Journal of Clinical and Preventive Cardiology

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Year
: 2017  |  Volume : 6  |  Issue : 2  |  Page : 73--77

Risk assessment, risk management, and prevention of acute vascular events


Gundu H R Rao 
 Department of Laboratory Medicine and Pathology, Thrombosis Research, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, USA

Correspondence Address:
Gundu H R Rao
Thrombosis Research, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota
USA

Abstract

South Asians have a very high incidence of cardiometabolic diseases such as hypertension, central abdominal obesity, metabolic syndrome, type 2 diabetes, heart disease, and stroke. In spite of the fact that common risk factors associated with these clinical conditions are known, we do not have point-of-care assays, to monitor the disease of the vessels, and the efficacy of antiplatelet therapy. We have a window of opportunity to develop three-dimensional ultrasound methodologies, to monitor the subclinical atherosclerosis, altered flow velocities of regional vascular beds, as well as plaque progression and regression in the major vessels. We also have opportunities to develop state-of-the-art methodologies for monitoring the efficacy or otherwise of antiplatelet therapies. In this overview, we share our views and strategies for the development of affordable medical technologies in India, for monitoring vessel wall pathology as well as for better management of antiplatelet therapies.



How to cite this article:
Rao GH. Risk assessment, risk management, and prevention of acute vascular events.J Clin Prev Cardiol 2017;6:73-77


How to cite this URL:
Rao GH. Risk assessment, risk management, and prevention of acute vascular events. J Clin Prev Cardiol [serial online] 2017 [cited 2021 Jan 21 ];6:73-77
Available from: https://www.jcpconline.org/text.asp?2017/6/2/73/203529


Full Text



 Introduction



Since the time Framingham studies developed the risk assessment and risk management strategies, there is a great emphasis on the management of observed risks for prevention of acute cardio- and cerebrovascular events.[1],[2],[3],[4] In view of these observations, Pharma companies are developing various drugs, to manage the well-characterized risk factors such as inflammation, vascular dysfunction, hypertension, obesity, lipid abnormalities, and platelet and coagulation hyperfunctions.[5],[6],[7] A few years ago, there was a debate about the possibilities for better management of these chronic diseases. Cohn et al. at the University of Minnesota advocated the management of disease of the vessels, rather than the management of risk factors that promote these diseases. They developed a 10-point diagnostic screening algorithm, to monitor the progress and regression of the disease.[8],[9],[10] Whereas the researchers at the Robarts Laboratory, Ontario, Canada, developed a three-dimensional (3D) ultrasound methodology, to follow the progression and regression of carotid artery plaques and showed the efficacy of this methodology for monitoring statin therapy as well as beneficial effects of lifestyle changes.[11],[12],[13] On the other hand, Belcaro et al. in England developed proprietary software and algorithms, to assess the altered morphology of carotid and femoral bifurcations, to predict the progress of subclinical atherosclerosis.[14],[15],[16] Of the various risk factors associated with the pathogenesis of acute vascular events, in our opinion, the progression of vessel wall disease, narrowing of the vessels, stiffening of the vessel walls, and the thrombotic state of the blood plays a critical role in developing acute vascular events. In view of these observations, we at the University of Minnesota developed and validated a point-of-care device, to monitor platelet-activation-dependent facilitation of clot formation.[17] This device used a stainless steel coil placed in the midsection of a capillary, to induce shear-mediated activation of platelets, which resulted in the promotion of clot formation in circulating blood. Just like the 3D ultrasound technology of Robarts laboratory, and the proprietary software and analytics of Professor Andrew Nicolaides, platelet reaction time monitor is also not available worldwide for clinical applications. In this overview, we will share with you our collective ideas as to how we can develop indigenous affordable medical technologies, to monitor the progression of vessel wall disease as well as antiplatelet therapies.

 Monitoring Vascular Physiology and Pathology



Alterations in the vessel wall physiology and compliance of the vessels and the changes if any, in the blood flow velocity, are the earliest stages of vascular dysfunction that could be detected.[18],[19],[20],[21],[22] There are several devices available in the market that can monitor changes in the flow velocity and provide information on endothelial dysfunction. Some of the devices in use include CVProfilor (Hypertension Diagnostics,™ USA: Hypertensiondiagnostics.com), Periscope (Genesis Medical System, Hyderabad, India: Genesismedicals.com), and TM-Oxi (LD Technologies, Florida: www.ldteck.com). Majority of the people who suffer heart attacks have no symptoms, making prevention very difficult. However, now with the availability of these devices, we will be able to identify heart disease (vessel wall disease or dysfunction) at its earliest stage in people with no symptoms. In spite of the advances made in the diagnostic medical device development, we still do not have a simple hand-held, point-of-care monitor for diagnosis and management of vascular dysfunction.

