Cardiovascular risks: New insights from Framingham -1988

2026-08-27 17:16


(下面中文使用 google 翻譯)
管心血管疾病仍是美國的主要死因，但其發生率在過去20年中持續下降。這一趨勢主要歸功於心血管危險因子的檢測和管理水平的提高。弗雷明漢心臟研究的開創性工作自1940年代末開始追蹤受試者，有助於揭示諸如高齡、高血壓、吸煙、血清膽固醇升高、糖尿病、左心室肥厚和肥胖等因素帶來的風險。由於這項持續的研究，臨床醫生對如何改變心血管風險有了更深入的了解，從而有望繼續降低死亡率。 （《美國心臟雜誌》1988; 116:266。）心血管疾病是工業化國家的主要死因。在美國，最常見的心血管疾病是冠狀動脈疾病，每年造成55萬人死亡和125萬例心臟事件。然而，在過去的20年裡，美國心血管疾病死亡率下降了33%，每年可能挽救了多達25萬人的生命。同時，中風死亡率也下降了。 拒絕50%。 ² 這些趨勢最可能的解釋是，由於檢測和治療的改進以及生活方式的改變，心血管疾病風險因素有所減少。 ³
弗雷明漢心臟研究收集了過去36年的數據，為心血管疾病的風險因素提供了寶貴的見解。這項研究始於1940年代末，共招募了5,209名男性和女性（均為麻薩諸塞州弗雷明漢居民），年齡介於30歲至62歲之間。在詳細了解病史後，這些受試者接受了全面的身體檢查、血液檢查、心電圖評估和胸部X光檢查。他們每兩年回來進行追蹤評估，目前正在進行第二十個週期的檢查。 ⁴
迄今為止，超過一半的最初受試者已經死亡，主要死因是心血管疾病。這些事件為我們提供了大量關於該疾病病因及其誘發因素的資訊。
例如，分析表明，男性心血管疾病的發生率幾乎隨年齡增長呈線性增加（圖1）。 ⁵ 另一方面，女性在停經前患有此類疾病極為罕見；女性的發生率比男性滯後15至20年。 ⁵
除了年齡之外，其他已知的風險因素還包括高血壓、吸菸、血清膽固醇水平升高、糖尿病、左心室肥厚和肥胖。值得注意的是，所有這些因素都是可以改變的。


高血壓的作用
對弗雷明漢研究數據的回顧顯示，高血壓在年輕人中相當少見，但隨著年齡增長，男性和女性的盛行率均上升。到大約 65 歲時，近 40% 的受試者被發現有高血壓。目前，研究族群中大部分是老年人（80 歲以上），且盛行率持續上升。 ⁵
對這些患者的觀察有助於消除許多關於高血壓與冠狀動脈疾病風險之間關聯的誤解。 ⁶ 首先，研究發現血壓與心血管疾病之間的關係是連續的，從遠低於 通常認為的血壓水平就開始發揮作用。高血壓一般來說，血壓越低，風險越低。此外，與普遍認知相反，老年人對血壓升高的耐受性並不比年輕人好。事實上，在任何血壓水平下，老年人罹患冠心病的相對風險都更高（圖2）。

