Lipoprotein(a)—60 Years Later—What Do We Know?
Round 1
Reviewer 1 Report
In the present work, Paslawska et al. summarize cumulative knowledge on the importance and function of Lp(a) as a marker of cardiovascular disease, as well as pharmacologic interventions in clinical use or under study mitigating it. The authors appraise current challenges as well as future directions in the measurement , standardization , clinical adoption and therapeutic targeting of Lp(a). The manuscript is well organized, detailed, appropriately referenced and without any evidence of bias or misrepresentation.
A few linguistic mistakes are noted which can be easily mitigated with minor editing.
Author Response
We would like to appreciate the guidance and kind remarks of the reviewer. We carefully followed the work from a linguistic point of view in order to ensure the best possible level of English.
Reviewer 2 Report
Pasławska et al wrote a very interesting manuscript. It is a well-writen review using recent literature.
Could the authors add data concerning the detailed lipid composition of Lp(a) lipoprotein?
Author Response
We are grateful for the valuable suggestions and feedback from the reviewer. According to his/her remark “Could the authors add data concerning the detailed lipid composition of Lp(a) lipoprotein?”, we have expanded information on the detailed lipid composition of Lipoprotein (a) as below.
â–º Chapter 2; line 56;
Lp(a) contains apo(a) and apo(b) in a molar ratio of 1:1, covalently bound by a disulfide bridge. The protein components constitute 30 % of the weight of the Lp(a) molecule, allied with associated cholesterol esters (35%), phospholipids (20%), free cholesterol (8%), cholesterol (5%) and triglycerides (2%) [9].
Reviewer 3 Report
In this review, the authors present the recent knowledge on Lp(a) based on clinical and scientific research. However before the manuscript can be accepted for publication, the authors need to add the following description in the manuscript:
1) detailed explanation on the current understanding on the pathophysiology of Lp(a) and ASCVD
2) effects of lifestyle interventions on Lp(a)
Several grammatical errors need to be corrected in the manuscript.
Author Response
We would like to thank you for your kind review and valuable comments. According to them, we have completed the manuscript as below:
1) “Detailed explanation on the current understanding on the pathophysiology of Lp(a) and ASCVD”
â–º Chapter 3; line 104
The uniqueness and dualism of Lp(a) particle, based on homology with both plasminogen and LDL-C, are supposed to underly the pathophysiological mechanisms of atherosclerotic cardiovascular disease development.
2) “Effects of lifestyle interventions on Lp(a)”
â–º Chapter 8; line 390; below the table 4.
Although lifestyle interventions may not directly influence Lp(a) levels or change them slightly, a healthy diet and/or regular physical activity are recommended for cardiovascular disease prevention. The mentioned lifestyle factors can improve the lipid profile. Decreasing LDL-C (suitable diet) and increasing HDL-C (physical activity) values is highly recommended to mitigate the synergistic risk of high LDL and Lp(a) concentrations and ought to be the basis of elevated Lp(a) cardiovascular prophylaxis.
Additionally, we would like to point to the in-text mentions of diet (195-199 lines) and physical activity (207-208 lines).
We have also followed the work from a linguistic point of view in order to avoid grammatical errors.
Reviewer 4 Report
This review comprehensively summarizes the previous background, current management and future therapeutic target of Lp(a), and could help readers quickly obtain the clinical significance of Lp (a). However, there are still some areas worth improving.
1. Page 2, Lines 54-57: What is the relationship among K, KV and KIV should be described.
2. Page 3, Lines 102-107: As the platelets were considered crucial in thrombosis, a detailed mechanism should be introduced.
3. Page 5, Lines 152: What is the exact relationships between Lp(a) levels and its size? As you summarized in Lines 57-58: The multiple copies are directly responsible for a different size heterogeneity of apo(a) isoforms that are inversely related to Lp(a) levels
4. Page 6, Lines 194-199: As you said physical activity and exercise have no or minimal impact on Lp(a) [40], should the physical activity be recognized as health-promoting behaviors for Lp(a)?
