gets choked when the flow Mach number (M) reaches one. Therefore, it is mandatory to retain the flow Mach
number always less than one for prohibiting the flow choking in CVS, which is reflected in Eqs. (2a)–(2c)with the multitude of variables.
Note thatEqs. (2b)and(2c)are the corollary ofEq. (2a), which explain the role of the vessel blockage, in terms of the vessel cross-sectional area and the ejection fraction in terms of biofluid/blood flow rate (X), on the risk of flow choking.
Note that for prohibiting the flow choking in CVS, all subjects must maintain BPR lower than thelower critical flow choking index (LCFI). It is same as thelower critical hemorrhage index(LCHI). It can be estimated from the lowest value of the BHCR of evolved gases in the CVS [see Eq.(3)]. For instance, if carbon dioxide (U¼1.289) is the dominant gas in the CVS, it is mandatory to maintain BPR lower than LCHI [i.e., 1.825 7—estimated using Eq. (3)] for creating an unchoked flow condition for prohibiting the shock wave generation and transient pressure-overshoot causing the risk. The LCFI and/or LCHI can be estimated throughin vitrostudy aiming at finding the dominant gases evolved (DGE) from blood samples of each subject (human being or animal) at different thermal levels. The upper critical flow choking index (UCFI) and/or the upper critical hemorrhage index (UCHI) can be predicted [see Eq.(4)] from the specific heat of blood at constant pressure (Cp) and the specific heat of blood at con- stant volume (Cv), estimated using the Differential Scanning Calorimeter—Perkin Elmer DSC 8000.
The boundary-layer-blockage (BLB) in the blood vessels can be predisposed by the variations in the biofluid viscosity and the BHCR of the flowing gas/nano plasma. Equation(5)relates the artery diame- ter (di), the inflow Mach number (Minlet), the axial Mach number (Maxis), and the BHCR (U), which is derived from compressible flow theory,14–16,31
BLB¼ 1 Minlet
Maxis
1=2 1þ U1 2
M2axis 1þ U1
2
M2inlet 2
66 64
3 77 75
Uþ1 4ðU1Þ
2 66 66 4
3 77 77
5di; (5a)
TBLBj@sonicfluidthroat
¼ 1Minlet1=2 2
Umþ1 1þUm1 2 Minlet2
4 1UmðUmþ1Þ
" #
di: (5b) Note that all flowing fluids in nature are compressible and viscous.14 Therefore, the BLB factor will never be zero and boundary layer block- age persuaded flow choking occurs at a critical blood pressure ratio irrespective of the magnitude of BLB factor.15At theboundary layer blockage persuaded flow chokingcondition, the creeping flow (low sub- sonic flow) will get augmented in a uniform cross-sectional area tube or vessel [seeFig. 2(a)] due to the area blockage caused by the bound- ary-layer-displacement-thickness [i.e., BLB inEq. (5a)]. The total 3D boundary layer blockage (TBLB) at boundary layer blockage per- suaded flow choking condition (Maxis ¼ 1) for diabatic flows is obtained and presented asEq. (5b).14–19,31Equation (5b)is the corol- lary of the striking result on the area Mach number relationship81of any choked variable area vessel or tube with the working fluid as calorically perfect gas. It was derived from the compressible flow the- ory.Equation (5b)reveals that Mach number at any location in the vessel is a function of the ratio of the local vessel cross-sectional area
to the sonic throat area (reported herein as % BLB factor). The solu- tion curve ofEq. (5b)is given inFig. 2(b).
It is pertinent to note that the accurate estimation of the flow Mach number is important for estimating the risk of flow choking in any artery. Therefore, accurate prediction of the local highest velocity and the velocity of sound in blood/biofluid medium are important for the risk assessment. Velocity of sound in blood medium can be obtained fromEq. (6)(Ref.22),
ablood¼ DP Dq 1=2
blood
: (6)
Under the choked flow condition, the speed of sound will be equal to biofluid/blood velocity in the artery (ablood¼VBR), where the sonic throat (i.e., M¼1) persists. Therefore, at the choked flow location, Eq.
