Diastolic Blood Pressure

Diastolic blood pressure (DBP) is the lower number in a blood pressure reading, representing the pressure in the arteries when the heart rests between beats and refills with blood. Along with systolic blood pressure (SBP), it is a fundamental physiological parameter reflecting cardiovascular health. Blood pressure is a heritable trait influenced by multiple biological pathways and responsive to environmental factors^[1].

Biological Basis

The regulation of diastolic blood pressure involves complex biological pathways. Genetic approaches have significantly advanced the understanding of the underlying mechanisms contributing to inter-individual variation in blood pressure^[1]. Studies, including genome-wide association studies (GWAS), have identified numerous genetic loci associated with DBP. For instance, research has detected significant association signals within a large region on chromosome 12q24, which includes genes like SH2B3, ATXN2, and TRAFD1 ^[1]. Other loci showing association or suggestive evidence of association with DBP include PLEKHA7 on chromosome 11p15, and regions in or adjacent to ULK4, CSK/ULK3, and CACNB2 ^[1]. These findings provide new insights into the genetics and biology of blood pressure, highlighting potential pathways involved in its regulation ^[1].

Clinical Relevance

Maintaining a healthy diastolic blood pressure is crucial for preventing cardiovascular disease. Even small increases in blood pressure are associated with an elevated risk of cardiovascular events^[1]. Hypertension, defined as a diastolic blood pressure of 90 mm Hg or higher, affects over a billion people worldwide^[1]. High DBP is a significant risk factor for various cardiovascular complications. Genetic research has further demonstrated clinical relevance, where a genetic risk score based on multiple significant genetic variants was associated with hypertension, left ventricular wall thickness, stroke, and coronary artery disease^[1].

Social Importance

Given its widespread prevalence and strong link to cardiovascular diseases, diastolic blood pressure holds considerable social importance. Hypertension and its associated health consequences place a substantial burden on global public health systems. Understanding the genetic and biological underpinnings of DBP variation offers opportunities for identifying novel therapeutic pathways for cardiovascular disease prevention, potentially leading to improved diagnostic tools and targeted interventions^[1].

Limitations

Several factors inherent in the study design, measurement methodologies, and the complex nature of diastolic blood pressure (DBP) as a phenotype introduce limitations that warrant careful consideration when interpreting the findings. These limitations underscore the ongoing need for further research to fully elucidate the genetic and environmental architecture of DBP.

Methodological and Statistical Considerations

The inherent variability of blood pressure measurements, evidenced by test-retest reliability estimates of approximately 0.65–0.75, poses a challenge for precisely detecting small genetic effects, especially at the individual clinical level. While large sample sizes are crucial for identifying group-level differences, this intrinsic variability can still influence the statistical power and the precision of effect size estimates for genetic variants. As one of the earlier genome-wide association studies (GWAS) for blood pressure, this research was conducted at a stage where sample sizes and genomic coverage were more constrained compared to subsequent, larger investigations, implying that some variants with modest effects might not have reached statistical significance. ^[1]

Despite the application of genomic control correction, a modest test statistic inflation was observed in the meta-analysis (λGC = 1.07 for DBP), which suggests a potential for residual confounding or population stratification that may not have been fully accounted for. Although corrected, such inflation can subtly affect the reported significance levels of associations, highlighting the importance of robust replication in independent cohorts to confirm findings. The overall challenge in identifying common variants for blood pressure through GWAS, compared to other complex disorders, further underscores the need for continued research with even larger and more diverse cohorts to fully map the genetic landscape of DBP. ^[2]

Ancestry and Generalizability

A significant proportion of the primary analyses and the largest follow-up cohorts in this study were composed of individuals of European ancestry. While associations with blood pressure were also observed in East Asian, South Asian, and African ancestry individuals, their representation in the initial stages and follow-up was considerably smaller. This predominant focus on European populations means that the generalizability of specific genetic findings to other global populations may be limited, as allele frequencies, linkage disequilibrium patterns, and genetic architecture can vary significantly across different ancestral groups. ^[1]

The limited representation of non-European ancestries could lead to an incomplete understanding of the genetic factors influencing DBP worldwide, potentially overlooking variants that are more common or have larger effects in other populations. Future studies with more balanced and extensive representation of diverse ancestries are essential to ensure that genetic insights into DBP are broadly applicable and to identify ancestry-specific genetic influences. ^[1]