5. Throughout: What are the differences between this review and the previous ones？Moreover, as you instructed the topic of peripheral arterial disease (PAD), we do not see a description of the most common PAD——Critical Limb Ischemia, let alone the aortic disease (aneurysm or dissection)
Author Response
We would like to thank for the review and valuable guidance. In order to improve our manuscript, we have made the following changes:
1) Page 2, Lines 54-57: “What is the relationship among K, KV and KIV should be described”
â–º Chapter 2; line 64.
We have pointed to the similarity of Kringle V and IV structure by adding the sentence as below:
… called “kringle” (K). “Each kringle (KV, KIV) has a distinctive triple loop structure through six retained cysteine residues that form three disulfide bonds.”
2) Page 3, Lines 102-107: „As the platelets were considered crucial in thrombosis, a detailed mechanism should be introduced.”
â–ºAccording to the suggestion, we have added the following data (Chapter 3; line 129):
Lp(a) is positively correlated with platelet aggregation independent of lipoprotein-associated phospholipase A2 (Lp-PLA2), which may be partly responsible for the atherothrombotic effect of Lp(a). The exact mechanisms demand further investigation.
- Liu, H.; Fu, D.; Luo, Y.; Peng, D. Independent association of Lp(a) with platelet reactivity in subjects without statins or antiplatelet agents . Sci Rep. 2022, 5,12(1):16609.
3) Page 5, Lines 152: „What is the exact relationships between Lp(a) levels and its size? (As you summarized in Lines 57-58: The multiple copies are directly responsible for a different size heterogeneity of apo(a) isoforms that are inversely related to Lp(a) levels)”
â–º The last sentence (line 193) has been removed in order to unify this issue.
4) Page 6, Lines 194-199: „As you said physical activity and exercise have no or minimal impact on Lp(a) [40], should the physical activity be recognized as health-promoting behaviors for Lp(a)?”
â–º We have added an additional description about the effects of lifestyle interventions on Lp(a) (Chapter 8; line 390; below table 4):
“ Although lifestyle interventions may not directly influence Lp(a) levels or change them slightly, a healthy diet or regular physical activity are recommended for cardiovascular disease prevention. The mentioned lifestyle factors can improve the lipid profile. Decreasing LDL-C (suitable diet) and increasing HDL-C (physical activity) values is highly recommended to mitigate the synergistic risk of high LDL and Lp(a) concentrations and ought to be the basis of high Lp(a) cardiovascular prophylaxis.”
5) „What are the differences between this review and the previous ones?”
â–º Our review is based on recent publications. The most important issues regarding Lp(a) are described compactly and comprehensively at the same time. This combination allows for efficient and versatile gaining of current knowledge by medical staff and patients. We have completed our manuscript with a chapter on „Lp(a) in children and youth” which was usually omitted in previous reviews.
6) „Moreover, as you instructed the topic of peripheral arterial disease (PAD), we do not see a description of the most common PAD——Critical Limb Ischemia, let alone the aortic disease (aneurysm or dissection)”
â–ºAccording to the suggestion, we have expanded the section on PAD (Chapter 4; line 169)
Moreover, Lp(a) concentration correlates with Peripheral Arterial Disease (PAD). Elevated plasma Lp(a) levels enhance the incidence of PAD and hospitalization related to the disease. Higher levels of Lp(a) are associated with multiple peripheral artery revascularization, and serious dismemberment among patients suffering from PAD or new peripheral lesions. Lp(a) concentration may be predictive of atherosclerosis correlated with cardiovascular events, including Critical Limb Ischemia or other lower-limb events among patients with PAD [36,37].
Nevertheless, we would like to emphasize that we are biochemists and pathologists, not clinicians. We do not feel to be right persons to describe clinical symptoms in details.
Reviewer 5 Report
The authors focus on the Lipoprotein (a) (Lp(a)) molecule, which includes two protein components: apolipoprotein (a) and 9 apoB100. This review is an interesting manuscript on LDL-cholesterol and clinical presentation (diseases). It is an up-to-date review, easy to read and of interest to general clinicians and cardiologists. It should be acceptable to publish in this format without modifications.
Author Response
We would like to thank for your comprehensive review and kind remarks.
Round 2
Reviewer 2 Report
It can be published in the present form.