(6)becomes22
DPblood¼VBR2 Dqblood: (7)
Equation(7)demonstrates that there are possibilities of the blood flow choking in the blockage region when the differential blood pressure (DPblood) is equal to the product of the differential blood density (Dqblood) and the square of the blood velocity (VBR) at the choked
flow location and/or the blockage region of the artery. Under this con- dition, BPR is a unique function of the BHCR, as dictated by Eq.(1).
Figure 2(a)shows the idealized physical model of an artery with the divergent region, andFig. 2(b)shows the corresponding chart [the solution curve of Eq.(5b)] relating to a case of gas embolism with car- bon dioxide as the chief evolved gas.Figures 2(a)and2(b)are clearly demonstrated the physical situation of boundary layer blockage per- suaded flow choking and the condition for prohibiting the flow- choking and shock wave generation in any artery. It is evident from thechart[seeFig. 2(b)] that irrespective of the local Mach number (M<1) and the percentage area blockage factor of the 3D vessel (i.e., theBLB factor persuaded and/or plaque or stenosis induced blockage), LCHI determines the risk of flow choking. Note that a reduction in the area blockage factor decreases the flow Mach number for satisfying the conservation law of nature (i.e., continuity condition set by nature), which reduces the risk of flow choking. It is crystal clear from the closed-form analytical model that for negating the flow choking, all subjects must retain BPR always less than the LCHI.
The BLB factor in the blood vessels could alter due to the sea- sonal effects [see Fig. 2(a)] because of the variations in the biofluid/
blood viscosity. If the blood vessel geometry is like the convergent- divergent (CD) nozzle passage [due to various physical situations as seen inFigs. 1(a)–1(n)], the divergent region of the CD nozzle-shaped vessel creates supersonic flow immediately after the flow choking (bio- fluid/boundary layer blockage persuaded flow choking). It leads to shock wave generation and transient pressure-spike as may be the case. As stated earlier, a minor disturbance to the supersonic flow cre- ates shock waves in the downstream region of the vessel (i.e., after the sonic throatlocation). Therefore, bulging and/or tearing of the vessel will always be at the downstream region of the sonic point [seeFigs.
1(a)–1(n)]. This physical situation could be forecast through reliable multi-phase, multi-speciesin silicomodels verified and validated at the boundary layer blockage persuaded flow chokingcondition, which is beyond the scope of this review.
An analytical model presented herein verifies that thestentscould reduce the risk of the heart attack (i.e., due to the reduction in the flow Mach number due to an increase in the vessel port area), but it is not better than drug or other health care management because the bio- fluid/boundary layer blockage persuaded flow chokingcould happen with and without stent [seeFig. 1(b)and1(k)] at a critical BPR. The self-explanatory equations [see Eqs. (1)–(8)], derived from the com- pressible flow theory,19,31are highlighting various influencing parame- ters for prohibiting the biofluid/boundary layer blockage persuaded flow chokingin CVS. Note that the ejection fraction is reflected in Eq.
(2c)in terms of biofluid/blood flow rate (X). It is apparent from the closed-form-analytical model [see Eq.(2c)] that the ejection fraction is not the lone factor for declaring the risk of acute heart failure, as com- prehended by Packer60and Kumaret al.22,116We observed that the coupled effects of ejection fraction, the local cross-sectional area of the vessel, local biofluid/blood velocity, local Reynolds number, lowest BHCR, and the local static pressure [i.e., diastolic blood pressure (DBP)] determine the risk of flow choking leading to asymptomatic stroke and acute heart failure.14–29,116 The local Reynolds number
Re¼qVdlH
can be estimated from the local hydraulic diameter of the vessel (dH), the highest local velocity of the biofluid/blood (V), the density of the biofluid/blood, and the dynamic viscosity of the FIG. 2.(a) and (b) Demonstrating the condition for prohibiting the boundary layer
blockage persuaded flow choking with respect to the percentage area blockage factor in a 3D vessel with the divergent region [seeFig. 2(a)].19,28[Reproduced from Kumaret al., Global Challenges5, 2000076 (2021). Copyright 2021, Authors licensed under a Creative Commons Attribution (CC BY) License]. (a) An idealized physical model of an artery with the divergent region (b) Chart: Condition for prohibiting flow choking in CVS.19,28
biofluid/blood (l). The Reynolds number (Re) helps to predict the flow patterns in different fluid flow situations. At lowRe, the flow tends to be dominated by laminar (sheet-like) flow, while at highRe, the flow tends to be turbulent. The high turbulence level increases the boundary layer displacement thickness (i.e., the boundary layer block- age factor) causing an early boundary layer blockage persuaded flow choking.