Environmental and Unmeasured Confounders

Several environmental factors known to contribute to inter-individual differences in blood pressure, such as dietary sodium and potassium intake or excessive alcohol consumption, were measured in only a minority of the samples. Consequently, these important potential confounders could not be meaningfully adjusted for across the entire study population. Although this omission was hypothesized to primarily reduce statistical power rather than systematically alter genotype-specific effects, the unmeasured influence of these factors could still obscure or modulate true genetic associations, contributing to remaining knowledge gaps regarding the interplay between genes and lifestyle. ^[1]

While body mass index (BMI) was adjusted for, explaining approximately 6–8% of the total variance in blood pressure, other complex gene-environment interactions or additional environmental and lifestyle factors may also significantly contribute to DBP variation. The inability to comprehensively account for all these multifaceted influences limits a complete understanding of the etiology of blood pressure and suggests the potential for residual confounding in the reported genetic associations. ^[1]

Variants

Genetic variations play a crucial role in influencing an individual’s susceptibility to various complex traits, including diastolic blood pressure. A number of single nucleotide polymorphisms (SNPs) across different genes have been identified as being associated with diastolic blood pressure, impacting diverse biological pathways from metabolic regulation to cellular signaling and vascular function.

One significant locus involves the ATXN2 gene, with variants such as rs7137828 , rs653178 , and rs4766578 . ATXN2, or Ataxin-2, is a protein involved in RNA metabolism and stress granule formation, processes critical for cellular responses to stress and the regulation of gene expression. The rs653178 variant, in particular, has been strongly associated with diastolic blood pressure, and it lies within a large genetic region on chromosome 12q24 that includes multiple genes linked by shared inheritance patterns. Variations in ATXN2 may influence blood pressure by affecting cellular signaling pathways or contributing to metabolic imbalances that impact vascular health. Also implicated in cellular regulation are variants inGALNT18 (rs10047474 ), which encodes a glycosyltransferase important for protein modification, potentially affecting cell surface receptors and signaling, and ZPR1 (rs964184 ), a zinc finger protein involved in cell cycle regulation and proliferation, which could influence the growth and function of vascular cells.

Metabolic pathways and ion transport are also key contributors to blood pressure regulation. The SLC39A8 gene, encoding the zinc transporter ZIP8, features variants like rs13107325 , rs11724128 , and rs17032400 . Zinc is an essential trace element vital for enzymatic activity, immune function, and antioxidant defense, and its transport dysregulation can impact vascular tone and inflammation, thereby influencing blood pressure. Similarly, the GCKR gene, with the variant rs780094 , encodes glucokinase regulatory protein, a key modulator of glucose metabolism in the liver. Variations in GCKR are well-known to affect glucose, triglyceride, and uric acid levels, all of which are interconnected with insulin resistance and the development of hypertension. TheCLCN6 gene, with variants rs55857306 , rs12567136 , and rs6699618 , encodes an intracellular chloride channel that plays a role in cellular ion homeostasis, a fundamental process for maintaining cell volume and function, including in vascular smooth muscle cells and kidney tubules that control fluid and electrolyte balance.

Further variants influence protein quality control and lipid metabolism. The HERPUD1 gene, alongside CETP, features the rs247617 variant. HERPUD1 is involved in the endoplasmic reticulum (ER) stress response, a cellular mechanism crucial for proper protein folding, while CETP (Cholesteryl Ester Transfer Protein) is central to cholesterol metabolism, affecting HDL and LDL levels. Given the strong link between lipid profiles, ER stress, and cardiovascular disease, variants in this region can indirectly or directly impact diastolic blood pressure. Another gene involved in protein quality control isLMAN1L (rs11636952 ), which encodes a lectin-like protein involved in ER-associated degradation, ensuring cellular health and function within the vasculature and kidneys.