另一個常見的誤解是，高血壓與心血管風險之間的流行病學關係僅限於舒張壓而非收縮壓水平。與此觀點相反，弗雷明漢研究的調查人員和其他研究人員都觀察到，收縮壓和舒張壓與預後的相關性同樣顯著。這原理對於老年族群尤其重要，因為老年族群中收縮性高血壓的盛行率高於舒張性高血壓。
弗雷明漢研究的數據也揭示了降血壓治療如何改變這些關係。研究期間，接受降血壓藥物治療的高血壓患者比例顯著增加，從約30%增加到70%。同時，血壓控制達標的高血壓患者比例也從約25%增加到70%。由於採取了更積極的治療措施，高血壓的發生率下降。同時，中風的發生率也出現下降；這種下降在女性中尤為顯著，但在男性中則不明顯。
與中風發病率的良好趨勢相反，儘管高血壓管理水平有所提高，但過去三十年來冠狀動脈疾病的發生率幾乎沒有變化。這種缺乏改善的原因一直令觀察者困惑不已，尤其是在高血壓與心血管疾病風險之間的關聯如此顯著的情況下。
對弗雷明漢研究數據的回顧提供了一些線索，或許有助於闡明這個難題。對接受治療和未接受治療的高血壓男性進行比較發現，前者實際上猝死的風險更高（圖3）。 多重危險因子乾預試驗（MRFIT）的亞組分析也得出了類似的結論。 這些觀察結果引發了人們對降血壓藥物治療潛在不良反應的擔憂，尤其是加重心律不整的風險。
為了更深入研究這些關係，我們分析了弗雷明漢研究數據，以確定687例接受利尿劑治療且無心血管疾病證據的高血壓患者中室性心律不整的發生率；並將結果與1031例未接受治療的高血壓 患者進行比較。我們發現，在接受利尿劑治療的患者群中，某些類型室性心律不整的年齡校正風險有增加的趨勢。相較之下，100例接受β受體阻斷劑治療的高血壓患者的心律不整發生率降低（圖4）。 ⁹ 新型降血壓療法在多大程度上（如果有的話）能夠降低冠心病的發生率，還需要進一步研究。
吸煙者與非吸煙者
弗雷明漢研究的數據也被用來分析吸菸對冠心病（包括急性心肌梗塞）風險的影響。結果顯示，與非吸菸者相比，吸菸者罹患心血管疾病的風險通常增加兩倍（圖 5）。有趣的是，無論吸的是過濾嘴香菸或非過濾嘴香菸，這種關聯都成立。弗雷明漢研究¹¹近期也證實了吸菸與中風風險之間有密切關聯。
膽固醇數據
血清膽固醇升高或許是心血管疾病中最常被誤解的危險因子。 1950 年收集的來自弗雷明漢健康男性（年齡 30 至 49 歲）的數據顯示，隨著基線血清膽固醇水平從 <204 mg/dl 升高至 ≥295 mg/dl，患有冠狀動脈疾病的風險呈階梯式增加。 ¹² 因此，膽固醇似乎會持續增加心血管疾病的風險，即使膽固醇水平低至 200 mg/dl 也開始增加。 MRFIT 研究人員也觀察到了非常相似的現象，他們報告稱，冠狀動脈疾病的風險呈階梯式增加，從膽固醇水平約為 180 mg/dl 開始。 ¹³
最近發表的一份關於弗雷明漢膽固醇數據的報告回顧了1950年基線膽固醇水平測量的受試者在30年隨訪期間的生存率。分析顯示，31至39歲的年輕健康男性中，基線血清膽固醇水準低於180 mg/dl者死亡率較低。膽固醇水平在180至220 mg/dl之間的人群死亡率略高，而膽固醇水平在220至260 mg/dl之間的人群死亡率則更高。基線膽固醇水平超過260 mg/dl的人群死亡率最高，令人擔憂。 ¹⁴
這些發現對確定最佳膽固醇水平具有重要意義。數據顯示，膽固醇水平在 220 至 260 mg/dl 之間與較高的心血管風險有關。一些臨床觀點認為，即使是 180 至 220 mg/dl 之間的膽固醇水平也值得關注。儘管關於具體閾值的討論仍在繼續，但研究普遍表明，維持較低的總膽固醇水平與降低冠心病及其相關併發症的風險之間存在相關性。
然而，總血清膽固醇水平僅能提供心血管風險綜合評估的一部分。 近年來，我們越來越意識到，低水平的高密度脂蛋白（HDL）膽固醇同樣會增加風險。弗雷明漢研究收集的男性和女性的資料顯示，隨著基線HDL膽固醇水平的升高，心血管疾病的風險顯著降低（圖6）。當HDL水準≥65 mg/dl時，風險極低。 ¹⁵
因此，在評估整體風險時，顯然必須同時考慮總膽固醇和高密度脂蛋白膽固醇（HDL-C）水平。在HDL-C篩檢普及之前，我們可能認為總膽固醇水平為190 mg/dl的患者罹患心血管疾病的風險並不高。然而，如今，如果我們發現這類患者的HDL-C水平為35 mg/dl，我們就會意識到其風險實際上非常高。反之，如果患者總膽固醇水平為260 mg/dl，我們過去可能會建議其徹底改變生活方式和飲食習慣，甚至可能需要藥物幹預。但憑藉現有的檢測方法，如果我們發現這類患者的HDL-C水平高於60 mg/dl，我們就會認為其心血管疾病的風險並未增加。
肥胖
肥胖已被認為是富裕人群心血管疾病的重要可控因素。 ¹⁶弗雷明漢研究發現肥胖與心血管疾病的發生與發展之間存在關聯。 ¹⁷然而，脂肪組織在評估中的作用一直存在爭議。 ¹⁶關於脂肪組織如何促進特定危險因子、其對風險的獨立貢獻以及肥胖模式的影響等問題仍未得到解答。 ^16-17
對弗雷明漢隊列進行30年的追蹤顯示，體重指數（衡量肥胖的指標）和肩胛下皮褶厚度處於最高三分之一的人群（圖7）全因死亡率、中風、心臟衰竭和冠心病風險增加。心血管事件發生率往往隨著全身肥胖和腹部肥胖程度的增加而增加。
相對體重增加和腹型肥胖程度均與心血管危險因子負擔加重有關，包括血清總膽固醇、血壓、血糖、尿酸和總膽固醇/高密度脂蛋白膽固醇比值。體重變化往往伴隨著這些危險因子的相應變化，體重每波動15磅，這些危險因子的變化趨勢呈線性。肥胖相關的部分（但非全部）心血管風險增加可歸因於這些危險因子的惡化。
由於體重對主要心血管危險因子的影響，控制體重是預防 心血管疾病的重要一環。然而，要達到顯著且持久的減重，還需要採取其他措施。
糖尿病
隨著年齡增長，人體葡萄糖耐受性會逐漸下降。然而，這並非無關緊要的衰老現象。在任何年齡段，糖尿病都會獨立地導致所有主要的動脈粥狀硬化性疾病，包括冠狀動脈心臟病、腦梗塞、週邊動脈疾病和心臟衰竭。由於冠心病的發生率較高，因此它是最常見的心血管後遺症。
糖尿病是少數幾種會消除女性相對於男性優勢的致動脈粥狀硬化代謝因素之一。糖尿病對女性所有心血管後遺症的影響都比男性更大。
糖尿病患者的心血管危險因子負擔往往比非糖尿病患者更重。心血管疾病風險增加的大部分可歸因於此，但似乎也存在一些獨特的效應，這可能與血栓形成增強有關。
糖尿病對心血管疾病的影響差異很大，取決於相關的心血管風險因素。由於風險很大程度上受合併風險因子水準的影響，因此糖尿病控制的概念應擴展至包括整個心血管風險因子的正常化。
風險因素的相互作用
弗雷明漢研究也檢視了8年期間發生冠狀動脈疾病的機率與已確定的各種風險因素之間的關係。透過建構一個針對健康、不吸菸的40歲男性（心電圖和血壓正常，膽固醇水平正常，且無左心室肥厚或糖尿病證據）的風險評估模型，數據顯示其冠狀動脈疾病風險極低（圖8）。如果此風險評估模型改變，例如血清膽固醇升高，風險會增加約四倍。如果再增加其他危險因子（例如糖尿病、吸菸、心電圖異常或左心室肥厚），風險會進一步增加。例如，對於一位40歲的糖尿病患者，如果同時吸菸、患有高血壓且血清膽固醇升高，則風險會增加100倍。 ¹⁵
從另一個角度審視這些問題，可以推薦一些臨界值來制定治療策略，以期獲得最佳的風險狀況。 基於弗雷明漢研究數據，我們可以得出結論：除非總膽固醇低於150 mg/dl，否則總膽固醇與高密度脂蛋白膽固醇的比值應≤4.5。血壓應維持在<140/90 mmHg的水平。應建議吸菸者戒菸，吸食雪茄和煙鬥的吸菸者也應如此。糖尿病患者必須嚴格控制血糖。此外，應將體重指數維持在<22 kg/m²。
結論
在過去三十年間，弗雷明漢心臟研究已確定了多種心血管疾病風險因素，包括高齡、高血壓、吸菸、高血脂、糖尿病、左心室肥厚和肥胖。過去二十年間，美國心血管疾病死亡率顯著下降。可以說，弗雷明漢研究的開創性工作促成了這一重大轉變，它使臨床醫生能夠評估患者的風險因素，並採取措施最大限度地減少不良心血管事件的發生。Cardiovascular risks: New insights from Framingham pdf英文全文
July 1988 Julius American Heart Journal Volume 116 Number 1, Part 2
Daniel Levy, MD>b and William B. Kannel, MDb Frumingham and Boston, Muss., and Bethesda, Md.



