Cardiology Plus

: 2019  |  Volume : 4  |  Issue : 2  |  Page : 43--46

Visual and measured clinical phenotypes: Potential targets for cardiovascular prevention

Chunsong Hu1, Tengiz Tkebuchava2,  
1 Department of Cardiovascular Medicine, Jiangxi Academy of Medical Science, Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
2 Office of the President/CEO, Boston TransTec, LLC, Boston, MA, USA

Correspondence Address:
Chunsong Hu
Department of Cardiovascular Medicine, Jiangxi Academy of Medical Science, Hospital of Nanchang University, Nanchang University, No. 461 Bayi Ave, Nanchang 330006, Jiangxi


This article discusses and briefly reviews several visual and measured clinical phenotypes, which include height, birth weight or preterm birth body mass index, index finger to ring finger distance ratio (2D: 4D), earlobe creases, hair graying or whitening, and xanthoma. As modifiable risk factors and non-modifiable clinical phenotypes (NMCPs), these factors are potential targets for cardiovascular prevention in the new era of precision medicine. A novel score method based on modifiable risk factors and NMCPs can help for more precise diagnosis and prevention of cardiovascular disease.

How to cite this article:
Hu C, Tkebuchava T. Visual and measured clinical phenotypes: Potential targets for cardiovascular prevention.Cardiol Plus 2019;4:43-46

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Hu C, Tkebuchava T. Visual and measured clinical phenotypes: Potential targets for cardiovascular prevention. Cardiol Plus [serial online] 2019 [cited 2019 Oct 23 ];4:43-46
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Cardiovascular diseases (CVD) are prevalent and challenging illnesses globally, and their related economic and social burdens are extremely high. Thus, it is extremely important to pursue cardiovascular prevention (CVP). Currently, CVP aims to control two groups of risk factors: those that are modifiable and those that are nonmodifiable. The former covers lifestyle, biochemical and physiological indexes, such as heart rate, blood pressure, lipid, serum sugar, and other biomarkers; the latter includes gender, blood types, ethnic groups, and family history. A study found ten potentially modifiable risk factors are associated with about 90% of stroke cases in different regions of the world.[1] However, there is not enough attention paid to nonmodifiable clinical phenotypes (NMCPs). In fact, increasing evidence shows that there is an association between NMCPs and susceptibility to CVD.

 Clinical Phenotypes and Cvp

Conventionally, genotype decides phenotype, but both genotypes and monogenic or polygenic human phenotypes may link to CVD during early or later life. For example, a recent study found Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel gene, which is associated with various arrhythmia phenotypes.[2] Distinct NMCPs have resulted from multilocus genomic variation, which affects different organ systems.[3] An early study found that SCN5A mutations are associated with susceptibility to early-onset dilated cardiomyopathy, atrial fibrillation (AF), and heart failure.[4] A multicenter registry study found that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome showed more arrhythmia and higher risk for cardiac events.[5]

It is well known that the height is a highly heritable, classic polygenic NMCP. So far, there are 83 height-associated variants which were identified through genome-wide association studies,[6] and some rare and low-frequency variants may alter adult height, which is highly associated with risk of CVD, including coronary artery disease (CAD), AF, and venous thromboembolisms.[7] Shorter height in adulthood is linked to an increased risk of CAD due to the association between shorter height and an adverse lipid profile, which can lead to the development of atherosclerosis.[8] Adult height is also a marker of altered cardiac conduction.[9] For example, one height-associated nonsynonymous single nucleotide polymorphisms (rs1046934) is independently associated with AF.[10]

Birth weight was associated with 60 loci, and approximately 15% of the variance was captured by assays of fetal genetic variation.[11] There are strong inverse genetic correlations between birth weight and systolic blood pressure or CAD. Therefore, both height and birth weight could be used as a marker for prediction and prevention of CAD as assessed by coronary angiography. One study showed that preterm birth may be a new risk factor or a phenotype for early heart failure, probably due to lower birth weight.[12] There is an association between high index finger to ring finger length ratio (2D: 4D) and CAD in both hands in Chinese men,[13] but there were no significant differences in women.