Finally, genes involved in growth factor signaling and transcription factor activity also contribute. Variants in the region encompassing PRDM8 and FGF5, such as rs13125101 , rs16998073 , and rs12509595 , are associated with diastolic blood pressure. PRDM8 is a transcription factor that regulates gene expression, while FGF5 (Fibroblast Growth Factor 5) is a signaling protein involved in cell growth, differentiation, and tissue repair. These genes could influence vascular development, endothelial function, or the overall integrity of blood vessels. Additionally, theRGL3 gene, with variants rs167479 , rs2291516 , and rs318719 , encodes a guanine nucleotide exchange factor for Ral GTPases, key molecular switches that regulate diverse cellular processes, including membrane trafficking, cytoskeletal organization, and cell migration, all of which are vital for proper vascular function and blood pressure regulation.

Key Variants

RS ID	Gene	Related Traits
rs10047474	GALNT18	diastolic blood pressure
rs7137828 rs653178 rs4766578	ATXN2	open-angle glaucoma diastolic blood pressure systolic blood pressure mean arterial pressure, alcohol drinking parental longevity
rs13125101 rs16998073 rs12509595	PRDM8 - FGF5	mean arterial pressure, alcohol drinking diastolic blood pressure systolic blood pressure atrial fibrillation erythrocyte count
rs247617	HERPUD1 - CETP	low density lipoprotein cholesterol measurement metabolic syndrome high density lipoprotein cholesterol measurement diastolic blood pressure level of phosphatidylcholine
rs55857306 rs12567136 rs6699618	CLCN6	diastolic blood pressure systolic blood pressure serum alanine aminotransferase amount hypertension pulse pressure measurement
rs964184	ZPR1	very long-chain saturated fatty acid measurement coronary artery calcification vitamin K measurement total cholesterol measurement triglyceride measurement
rs167479 rs2291516 rs318719	RGL3	diastolic blood pressure pulse pressure measurement mean arterial pressure systolic blood pressure hypertension
rs13107325 rs11724128 rs17032400	SLC39A8	body mass index diastolic blood pressure systolic blood pressure high density lipoprotein cholesterol measurement mean arterial pressure
rs11636952	LMAN1L	blood protein amount systolic blood pressure, alcohol consumption quality systolic blood pressure, alcohol drinking mean arterial pressure, alcohol consumption quality mean arterial pressure, alcohol drinking
rs780094	GCKR	urate measurement alcohol consumption quality gout low density lipoprotein cholesterol measurement triglyceride measurement

Classification, Definition, and Terminology

Definition

Diastolic blood pressure (DBP) is a physiological trait representing the pressure in the arteries when the heart rests between beats.^[1] It is analyzed as a phenotype in research studies. ^[1] DBP values are typically expressed in millimeters of mercury (mm Hg). ^[1] Analyses of DBP phenotypes are often conducted independently, with residuals obtained from models that account for factors such as sex, age, and Body Mass Index (BMI). ^[1] For DBP, age-squared may also be included in these models. ^[1]

Classification

Diastolic blood pressure is assessed in relation to health outcomes, particularly hypertension.^[1]Studies evaluate deviation from mean diastolic blood pressure.^[1]Weighted risk scores for DBP are utilized to determine odds ratios for hypertension.^[1]

Terminology

• DBP:Diastolic blood pressure^[1]
• SBP:Systolic blood pressure^[1]
• BP: Blood pressure ^[1]
• HTN:Hypertension^[1]
• mmHg: Millimeters of mercury ^[1]
• Phenotype:A measurable characteristic of an organism, such as diastolic blood pressure, which is analyzed in genetic and health studies.^[1]

Causes of Diastolic Blood Pressure

Diastolic blood pressure (DBP) is a heritable trait influenced by multiple biological pathways and responsive to environmental stimuli.^[3]Elevated blood pressure, including DBP, is a common and heritable cause of cardiovascular disease globally.^[3]Hypertension, defined as a DBP of ≥90 mm Hg, affects over one billion people worldwide, and even small increases in blood pressure are linked to an elevated risk of cardiovascular events.^[3]

Genetic Factors

Numerous genetic variations have been associated with DBP, identified through genome-wide association studies (GWAS) involving individuals of various ancestries, including European, East Asian, South Asian, and African. ^[3] These studies have revealed both novel loci and genes previously suspected of regulating blood pressure.