In high-risk subjects (BPR close to LCHI and/or Mach number close one), a slight oscillation in the BPR predisposes to the transient choking and the unchoking events heading toarrhythmia.It is appro- priate to mention here that, generally heart valve problems involve in aortic and mitral valves. These valve problems are possibly because of its geometric shape like a CD nozzle flow passage. Further delibera- tions of valve problems andarrhythmiaare beyond the scope of this review. Briefly, the biofluid/boundary layer blockage persuaded flow chokingcould create unusual transient pressure-overshoot in vessels with divergent/bifurcation regions, which increases memory effects (stroke history/arterial stiffness) leading to artery tear in the subse- quent stroke. The magnitude of the pressure-overshoot depends on the strength of the shock. It is decided by the flow Mach number and the heat capacity ratio of the fluid.
Equation(8), derived from compressible flow theory,14–29shows the relation between critical pressure ratio (CPR) and BHCR pertain- ing to the flow choking (biofluid/boundary layer blockage persuaded flow choking).
CPR¼ SBP DBP
choking
¼ Uþ1 2 U1U
: (8)
Equation(8)tells us that the risk of flow choking causing asymptom- atic vascular diseases can be negated by keeping low BPR (BPR¼SBP/
DBP) and/or high BHCR (U). Note that the high thermal tolerance of blood indicates high BHCR (U), which reduces the risk of flow- choking. It can be mathematically proved that the risk of flow choking is more severe when DBP decreases drastically (causing natural mor- tality) than SBP increases with the same percentage.
The undesirable flow choking and shock wave generation in human circulatory system over the years’ (arterial aging)80could create memory effect (stroke history) on the artery of any subject.
Admittedly, the gradual increase in stiffness leads to the so-called nat- ural mortality because of the life-threatening-vessel tearing due to memory effect (arterial stiffness/stroke history). Note that the shock wave persuaded transient pressures spike alters the viscoelastic proper- ties of the blood-vessels. This physical situation was new to medical sciences until establishing the concept of compressibility of water and biofluid/blood flow choking.14–29Frequent flow choking due to gas embolism is very dangerous because it leads to stroke epidemic in COVID-19 patients and others. Furthermore, a minor swinging in the BPR disposes to the choking and the unchoking phenomena. It could lead toarrhythmiaandmemory effectin high-risk subjects (i.e., BPR is very close to the LCFI).
The self-explanatory mathematical models highlighted herein as Eqs.(1)–(8)are obtained from the well-known theory of compressible viscous flows.1–16,31,81Equations(1)and(2)are two separate physical situations set for annulling the undesirable flow choking in the CVS, which are, however, complementing each other. Note that Eqs.(2b) and (2c) are revealing numerous impelling variables and the
conflicting conditions to negate the flow/biofluid choking in the nano- scale and large-scale fluid flow systems. Equations(3)and(8)reveal that the CPR and/or LCHI must always be higher than BPR for negat- ing undesirable flow choking in CVS. Equations(2b), is a subsidiary of Eq. (2a), which discloses that relatively high and low viscosities are risk factors for biofluid choking causing asymptomatic cardiovascular diseases. It is well-known that viscosity of fluid increases with pressure.