Although cardiovascular disease remains the leading cause of death in the United States, its incidence has decreased steadily during the past 20 years. This trend is largely attributable to improved detection and management of cardiovascular risk factors. The pioneering work of the Framingham Heart Study, which has followed subjects since the late 19408, has helped shed light on the risks conferred by factors such as advancing age, hypertension, smoking, elevated serum cholesterol, diabetes, left ventricular hypertrophy, and obesity. As a result of this ongoing investigation, clinicians have gained a better understanding of the ways in which cardiovascular risks can be modified so that mortality rates will hopefully continue to decline. (AM HEART J 1988; 116:266.) Cardiovascular disease is the leading cause of death in industralized nations. In the United States, the most common form of cardiovascular disease is coronary artery disease, which accounts for 550,000 deaths and 1,250,OOO cardiac events each year.’ During the past 20 years, however, the incidence of mortality from cardiovascular disease has decreased by 33% in the United States, perhaps saving as many as 250,000 lives annually. At the same time, the incidence of death from stroke has declined 50%.² The most likely explanation for these trends is a reduction in cardiovascular risk factors as a result of improved detection and treatment, as well as life-style modifications.³
Valuable insights into risk factors for cardiovascular disease have emanated from the Framingham Heart Study, which has collected data for the past 36 years. Beginning in the late 1940s, this investigation enrolled 5209 men and women (all residents of Framingham, Mass.), who ranged in age from 30 to 62 years. After thorough histories were obtained, these subjects underwent extensive physical examinations, blood tests, ECG assessments, and chest x-ray films. They have returned for follow-up assessments every 2 years and are currently undergoing the twentieth cycle of examinations.⁴
To date more than half the original subjects have died, primarily of cardiovascular disease. These events have provided a wealth of information on the cause of the disease as well as its predisposing factors.
For example, analyses have shown that the incidence of cardiovascular disease in men increases in an almost linear fashion with advancing age (Fig. 1).⁵ On the other hand, in women such disease is extremely uncommon before menopause; the incidence in women lags 15 to 20 years behind that in men.⁵
Apart from age, factors identified as conferring increased risk include hypertension, smoking, elevated serum cholesterol levels, diabetes, left ventricular hypertrophy, and obesity. It is important to note that all these factors are amenable to modification.