Hypertension diagnostics (www.hypertensiondiagnostics.com) of Minneapolis, Minnesota, has developed a method for noninvasively measuring the elasticity of large and small arteries, of which small artery elasticity is the earliest and most sensitive marker for cardiovascular (CV) disease. One of the tests that the University of Minnesota uses in their 10-point risk assessment is CVProfilor. The device collects 30 s of blood pressure waveform data from a small artery and a large one, performs analysis of the digitized blood pressure waveforms and generates a report that contains information on the blood pressure, body surface area, body mass index, and both C-1 large and C-2 small artery elasticity indices. According to the researchers who have used this device, changes in the small artery elasticity have been highly predictive of CV disease.[23] Its main product CV Profilor, Hypertension Diagnostics, Minneapolis, MN has been approved by the US Food and Drug Administration.

Genesis Medical Systems of Hyderabad (www.genesismedicals.com), India, have developed a simple noninvasive oscillometric device (Periscope), to monitor pulse wave velocity (PWV) in small arteries. The report generated by this system provides 8-second tracings of electrocardiography, all pressure pulse waveforms, and calculated results. PWV is the speed at which the blood pressure pulses travel from the heart to the peripheral artery after the blood rushes out during contraction. This measurement is used for evaluating arterial stiffness. PWV increases with stiffness of the arteries. The PWV is considered one of the most important clinical parameters for evaluating CV risk, and therapeutic efficacy.[24] The commercial devices dedicated to PWV measurements estimate a regional assessment, measured between two vessels. However, we feel that a local measurement or regional measurement is more precise for evaluation of the health of the vessels. Peripheral arteries are stiffer than the deeper arteries. The heterogeneity of the structure of arterials wall and its components pose challenge for PWV measurements and computations.

Ultrasonography has been used extensively as a diagnostic imaging modality. Dr. Aaron Fenster et al. at Robarts Research Institute, London, Canada, have developed 3D ultrasound imaging for improving the visualization and quantification of atherosclerotic plaque in the carotid artery [Figure 1].[11],[12],[13]{Figure 1}

This technology if available worldwide will be of great help in monitoring the morphology, volume of the plaque, and for the assessment of therapeutic efficacy. There are several types of ultrasound systems for obtaining 3D images. The commonly used options are the mechanical linear 3D ultrasound scanning and the sensed free-hand techniques. A 10-year follow-up study by Nicolides et al. on carotid and femoral bifurcation ultrasound screening demonstrated the usefulness of this simple technique in identifying populations with varying degree of risks for CV events, depending on the progression of arteriosclerotic vascular disease. They were able to classify those with low risk, limited risk, moderate risk and high risk, based on carotid and femoral bifurcation morphology.[16]

As we mentioned earlier, B-mode ultrasound is in use for several years as a convenient, safe diagnostic tool. This method has been extensively used for monitoring carotid and femoral bifurcation morphology, to detect subclinical atherosclerosis, plaque volume, plaque morphology, plaque texture, obstruction of the arteries (arterial sonography), venous thrombosis (thrombosonography), venous insufficiency (venosonography), progression of the plaque volume, and response to therapies.[13],[16] We have discussed with major manufacturers of ultrasound equipment (Fujifilm Holdings, GE Healthcare, Siemens Healthcare, Phillips Healthcare, Shimadzu Corporation, Toshiba Medical Systems, Carestream Health and Hitachi Medical) the need for a hand-held device. Some of these manufactures already have high-end equipment capable of imaging peripheral arteries and veins. We the members of a Consortium for the development of affordable medical technologies, National Design Research Foundation (NDRF), Bangalore, India, are interested in developing a simple hand-held ultrasound imaging device, which can be interfaced with existing noninvasive diagnostic platforms such as RISC and TM-Oxi, with proprietary software and analytics, so that the imaging of the peripheral arteries and veins could be done at the clinics, to follow flow velocity alterations due to subclinical atherosclerosis or blocks.

 Aspirin Resistance



The role of platelets in the promotion of thrombus formation and growth leading to acute vascular events is well established. When it comes to antiplatelet therapies, aspirin and clopidogrel have been the drugs of choice. According to the National Commission on Macroeconomics and Health, 62 million people in India have coronary artery disease.[25] Even if half of these populations are on antiplatelet therapies, we will have close to 30 million people who are on aspirin or clopidogrel prophylaxis. Aspirin has been is use for several decades for prophylaxis. However, in recent years, there is considerable concern about subjects developing resistance for this drug. In our opinion, there is no such thing as aspirin resistance.[26],[27],[28],[29],[30] In our experience of four decades, we have never come across a patient whose platelet cyclooxygenase (COX) was not inhibited by oral aspirin. However, there seems to be some clinical evidence to suggest that those on aspirin therapy found to have increased urinary metabolites of thromboxane will be at higher risk for acute vascular events. Therefore, optimization of therapies would yield better results and greater protection, if we develop point-of-care assays to monitor the efficacy of these therapies. What are some of the options? Simplest would be to monitor platelet activation by the substrate arachidonic acid (AA) using a conventional aggregometry. One can also use flow cytometer and monitor activation of GP11b/111a receptor on platelets post, AA-mediated stimulation.[31]