Therefore, high viscosity and high pressure are risk factors. Note that the number of red blood cells (hematocrit) is directly correlated with blood viscosity. Therefore, for negating, the undesirable flow choking either increases the BHCR and/or decreases the BPR. The closed-form analytical models further reveal that decreasing the blood viscosity and simultaneously reducing the turbulence level are the conflicting key tasks to prevent the flow choking in CVS for reducing the cardiovascu- lar risk.15–29Admittedly, these two tasks battle each other. The fact is that the Reynolds number goes up with the large viscosity reduction (i.e., an overdose of blood thinners), which creates high turbulence leading to large boundary layer blockage. On the other hand, the rela- tively high viscosity increases the BLB factor leading to an early flow choking. Therefore, prescribing the exact blood-thinning course of therapy is crucial for achieving the anticipated curative value and fur- ther annulling adverse flow choking (biofluid/boundary layer blockage persuaded flow choking) in CVS. As stated earlier, these conflicting tasks (viz., decreasing the blood viscosity and simultaneously reducing the turbulence level15,19,21,116–118) can be achieved together by increas- ing the BHCR and/or by decreasing the BPR. This is a remarkable ana- lytical finding for taking the necessary health care management for decreasing the risk of flow/biofluid flow choking causing possible shock wave creation and transient pressure-spike heading to asymp- tomatic cardiovascular diseases and neurological disorders. Note that periodic flow choking and unchoking phenomena could occur in the CVS due to the large oscillations in BPR, which leads to the memory effect (stroke history/arterial stiffness). Such a physical situation would increase the risk of aneurysm, arrhythmia, asymptomatic-hemorrhage, and acute-heart-failure.
The 3D-BLB factor in the sonic-fluid-throat region (i.e., bound- ary layer blockage persuaded flow choking point) of any artery can be obtained using Eq.(5b), and it can be used as universal benchmark data for performing high-fidelityin silico,in vitro, andin vivoexperi- ments for the lucrative design optimization of fluid flow systems in gravity and micro-gravity environments. Note that producing bench- mark data from the nanoscale fluid flow system is a daunting task15,16,82,83or quite impossible using conventionalin vitromethods.
The region of the flow choking, the site of the shock wave production, and the coordinate of pressure overshoot would vary because of the altered streamline-pattern of the fluid at the various time and region because of the pulsatile flow condition in the cardiovascular system.
Therefore, the exact mapping of the memory effect (i.e., predicting the variations of relaxation modulus due to the stroke history/pressure- overshoot) is a challenging research topic of topical interest, which is beyond the scope of this review.
Admittedly, until now, the value of BHCR is not considering for the diagnosis and medication of numerous asymptomatic cardiovascu- lar diseases and disorders, as its significance was not known to the medical sciences.14–31Note that the BHCR is the unique controlling determinant of CPR for flow choking, which is a significant finding for the risk assessments. The flow choking occurs under the creeping
inflow condition anywhere in CVS once the blockage region attains CPR. Note that the flow choking leads to the undesirable pressure overshoot in the convergent–divergent (CD) nozzle -shaped-passage causing alterations in viscoelastic properties, essentially the stiffness of the blood vessels. As stated earlier, the strength of the shock wave depends on the flow Mach number, which determines the magnitude of the pressure-overshoot. It is important to note that the sharp pressure-overshoot developed due to the normal shock generation cre- ates a physical situation of balloon-like bulging (aneurysm) of visco- elastic vessels and/or the catastrophic failure of the fluid flow systems in CVS leading to hemorrhagic stroke and/or acute heart failure. The phenomenon of boundary layer blockage persuaded flow choking dis- closes that in a blood vessel with the uniform port diameter, the creep- ing inflow accelerates to sonic condition at a critical blood pressure ratio without any iota of symptoms of plaque deposit (atherosclerosis).
The sonic flow becomes the supersonic flow in the downstream region of the vessel if the port geometry is having bifurcation or divergence. It corroborates that the flow choking is the main cause of asymptomatic cardiovascular diseases. The fact is that the cardiovascular risk factor is not blood pressure but the blood pressure ratio triggering for an unde- sirable flow choking [see Eq.(1)]. It further corroborates that the car- diovascular risk would occur in both hypertension and hypotension subjects. Therefore, thein vitroestimation of BHCR is a significant goal for predicting the cardiovascular risk factors in terms of LCHI and UCHI, which we have carried out and reported herein in Sec.III B as follows.