ROLE OF HYPERTENSION
A review of the Framingham data reveals that hypertension is fairly uncommon in young persons but increases in prevalence with advancing age in both men and women. By approximately 65 years of age, nearly 40% of the subjects were found to be hypertensive. At present much of the study population is elderly (over the age of 80 years), and the prevalence has continued to increase.⁵
Observations in these patients have helped dispel many myths regarding the association between hypertension and the risk of coronary artery disease.⁶ First, the relationship between blood pressure and cardiovascular disease has been found to be continuous, beginning at levels well below those typically regarded as hypertensive. The general rule of thumb is, the lower the blood pressure, the lower the risk. In addition, contrary to widespread belief, blood pressure elevations are not tolerated better by the elderly than by younger persons. In fact, at any level of blood pressure the elderly exhibit a greater relative risk of coronary disease (Fig. 2).

Another common misconception is that the epidemiologic relationship between hypertension and cardiovascular risk extends only to levels of diastolic rather than systolic blood pressure. Contradicting this notion, both the Framingham investigators and other workers have observed that systolic and diastolic pressures correlate equally well with outcome. This principle is of particular importance with regard to the elderly, in whom systolic hypertension is more prevalent than diastolic hypertension.
The Framingham data have also provided insights into how these relationships may be altered via the use of antihypertensive therapies. During the study the proportion of hypertensive subjects receiving such agents has increased dramatically—from approximately 30% to 70%. At the same time, the proportion of hypertensive subjects attaining blood pressure control has increased from approximately 25% to 70%. As a consequence of more aggressive management, the incidence of hypertension has declined. A concomitant decrease in the incidence of stroke has been observed; this reduction has been significant among women but not among men.
In contrast to the favorable trend with regard to stroke, the incidence of coronary artery disease has changed little during the past 3 decades despite improved hypertension management. The reason for this lack of effect has baffled observers, particularly since the relationship between hypertension and the risk of cardiovascular disease is so compelling.
A review of the Framingham data yields some clues that may help shed light on this dilemma. A comparison of treated and untreated hypertensive men shows that the former group actually sustained a higher risk of sudden cardiac death (Fig. 3).7 Subgroup analyses from the Multiple Risk Factor Intervention Trial (MRFIT) have yielded similar findings.8 These observations have given rise to concern regarding the potentially adverse effects of antihypertensive drug therapy, particularly aggravation of arrhythmias.
To examine these relationships more closely, we analyzed the Framingham data to determine the incidence of ventricular arrhythmias in 687 diuretic-treated hypertensive patients who were free of any evidence of cardiovascular disease; the findings were compared with those in 1031 untreated hypertensive subjects. We identified a trend toward an increased age-adjusted risk of some forms of ventricular arrhythmias in the group receiving diuretics. In contrast, the rate of arrhythmias was decreased among 100 hypertensive patients treated with β-blockers (Fig. 4).⁹ The extent, if any, to which newer antihypertensive therapies can reduce the incidence of coronary disease will require additional investigation.
SMOKERS VS NONSMOKERS
The Framingham data have also been analyzed to determine the effect of smoking on the risk of both coronary heart disease in general and acute myocardial infarction in particular. The results show that smokers generally have a twofold increased risk of cardiovascular disease compared with nonsmokers (Fig. 5). Interestingly, this relationship has held true regardless of whether filtered or nonfiltered cigarettes have been smoked. A strong relationship between smoking and stroke risk has also been recently demonstrated in the Framingham Study.¹¹
CHOLESTEROL DATA
Elevated serum cholesterol is perhaps the most widely misunderstood risk factor for cardiovascular disease. Data gathered in 1950 from healthy Framingham men 30 to 49 years of age show that the risk of developing subsequent coronary artery disease increases stepwise as baseline serum cholesterol levels rise across the population from <204 to ≥295 mg/dl.¹² Therefore it appears that cholesterol increases the risk of cardiovascular disease along a continuum, beginning at levels as low as 200 mg/dl. A remarkably similar observation was made by the MRFIT investigators, who reported a stepwise increase in the risk of coronary artery disease, starting at cholesterol levels of approximately 180 mg/dl.¹³
A recently published report on the Framingham cholesterol data reviewed survival rates during 30 years of follow-up of subjects whose baseline levels were measured in 1950. The analysis showed that among young, healthy men, ages 31 to 39 years, those with baseline serum cholesterol levels <180 mg/dl had a slow rate of mortality. Those with levels ranging from 180 to 220 mg/dl died at a slightly faster rate, and the rate among those with levels of 220 to 260 mg/dl was faster still. The most alarmingly rapid mortality rate was seen in the group exhibiting baseline cholesterol levels in excess of 260 mg/dl.¹⁴
These findings have important implications for determining optimal cholesterol levels. Data suggests that levels ranging from 220 to 260 mg/dl are associated with higher cardiovascular risks. Some clinical perspectives suggest that even levels between 180 and 220 mg/dl may warrant attention. While discussions regarding specific thresholds continue, research generally indicates a correlation between maintaining lower total cholesterol levels and a reduced risk of coronary disease and related health complications.