Specific genetic findings include:

• Novel Loci: GWAS have identified 16 novel loci influencing blood pressure. Six of these loci contain genes (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3) previously known or suspected to regulate blood pressure, while the other 10 provide new insights into blood pressure physiology. ^[3]
• C10orf107: A single nucleotide polymorphism (SNP) rs1530440 on chromosome 10q21, intronic to C10orf107, has shown a significant association with DBP. ^[3] While the function of C10orf107 is unknown, nearby genes include ARID5B, TMEM26, RTKN2, and RHOBTB1. ARID5B is highly expressed in cardiovascular tissue and plays a role in smooth muscle cell differentiation. The Rho family of GTPases, which includes RTKN2 and RHOBTB1, converts guanine triphosphate to inactive guanine diphosphate, and the activity of other GTP-modulating enzymes may influence salt-sensitive hypertension.^[3]
• ZNF652: The SNP rs16948048 on chromosome 17q21, located upstream of the ZNF652 and PHB genes, has also been associated with DBP. ^[3]
• Other Associated Genes: Common variants near genes such as CYP17A1, CYP1A2, FGF5, SH2B3, MTHFR, and PLCD3have been associated with both systolic and diastolic blood pressure.^[3]
• Renal Sodium Handling: Studies of rare Mendelian blood pressure disorders have identified multiple defects in renal sodium handling pathways, indicating their importance in blood pressure regulation. ^[3]

Environmental Factors

Diastolic blood pressure is responsive to environmental stimuli.^[3]One such interaction involves the genetic pathways related to GTP-modulating enzymes, which may play a role in modulating salt-sensitive hypertension.^[3] This suggests that dietary salt intake could interact with genetic predispositions to influence DBP levels.

Biological Background

Diastolic blood pressure (DBP) is a critical physiological measure, and its elevation, even within what is typically considered a normal range, has a continuous and graded impact on cardiovascular disease risk. High DBP is a significant contributor to approximately half of all cardiovascular deaths worldwide^[4]. The regulation of blood pressure is complex, influenced by a combination of lifestyle factors and genetic predispositions. Lifestyle elements such as dietary sodium intake, excessive alcohol consumption, elevated body mass index, and insufficient physical activity are known to contribute to increased blood pressure ^[5]. Furthermore, studies of familial aggregation indicate a substantial heritable component influencing blood pressure levels ^[6].

Understanding the molecular and cellular pathways underlying DBP regulation offers insights into potential targets for preventing cardiovascular disease. Significant progress in this area has come from studies of rare Mendelian disorders of hypertension and hypotension, which have demonstrated that mutations in genes affecting renal salt handling can severely impact blood pressure^[5]. For instance, variations in the WNK1 gene, known to be involved in renal salt handling, have been associated with differences in blood pressure ^[7].

Genetic studies have identified several genes and pathways potentially involved in DBP regulation:

• Fibroblast Growth Factor 5 (FGF5): This protein is a member of the fibroblast growth factor (FGF) family, which is known to stimulate cell growth and proliferation across various cell types. FGF5 specifically contributes to the growth of cardiac myocytes and has been linked to angiogenesis, the formation of new blood vessels, in the heart ^[1].
• Cytochrome P450 Enzymes (e.g., CYP1A2): Cytochrome P450 enzymes are a group of proteins primarily responsible for metabolizing drugs and foreign chemicals in the liver. They also play a role in the cellular metabolism of arachidonic acid derivatives. Some of these arachidonic acid derivatives are known to influence renal function, peripheral vascular tone, and consequently, blood pressure ^[1]. CYP1A2 is widely expressed, constituting a significant portion of the CYP450 enzymes in the liver, and is involved in metabolizing various substances, including caffeine^[1].
• ARID3B (AT Rich Interacting Domain protein 3B): This gene is crucial for embryonic development, as its knockout in mice results in embryonic lethality and abnormalities in branchial arch and vascular development ^[1]. While its specific mechanism in adult DBP regulation is not fully detailed in these studies, its role in vascular development suggests a fundamental connection to cardiovascular health.
• ATXN2 (Ataxin 2) and CSK (c-src tyrosine kinase): Genetic variations within or near these genes have been associated with DBP levels ^[1]. However, the specific molecular or cellular mechanisms by which ATXN2 and CSK influence blood pressure are not elaborated in the provided research.