B.In vitromethodology
Comprehensive in vitro studies are performed using well- calibrated Perkin Elmer instruments at the NCCRD, Indian Institute of Science (IISc), Bangalore, based on the analytical findings of Kumar et al.22,31,116 All the experimental methods reported herein are in accordance with relevant guidelines and regulations. Also note that for the randomized studies, the blood bank (Bangalore Blood Bank &
Diagnostic Laboratory—A Unit of Indian Trust for Social Action, License Number: KTK/28C/1/94), who supplied blood samples of healthy subjects obtained the written and informed consent from all the healthy human being prior to the test conducted at NCCRD/IISc, India. (Blood sample of healthy Guinea pig is directly obtained from the animal living in an approved Animal House Facility in M.S. Ramaiah University of Applied Sciences, Bangalore 560054, India.)
We are mainly focused herein on estimating the biofluid/blood HCR of human being at various temperatures for predicting the LCHI and UCHI using Eqs.(3)and(4), respectively. In the first phase of our study, we estimated the HCR of blood using the Differential Scanning Calorimeter (DSC)—Perkin Elmer DSC 8000. Blood samples are taken from healthy subjects living in the southern part of Indian union. The healthy males having age group 23–56 years with different blood groups, viz., Aþ, Bþ, and Oþ are analyzed and reported herein.
Among animals, the blood sample of a four-week old healthy male Guinea pigis selected for thermal analyses in this pilot study. It is well known that the Guinea pigs have many biological similarities to humans, beyond the simple fact that they are mammals, which make them useful in many fields of research.
We have performed thoroughin vitrostudies at different temper- atures of fresh 180ll blood samples (blood groups: Aþ, Bþ, and Oþ) of healthy subjects (the human being: 23–56 age group/Guinea pig:
four-week-old at a heating rate of 10C/min and predicted the LCHI and the UCHI to establish the proof of the concept of flow choking in the cardiovascular system due to the compressible biofluid/blood flow effect). The normal human body temperature range is typically stated as 36.5–37.5C (97.7–99.5F). According to the Guinness Book of World Records, a person with a body temperature of 115 F (46.1C) with a symptom ofheatstrokeis the highest-reported body tempera- ture, who survived after medical care. On this rationale, we have con- ducted comprehensive in vitro studies (see Secs. III B 1–III B 3) beyond the highest-reported body temperature with diverse scientific goals, as a pilot study on thisin vitro.
We have estimated the heat capacity (Cp) of blood samples of healthy subjects taken from the (ethylenediamine tetraacetic acid) EDTA and lithium heparin tubes and found that its value is 32.79%
and 33.16% lower, respectively, than the fresh samples of the same healthy subjects tested within 5 min of collection. It indicates that drugs with anticoagulant properties could reduce the BHCR. During in vitrostudies, we have extended the thermal tolerance level beyond the pathophysiological range with different research objectives. We observed that around 60–85C (140–185F), all the blood samples of human being boiloff in a non-linear fashion. We also observed that the boiloff temperature of the blood of healthyGinea pigis higher than that of the human being tested herein. In the second phase of our study, the speciation analyses of blood of healthy subjects (human being/animal) have been carried out. We observed, through the in vitrostudies reported herein, that different gases are evolved while increasing the temperature of the blood from 30C (86F) to 120C (248F) at a heating rate of 10C/min.
1. Thermo-gravimetric analysis of blood
The thermo-gravimetric analysis was carried out using Perkin Elmer Simultaneous Thermal Analyzer (STA) 6000 (seeFig. 3). Both thermogravimetric (TGA) and differential thermal analysis (DTA) can be performed simultaneously using this set up. The instrument has the ramp rate of 0.1–200C/min with the temperature range from 15 to 1000C with temperature accuracy < 60.5C. The PT-PT/Rh (R- type) thermocouple is used for accurate heat sensing. Samples are taken in 180ll alumina crucibles as shown inFig. 4. The instrument is controlled by using a proprietary Pyris software. The instrument is cal- ibrated using indium as a standard, for baseline corrections. For the current experiments, sample weight was maintained at<8ll. Helium
FIG. 3.Test setup of thermo-gravimetric analysis20—Perkin Elmer STA 6000.
was used as the purge gas with the flow rate of 40 ml/min. The samples were heated from 30C (86F) to 120C (248F) at 10C/min. The thermograms obtained could give information on thermal stability, boiling point, associated weight loss, residue weight percentage, vola- tile content percentage, and enthalpy associated with decomposition and rate of weight loss, which could be used later for kinetic studies.