However, total serum cholesterol levels provide only one part of a comprehensive cardiovascular risk assessment. only part of the picture. In recent years we have become more aware of the fact that low levels of high-density lipoprotein (HDL) cholesterol likewise increase risk. Information gathered in Framingham men and women has revealed that the risk of developing cardiovascular disease decreased dramatically as baseline levels of HDL cholesterol increased (Fig. 6). At HDL levels ≥65 mg/dl, the risk was extremely low.15
Thus when assessing overall risk, it is clear that both total and HDL cholesterol levels must be taken into consideration. Before the availability of HDL screening, we may have considered that a patient with a total cholesterol level of 190 mg/dl was not at increased risk for cardiovascular disease. Today, however, if we found that such a patient had an HDL level of 35 mg/dl, we would recognize that the risk is actually extraordinarily high. Conversely, faced with a patient whose total cholesterol is 260 mg/dl, we may have previously recommended sweeping life-style changes and dietary modifications and possibly pharmacologic intervention. With the methodology now available to us, if we were to find that such a person had an HDL cholesterol level >60 mg/dl, we would recognize that the risk of cardiovascular disease was not increased.
OBESITY
Obesity has been implicated as an important modifiable contributor to cardiovascular disease in affluent populations.16 Investigations in the Fra-mingham Study have found a connection between obesity and the subsequent development of cardiovascular disease.¹⁷ Nevertheless, the role of adiposity in the evaluation has been controversial.¹⁶ Questions remain about its promotion of specific risk factors, its independent contribution to risk, and the influence of the pattern of obesity.¹⁶⁻¹⁹
A 30-year follow-up of the Framingham cohort has shown an increased risk of all-cause mortality, stroke, cardiac failure, and coronary disease in persons who were in the upper tertile of body mass index (a measure of obesity) and subscapular skinfold thickness (Fig. 7). Cardiovascular event rates tended to increase with the degree of general and abdominal obesity.
Both increased relative weight and degree of abdominal obesity are associated with an increased burden of cardiovascular risk factors, including serum total cholesterol, blood pressure, glucose, uric acid, and total/HDL cholesterol ratio. Changes in weight tend to be mirrored by corresponding changes in these risk factors, with linear trends observed for a 15-pound fluctuation in weight. Some but not all of the increased cardiovascular risk associated with obesity is attributable to this worsening of risk factors.
Because of the influence of weight on the major cardiovascular risk factors, weight control is an important feature of a preventive program against cardiovascular disease. However, other measures are sorely needed for achieving substantial, sustained weight loss.
DIABETES
Progressive impairment of glucose tolerance occurs as persons age. However, this cannot be viewed as an innocuous aging phenomenon. At all ages, diabetes contributes independently to all the major atherosclerotic disease outcomes, including coronary disease, brain infarction, peripheral arterial disease, and cardiac failure. Because of its greater incidence, coronary heart disease is the most common cardiovascular sequela.
Diabetes is one of the few atherogenic metabolic factors that eliminates the female advantage over men. Diabetes has a greater impact on all cardiovascular sequelae in women than in men.
Diabetic patients tend to have a larger burden of cardiovascular risk factors than nondiabetic persons. Much of the excess risk of cardiovascular disease can be ascribed to this, but there also appears to be some unique effect that may be attributable to enhanced thrombogenesis.
The impact of diabetes on cardiovascular disease is quite variable, depending on the associated cardiovascular risk profile. Since the risk is greatly influenced by the level of coexistent risk factors, the concept of diabetes control should be broadened to include normalization of the entire cardiovascular risk profile.
INTERACTIONS OF RISK FACTORS
The Framingham Study also examined the probability of developing coronary artery disease over an 8-year period in relation to the various risk factors identified. By developing a profile for a healthy, nonsmoking 40-year-old man with a normal ECG and blood pressure, normal cholesterol levels, and no evidence of left ventricular hypertrophy or diabetes, the data shows that the risk of coronary disease is very low (Fig. 8). If this profile is altered such that serum cholesterol is elevated, the risk is increased approximately fourfold. If other risk factors are then added (such as diabetes, smoking, ECG abnormalities, or left ventricular hypertrophy), the risk increases further. For instance, in a 40-year-old diabetic person who smokes, is hypertensive, and has elevated serum cholesterol, the risk would be increased 100-fold.¹⁵
Examining these concerns from the opposite perspective, certain cutoff values can be recommended to devise therapeutic strategies. directed toward producing an optimal risk profile. Based on the Framingham data, we can conclude that the ratio of total to HDL cholesterol should be ≤4.5 unless total cholesterol is <150 mg/dl. Blood pressure should be maintained at a level of <140/90 mm Hg. Cigarette smokers should be advised to quit, as should cigar and pipe smokers who inhale. Patients with diabetes must be kept under strict glycemic control. In addition, a body mass index <22 (kg/m²) should be maintained.
CONCLUSIONS
During the past 3 decades, the Framingham Heart Study has identified numerous risk factors for cardiovascular disease, including advancing age, hypertension, smoking, hyperlipidemia, diabetes, left ventricular hypertrophy, and obesity. During the past 2 decades, the incidence of mortality from cardiovascular disease has declined dramatically in the United States. It is safe to say that the pioneering work of the Framingham Study has contributed to this momentous change by allowing clinicians to assess the presence of risk factors in their patients and institute measures to minimize adverse cardiovascular outcomes.