Pathways and Mechanisms

Diastolic blood pressure (DBP) is a complex trait influenced by an intricate interplay of genetic predispositions and environmental factors. Its regulation involves multiple biological pathways that affect cardiovascular function, fluid balance, and vascular tone^[3].

Environmental and Lifestyle Influences

Lifestyle choices significantly impact DBP. Factors such as high dietary sodium intake, excessive alcohol consumption, elevated body mass index, and a lack of physical exercise are known contributors to increased blood pressure ^[5]. These influences interact with an individual’s genetic background to determine overall DBP levels.

Genetic Contributions

Studies of familial aggregation indicate a substantial heritable component to blood pressure ^[6]. Significant progress in understanding this genetic basis has come from studies of rare Mendelian disorders of hypertension and hypotension. These studies reveal that mutations in genes affecting renal salt handling can have a severe impact on blood pressure^[5]. The kidneys play a critical role in maintaining fluid and electrolyte balance, which directly influences blood volume and, consequently, blood pressure.

Genome-wide association studies (GWAS) have identified numerous genetic loci associated with DBP, pointing to specific molecular pathways:

• ATP2B1: This gene has been implicated in blood pressure regulation. Research has shown lower levels of ATP2B1 in spontaneously hypertensive rats compared to non-hypertensive controls, suggesting its role in maintaining normal blood pressure ^[1]. ATP2B1 encodes a plasma membrane calcium ATPase, an enzyme involved in calcium transport, which is crucial for vascular smooth muscle contraction and relaxation.
• PLEKHA7:Genetic variants near PLEKHA7 on chromosome 11p15 have shown association with diastolic blood pressure^[1].
• CSK (c-src tyrosine kinase): A single nucleotide polymorphism (SNP) within an intron of the CSK gene (rs1378942 ) on chromosome 15q24 shows a strong association with higher diastolic blood pressure^[3]. CSK is a tyrosine kinase that plays a role in cellular signaling pathways, which can impact cell growth, differentiation, and adhesion, potentially affecting vascular structure and function.
• CYP1A2 (cytochrome P450 enzyme): Located near CSK, the CYP1A2 gene encodes a cytochrome P450 enzyme. These enzymes are vital for metabolizing various substances, including arachidonic acid derivatives. Some of these derivatives are known to influence renal function, peripheral vascular tone, and blood pressure ^[3]. A correlated SNP (rs762551 ) in CYP1A2 has been linked to caffeine metabolism, suggesting a potential pathway through which environmental factors interact with genetic predisposition^[3].
• Other Loci: Suggestive evidence of association with DBP has also been found for loci in or adjacent to ULK4 (chromosome 3p22.1), CSK/ULK3 (chromosome 15q24), and CACNB2 (chromosome 10p12) ^[1]. Broader studies have identified additional loci, including GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, and GNAS-EDN3, which are involved in various aspects of blood pressure physiology ^[3].

These genetic findings highlight diverse pathways, from ion channel function and cellular signaling to metabolic processes and vascular tone regulation, all contributing to the complex mechanisms that determine diastolic blood pressure. Understanding these pathways may offer insights into novel targets for interventions to prevent cardiovascular disease.

Clinical Relevance

Diastolic blood pressure (DBP) plays a significant role in assessing cardiovascular health and predicting disease risk. It is recognized as a predictor of cardiovascular disease risk, particularly in men^[8]. Furthermore, research indicates the age-specific relevance of usual blood pressure, including DBP, to vascular mortality^[9]. These studies highlight the importance of DBP in clinical evaluations for its prognostic value in relation to cardiovascular outcomes and overall vascular health.

Frequently Asked Questions About Diastolic Blood Pressure

These questions address the most important and specific aspects of diastolic blood pressure based on current genetic research.

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1. My parents have high DBP. Does that mean I will too, even if I’m healthy?

Yes, high diastolic blood pressure is a heritable trait, meaning you can inherit a genetic predisposition. Studies have identified specific genes, likeSH2B3 and ATXN2, that influence DBP. However, your healthy lifestyle choices can significantly help manage this genetic tendency and reduce your risk.