2. Thermolysis of blood
The Perkin Elmer Clarus 680 gas chromatography (GC) with Clarus SQ8T mass spectrometer (MS) is used for thein vitroanalysis of gaseous species evolved during the thermolysis of blood of healthy subjects (the human being/Guinea pig). A gas chromatogram consists of an oven and a series of columns. It uses helium as the carrier gas. It houses FID (flame ionization detector) and TCD (thermal conductiv- ity detector). GC is used to get better separation of the gas species, which could facilitate the identification of species more accurate in the mass spectrometer. Different capillary columns that could separate both polar and non-polar gases were used under specific conditions of oven and injectors that facilitate good resolution. For the present work, MS is used as the main detector. The GC-MS setup is shown in Fig. 5. The mass spectrometer used in the present study is Perkin Elmer SQ8T, which uses the electron impact detector. The mass spec- trum was programed to look for species whose m/z was set from 10 to 60 amu. The data were collected and analyzed using a proprietary soft- ware supplied with the instrument.
3. Speciation analysis of blood
Speciation analysis is a method of segregating and enumerating dissimilar molecular versions of a compound, which could reveal very diverse physiochemical properties, including changing toxicities. A hyphenated technique in speciation analysis is a vital starter to elemen- tal speciation analysis, and it provides a critical overview for a credible decision making in the research carried out. Hyphenated methods conglomerate chromatographic and spectral techniques to utilize the benefits of both. Chromatography harvests pure or nearly pure seg- ments of chemical constituents in a blend. Spectroscopy generates choosy information for classification using standards or library spec- tra. In this in vitro analysis, a hyphenated technique was used to evaluate the gases evolved from blood samples at a heating rate of 10C/min as a function of time and temperature. A known quantity of the sample around 8ll is taken in a ceramic crucible and carefully placed inside the STA onto a platinum sensor. The lid is covered by a transfer line, whose temperature is maintained at 250C in order to avoid any condensation of evolved gas during the thermolysis. The flow within the transfer line is maintained at 100 ml/minheliumgas, which also acts as a purge cum carrier gas. The transfer lines are con- nected to STA-FTIR-GC-MS (seeFig. 6).
Once the thermolysis of the sample starts, the other instruments, i.e., FTIR and GC-MS, start immediately, which is controlled by Perkin Elmer TL 9000 console. For the ease of understanding the com- position of evolved gas as a function of both time and temperature, STA-GC-MS data are generated for our analyses. The operation win- dow for the gas sampling inside the MS chamber was kept between 10 and 60 m/z and was maintained as a standard throughout the experi- ment. As soon as the heating of the blood sample starts, the mass spec- trum starts acquiring data.
The estimated LCHI of all healthy human being is found 1.82, which is based on the evolved dominant carbon dioxide gas (BHCR¼1.289). In the case ofGuinea pig,the LCHI is estimated as 1.89, which is based on the dominant nitrogen gas (BHCR¼1.4). We found that there are variations in the heat capacity of blood samples collected in three different vacutainers of same healthy subjects. We observed that theanticoagulantreduces the BHCR and susceptible to an early biofluid choking in blood vessels. More specifically, if BHCR is relatively high the evaporation or degasification temperature of blood will also become high and as a result the risk of gas embolism followed by internal flow choking can be reduced. The most popular consequence of medication with anticoagulant drug is bleeding. The clinical reports of various investigators1,2,8,76,84–86 are corroborating FIG. 4.Alumina crucibles used for thermo-gravimetric analysis.20
FIG. 5.Perkin Elmer GC-MS setup.20
FIG. 6.Test setup for speciation analysis of blood20[Figures 3–6are reproduced with permission from Kumaret al., AIAA Paper No. 2021-0357, 2021. Copyright 2021 American Institute of Aeronautics and Astronautics].