Framingham Heart Study

2026-08-27 16:50
關於弗雷明翰心臟研究在維基百科有介紹.
下面截錄維基百科的內容
風險因子概念的確立
在1961年發表的一篇里程碑式的論文中，研究人員首次使用了「風險因子」（factors of risk）這一術語來描述與冠心病發生相關的特徵，這個術語隨後被醫學界廣泛採用[4][7]。研究識別出的主要風險因子首先是高血壓。研究證實，無論是收縮壓還是舒張壓的升高，都是冠狀動脈疾病、中風和心臟衰竭的強烈獨立預測因子，徹底推翻了當時認為「高血壓是衰老正常現象」的錯誤觀念[4][7]。其次是高膽固醇，研究明確了總膽固醇和低密度脂蛋白膽固醇水平升高會增加心血管疾病風險，而高密度脂蛋白膽固醇水平較高則具有保護作用[7]。此外，吸菸也被證實是心肌梗塞和猝死的獨立風險因子之一[7]。研究還發現，肥胖和缺乏體力活動均會顯著增加心血管疾病的風險[7]。最後，研究揭示了糖尿病患者罹患心血管疾病的風險是普通人群的2至3倍，尤其對女性影響更大[7]。

JACC-Framingham Heart Study: JACC Focus Seminar, 1/8

** 全文pdf檔案(英文)
Manuscript received October 14, 2020; revised manuscript received January 4, 2021, accepted January 20, 2021
自1948年起，弗雷明漢心臟研究（FHS）邀請了5,209名成年男女（約佔弗雷明漢鎮總人口的19%）參與，這些受試者在入組時均無明顯的心血管疾病（CVD）（最初的研究者稱之為「正常人」）。首位受試者於1948年9月29日進入心臟研究大樓接受全面的臨床檢查。
由15名鎮居民組成的執行委員會負責監督研究，並強調在抽樣過程中不應拆散家庭。因此，最初的研究樣本包含了對家庭（即夫妻）的過度抽樣，這有利於研究各種風險因素和疾病的家族聚集性，以及未來的遺傳關聯研究。這種方法的另一個值得注意的優點是，超過 50% 的參與者是女性，這在當時任何慢性病科學研究中都是不尋常的。


研究最初的目的是對入組參與者進行20年的隨訪，觀察其冠心病（CHD）的發生情況（即直至20世紀60年代末）。在這最初的20年期間獲得的資訊促成了4年內發生冠心病風險的首次描述（發表於1957年），顯示高血壓、高膽固醇和超重與新發冠心病顯著相關（4）。四年後，即1961年，Kannel等人（5）發表了一篇關於冠心病「風險因素」的開創性論文，該論文基於前6年的隨訪數據，表明高血壓、高膽固醇以及心電圖上的左心室肥厚是後續發生冠心病的強預測因子（5）。此後不久，有研究報告指出吸菸和缺乏運動與冠心病風險密切相關（6 , 7 , 8）。 1967年，多變量風險模型首次被應用，與傳統的分層方法相比，它具有多項優勢，包括能夠在大型研究隊列中同時研究多個變量之間的關係（9）。