2. I try to live healthy, but my DBP is still a bit high. Is it something I can’t control?

While lifestyle is crucial, genetics play a significant role in DBP regulation. Even with healthy habits, your genetic makeup, involving pathways linked to genes like PLEKHA7 or CACNB2, can predispose you. This highlights the complex interplay between your genes and environment.

3. I’m not of European background. Does my ancestry affect my DBP risk differently?

It’s possible. Many initial genetic studies on DBP focused predominantly on individuals of European ancestry. Genetic factors influencing DBP can vary significantly across different ancestral groups, meaning your specific background might have unique risk factors or protective variants.

4. My sibling has normal DBP, but mine is high. Why the difference between us?

Diastolic blood pressure is influenced by a complex interplay of many genes and environmental factors. Even with shared family genetics, slight differences in the specific genetic variants you inherited (like those nearULK4 or CSK/ULK3) and unique lifestyle choices or exposures can lead to different DBP levels between siblings.

5. Does cutting back on salt really help my DBP if high blood pressure runs in my family?

Yes, absolutely. While your genetic background can make you more susceptible, environmental factors like dietary sodium intake are crucial contributors to DBP. Reducing salt can be a very effective way to help manage your DBP, even with a family history.

6. I drink alcohol sometimes. Could that affect my DBP differently than my friends?

It’s possible. While excessive alcohol consumption is a known environmental factor influencing DBP, individual genetic predispositions can affect how your body responds to alcohol. The full interplay between your specific genes and alcohol intake on DBP is an area of ongoing research.

7. Could a genetic test tell me my personal risk for high DBP and related issues?

Yes, to some extent. Genetic research has shown that a “genetic risk score” based on multiple significant variants (like those identified in regions on chromosome 12q24) can be associated with hypertension, stroke, and coronary artery disease. This could offer insights into your personal predisposition.

8. Why does my DBP seem to change every time I measure it?

Diastolic blood pressure naturally varies throughout the day due to many factors like stress, activity, and even your hydration level. This inherent variability makes precise measurement challenging. While genetics influences your baseline, these daily fluctuations are normal.

9. If high DBP runs in my family, can my healthy habits truly protect me?

Yes, absolutely. While you may have a genetic predisposition due to inherited variants, your lifestyle choices are incredibly powerful. Maintaining a healthy diet, getting regular exercise, and managing stress can significantly lower your risk and help keep your DBP in a healthy range.

10. Why is my DBP so important for my heart health, even if my other numbers are okay?

Diastolic blood pressure reflects the pressure in your arteries when your heart rests and refills with blood, which is fundamental for cardiovascular health. Even small increases in DBP are associated with an elevated risk of cardiovascular events. Genetic research further emphasizes its importance, linking genetic risk scores for DBP to conditions like stroke and coronary artery disease.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Levy, Daniel, et al. “Genome-wide association study of blood pressure and hypertension.”Nat Genet., vol. 41, no. 6, 2009, pp. 677–687.

[2] Devlin, B., and K. Roeder. “Genomic Control for Association Studies.” Biometrics, vol. 55, no. 4, 1999, pp. 997-1004.

[3] International Consortium for Blood Pressure Genome-Wide Association Studies. “Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk.”Nat Genet., vol. 43, no. 10, Oct. 2011, pp. 1005–1016.

[4] Kearney, Patricia M., et al. “Global burden of hypertension: analysis of worldwide data.”Lancet, vol. 365, no. 9455, 2005, pp. 217–223.

[5] Lifton, Richard P., et al. “Molecular mechanisms of human hypertension.”Cell, vol. 104, no. 4, 2001, pp. 545–556.

[6] Newton-Cheh, Christopher, et al. “Genome-wide association study identifies eight loci associated with blood pressure.” Nat Genet., vol. 41, no. 6, 2009, pp. 666–676.

[7] Newhouse, Stephen J., et al. “Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study.”Hum Mol Genet., vol. 14, no. 13, 2005, pp. 1805–1814.

[8] Sesso, H. D., et al. “Systolic and diastolic blood pressure, pulse pressure, and mean arterial pressure as predictors of cardiovascular disease risk in Men.”Hypertension, vol. 36, 2000, pp. 801–7.

[9] Lewington, S., et al. “Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.”Lancet, vol. 360, 2002, pp. 1903–13.