Since aspirin is a specific inhibitor of COX enzymes, one can monitor the ability of platelets from patients undergoing aspirin prophylaxis to generate COX metabolites. One can assay for the final stable metabolite of thromboxane B2 in the plasma or the urinary metabolite of thromboxane (11-dehydro TXB2). Commercial Elisa kits are available for monitoring these metabolites in plasma and urine.[32],[33],[34] Since these kits have to be imported, the cost per assay is going to be quite high. One can develop these assay kits provided we develop the capability to produce TXB specific antibodies in India. Another alterative methodology will be to develop assay for urinary metabolites using gas chromatography/liquid chromatography-mass spectrometry. It is possible to develop all these methodologies. However, the limitations are the cost associated with the development of these technologies, creation of awareness among the clinicians, and effective marketing.

 Clopidogrel Resistance



Clopidogrel is a pro-drug and needs to be metabolized by the liver (P450) enzymes to generate active metabolites. There is considerable concern about the possible existence of clopidogrel resistance in the patient population. Similar to aspirin resistance, there is no real clopidogrel resistance. Having said that, we need to explain why certain people do not get the maximum protection from this kind of therapy. Not everyone has the same level of P450 activity. In addition, there seems to be some genetic heterogeneity in population as far as the function of this enzyme at the gene level. What are our options? We can monitor platelet response to adenosine diphosphate using conventional aggregometry. We can also monitor platelet function using flow cytometry and enzyme immunoassay that measure phosphorylation status of vasodilator phosphoprotein by aggregometry as well as by flow cytometry of P-selectin expression.[35],[36],[37]

Genetic polymorphisms of CYP2C19 modulate clopidogrel pharmacokinetics and pharmacodynamics in healthy volunteers, as well as in patients. As compared with subjects with no CYP2C19 variant allele, subjects carrying one or two CYP2C19 loss-of-function alleles have been shown to have lower plasma concentrations of the active metabolite of clopidogrel and a decrease in the antiplatelet effect of clopidogrel in ex vivo aggregation tests.[38] Results of several recent studies support and extend these findings from previous studies by showing a worse clinical outcome in patients carrying two CYP2C19 loss-of-function alleles who were treated with clopidogrel after acute myocardial infarction.[38],[39],[40],[41],[42],[43],[44]

 Detection of the Cyp Genotyping by Taqman Polymerase Chain Reaction Assay



SNPs of each gene can be genotyped by TaqMan assay on ABI 7300 Real-Time PCR System (Applied Bio systems, Foster City, CA) as described by Ota et al.: (Int. J Med. Sci. 12 (1) 2015 PMC 4278879. The TaqMan assays could be performed with a 20 μL reaction volume with 10 μL of thunderbird probe quantitative polymerase chain reaction (PCR) Mix (TOYOBO), 0.4 μL of 50 × ROX reference dye (TOYOBO), 1 μL of 20 × each TaqMan probe and each Primer Mix, 2 μL of 2 × PCR Buffer for KOD FX Neo (TOYOBO), and 6.6 μL of distilled water. The dried saliva on a sampler could be used for these assays for DNA extraction. The thermal cycling process could be performed according to the Applied Biosystems PCR conditions: 2 min at 50°C, 10 min at 95°C, forty cycles of denaturation at 95°C for 15s, and annealing and extension at 60°C for 1 min. The results could be analyzed by ABI Prism 7300 SDS software. Alternately, Clopidogrel and its active metabolite, clopidogrel carboxylic acid could be monitored in plasma using high-performance liquid chromatography/mass spectroscopy.[41] Determining the concentration of the active metabolite in the plasma will serve as a useful tool for monitoring the compliance as well as for determining the variability in the metabolism between the various subjects.

South Asians have very high incidence of cardiometabolic diseases, such as inflammation, vascular dysfunction, abdominal obesity, metabolic syndrome, Type-2 diabetes, heart disease and stroke.[45],[46],[47],[48] These chronic metabolic diseases by and large are due to alteration in vascular physiology and function. Therefore, development of cost-effective, noninvasive devices to monitor flow velocity and fluid dynamics of regional vascular beds will help us in early detection of vascular disease. We at the NDRF, Institution of Engineers, Bengaluru, are putting together a consortium of experts, to facilitate the development of affordable medical technologies. Once we have identified the experts and their field of expertise, we would encourage them to build prototypes of devices that can monitor flow velocity and morphology or peripheral arterial and venous circulation. Availability of such device and clinical data will be useful for developing proprietary software and analytical tools for risk assessment and monitoring of therapy.[49],[50] We at the University of Minnesota have been working on morphology, biochemistry, physiology and pharmacology of platelets for over four decades. We have developed extensive contacts in India with cardiac caregivers. We are in a very good position to develop specific point-of-care assays to monitor antiplatelet therapies.[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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