自1971年起，心臟研究計畫（FHS）的資金得以在最初計劃的20年期限之外繼續維持，這得益於美國國家心臟研究所（後更名為美國國家心肺血液研究所）與波士頓大學簽訂的一份合同，該合同為FHS的持續研究項目提供了聯邦支持。同時，FHS擴展了研究規模，新增了子代隊列（成立於1971年），該隊列由父母參與原始隊列的子女及其配偶組成（10）。 2002年，隨著第三代隊列的招募，FHS的跨代研究設計得到了進一步擴展，該隊列由子代隊列參與者的子女組成（即原始隊列參與者的孫輩）（11）。將子代隊列和第三代隊列納入弗雷明漢心臟研究 (FHS) 的目標包括研究冠心病 (CHD) 風險因素的時間趨勢（包括出生隊列效應）、調查家族聚集模式以及評估 CHD 及其風險因素的遺傳決定因素 ( 10 )。子代隊列和第三代隊列納入時的年齡分佈與原始隊列相似（圖 1）。為了反映弗雷明漢地區人口特徵的變化，FHS 分別於 1995 年和 2002 年額外招募並納入了兩個由少數族裔群體組成的隊列，分別稱為 Omni-1 和 Omni-2（n 分別為 506 和 410）。這些隊列包括非裔美國人、西班牙裔、亞裔、印度裔、美洲原住民和太平洋島民後裔。

高血壓

高血壓是美國乃至全球心血管疾病的重要危險因子（12），自弗雷明漢心臟研究（FHS）啟動以來，它一直是這項研究的重點。在FHS啟動之初，人們對高血壓對心血管不良重塑和冠心病/心血管疾病風險的影響認識不足。事實上，在FHS開展之前，人們普遍認為老年人血壓升高是一種代償機制，旨在維持隨著年齡增長而出現的正常器官灌注。 FHS發表了多篇里程碑式的論文，徹底改變了我們對高血壓發展及其重要性的理解。其中一篇早期論文指出，高血壓是冠心病發生的最重要危險因子之一。 1970年代初，FHS的數據確立了高血壓作為中風和充血性心臟衰竭首要危險因子的重要性（13 , 14 , 15）。值得注意的是，弗雷明漢心臟研究（FHS）從一開始就明確了收縮壓（相對於舒張壓）在心血管疾病風險中的主要作用；收縮壓作為心血管疾病和卒中發病機制中可治療的危險因素的認識和廣泛接受，是在隨後的幾十年中逐步形成的。之後，研究人員概述了短期高血壓風險的因素（16），並發現終生患高血壓的風險極高（90%）（17）。 FHS 的臨床重要數據也表明，運動時血壓反應過度和血清醛固酮水平升高是顯性高血壓發生的重要危險因子（18 , 19）。 FHS 的數據也為了解社區人群中血壓從正常水平發展到高血壓的進展速度提供了重要見解（20）。最近，我們透過證明動脈僵硬度增加通常先於收縮期高血壓的發生，而非反之，闡明了主動脈僵硬度與高血壓之間的長期關係（21 ）。這種時間關聯（動脈僵硬度與血壓升高之間）隨後得到了進一步的觀察結果的支持，這些觀察結果表明，父母高血壓與其非高血壓子女（即高血壓發生之前）的血管僵硬度增加相關（22）。

HYPERTENSION. 

Hypertension, a critical risk factor for CVD in the United States and worldwide (12), has been a main focus for the FHS since its early days. At the time of the initiation of the FHS, the consequences of high blood pressure on adverse cardiovascular remodeling and CHD/CVD risk were not well recognized. A common belief before the FHS was, indeed, that higher blood pressure in the elderly represented a compensatory mechanism to maintain normal organ perfusion with aging. The FHS has contributed several landmark papers that have transformed our understanding of the development and importance of hypertension. In one of the first papers, hypertension was shown to be one of the most important risk factors for the development of CHD. During the early 1970s, data from the FHS established the importance of hypertension as a premier risk factor for stroke and congestive heart failure (13–15). Notably, FHS data from the very outset identified the primacy of systolic blood pressure (relative to diastolic blood pressure) in terms of contributions to CVD risk; the recognition and widespread acceptance of systolic pressure as a treatable risk factor for CVD and stroke pathogenesis evolved over several subsequent decades. Factors for the short-term risk of developing hypertension were later outlined (16), and it was shown that the lifetime risk of developing hypertension was exceedingly high (90%) (17). Clinically important data from the FHS have also shown that exaggerated blood pressure response during exercise and higher serum aldosterone levels are important risk factors for the development of overt hypertension (18,19). Data from the FHS have also provided important insights into the rates of progression from optimal blood pressure levels to hypertension in the community (20). More recently, we clarified the long-term relations between aortic stiffness and hypertension by demonstrating that most often, higher arterial stiffness preceded the onset of systolic hypertension rather than the other way around (21). Such a temporal association (between arterial stiffness and elevated blood pressure) was supported subsequently by observations demonstrating that parental hypertension was associated with increased vascular stiffness in their nonhypertensive offspring (i.e., before the onset of hypertension) (22).