Genetic association analyses show that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause.[14] Obesity is a classic phenotype of CVD, and DNA methylation may predict future development of obesity-related CVD, diabetes, cancer, and CVD, diabetes and cancers strips.[15] Due to a potential proatherogenic role, ADAMTS-7 is associated with a high-risk plaque phenotype in human carotid lesions.[16] The presence of premature hair whitening is independently related to carotid artery intima-media thickness,[17] it may be useful in identifying individuals with an increased risk of CVD.

Earlobe creases (Frank's sign) as a risk factor and easily identifiable phenotype is significantly and independently associated with CVD,[18] such as hypertension and CAD, probably due to vascular inflammation and oxidative stress. Resistant hypertension is relevant to age; younger individuals have distinct phenotypes when compared with elderly.[19] As a positive phenotype, xanthomas links to genetic familial hypercholesterolemia diagnosis and CAD risk.[20],[21] Phenotypic factors influencing the variation in response to circulating cholesterol level to personalized dietary advice, and may help to develop precision nutrition.[22] These studies help to find and understand visual and measured phenotypes as potential targets for CVP [Figure 1].{Figure 1}

As potential risk factors for CVD and stroke, NMCPs could be changed in the future by revision of individual's genotypes with a structure or gene-editing technology, for example, CRISPR/cas9 or Cpf1. Some phenotypes are highly associated with CVD; others like the unique lipoprotein phenotype are associated with healthy aging and exceptional longevity. For example, the variant distribution of NKX2-5, GATA4, and TBX5 genes is tightly associated with particular congenital heart disease subtypes.[23] Thus, gene-linked NMCPs and mutation detection can help guide treatment and prevention of CVD[5],[24] and cancer,[25],[26] they are potential targets for CVP in the era of precision medicine.


With the development of advanced instruments (e.g., single-particle cryo-electron microscopy)[27] and new technologies (e.g., single-cell sequencing),[28],[29] it is possible to determine early cell or gene structure and mutation and linked NMCPs, function and diseases, so that we can easily realize our expectation in CVP by SEEDi1.0–3.0 technologies,[30],[31],[32],[33] especially in improving atherosclerotic CVD (ASCVD) prevention through a combination of various new drugs, for example, proprotein convertase subtilisin/kexin 9 inhibitors.[34]

Obesity is an important biomarker and a modifiable phenotype for women and men, even in childhood. There is still no evidence of vascular damage in younger individuals due to physiological adaptation;[35] however, it represents a good opportunity for early prevention of obese cardiovascular risk in adulthood. The left ventricular hypertrophy is a detectable and modifiable target for the prevention of heart failure.[36] There are several inflammatory biomarkers for lower extremity peripheral arterial disease (PAD); however, a genetic marker for PAD has not been identified.[37] The chromosome 4q25 locus associated with AF risk is a detectable but not modifiable biomarker,[38] and will help to determine mechanisms and explore genetic associated new strategy for AF prevention in the future.

Thus, a novel score method based on modifiable risk factors and NMCPs screening for more precise diagnosis and prevention of CVD, which includes C-type hypertension[39] and emotionally induced cardiovascular events,[40] can be developed in the future to enhance rare-variant interpretation and identify distinct genetic causes for common diseases.[41] Simultaneously, enhancing policy prevention or grade-zero prevention[42] and developing novel technologies such as the “polypill” (SEEDi1.5)[43] or other SEEDi1.0–3.0 technologies,[30] will help increase CVP through lifestyle choices that may affect or change the function of genes and NMCPs.[44] Of course, the novel score method will also help to choose statins-based lipid-lowering and percutaneous coronary intervention for ASCVD.[45],[46]


The editors and reviewers are gratefully acknowledged for critical review.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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