22. Andersson C, Quiroz R, Enserro D, et al. Association of parental hypertension with arterial stiffness in nonhypertensive offspring: the Framingham Heart Study. Hypertension 2016;68: 584–9.

冠心病

一些最早且影響深遠的研究奠定了我們對冠心病病因的理解，這些研究均源自弗雷明漢心臟研究（FHS）。早期報告證實，習慣性體能活動（8）、吸菸（8）、糖尿病（23）、血膽固醇水平（24）和肥胖是冠心病的危險因子（25）。最初對冠心病「危險因子」的描述（5）也出自FHS，這些因素後來被納入冠心病10年和30年風險評分中（26 , 27）。 FHS的10年冠心病風險計算器多年來一直被納入美國國家膽固醇教育成人治療組第三次報告（NCPE ATP III），並用於確定一級預防中降脂治療的建議（28）。隨後，冠心病風險方程式擴展為更通用的心血管疾病風險方程式（29）。 FHS隊列也參與了近期對美國心臟協會/美國心臟病學會聯合隊列動脈粥樣硬化性心血管疾病方程中10年動脈粥樣硬化性心血管疾病風險評估的工作，該方程式是目前美國國家降脂治療啟動指南的基礎（ 30）。 FHS隊列進行的一項研究率先強調了父母冠心病作為子代疾病風險獨立危險因子的重要性（31）。此外，FHS隊列還提供了社區人群終生冠心病風險的估計值（32）。

CORONARY HEART DISEASE. Some of the first and most impactful studies underlying our understanding of the causes of CHD originated from the FHS. Early reports established that habitual levels of physical exercise (8), cigarette smoking (8), diabetes (23), blood cholesterol levels (24), and obesity were risk factors for CHD (25). The initial description of “factors of risk” for CHD (5) that were later incorporated into 10- and 30- year risk scores for the development of CHD also emerged from the FHS (26,27). The FHS 10-year CHD risk calculator was for many years incorporated into the National Cholesterol for Education Adult Treatment Panel III and determined recommendations for lipid-lowering treatment in primary prevention settings (28). The CHD risk equation was subsequently expanded to a more general CVD risk equation (29). The FHS cohort has also been part of the more recent efforts of estimating the 10-year risk of developing atherosclerotic cardiovascular disease in the American Heart Association/American College of Cardiology pooled-cohort atherosclerotic cardiovascular disease equation that is the basis of current national recommendations for the initiation of lipid-lowering therapy (30). One of the first studies to highlight the importance of parental CHD as an independent risk factor for disease risk in Offspring was conducted in the FHS (31). Finally, the FHS has provided estimates on the lifetime risk of CHD in the community (32).

心臟衰竭

弗雷明漢心臟研究（FHS）是最早闡明社區心臟衰竭流行病學的研究之一（ 33 , 34）。在FHS原始隊列和子代隊列中，研究人員確定了心臟衰竭的主要危險因素，包括糖尿病（34 , 35）、肥胖（36）、高血壓（14 , 15）和父母心臟衰竭史（37）。隨後，基於連續觀察，研究人員發表了用於評估心臟衰竭發生風險的綜合風險評分（38）。 FHS族群終生發生心臟衰竭的風險估計為20%（39 ）。 FHS也透過其開創性工作，加深了我們對射血分數保留型心臟衰竭（HFpEF）和射血分數降低型心臟衰竭（HFrEF）流行病學的理解。作為該領域最早的里程碑式論文之一，弗雷明漢心臟研究（FHS）的數據表明，社區中約50%發生臨床心臟衰竭的個體左心室射血分數（LVEF）保留，且與年齡匹配的對照組相比，這部分HFpEF患者的長期死亡率較高（40）。隨著時間的推移，FHS中所有心臟衰竭病例中LVEF保留的比例增加，部分原因是HFrEF某些危險因子（如冠狀動脈疾病和高血壓）的治療效果有所改善（41 , 42）。近期，FHS數據表明，心臟衰竭亞型（即HFpEF與HFrEF）本身並不能很好地區分住院風險和住院原因（43）。相反，在患有明顯心臟衰竭的參與者中，其合併症負擔和特定原因的住院治療會導致因相同原因而頻繁復發性住院（43）。

HEART FAILURE. The FHS was one of the first studies to illuminate the epidemiology of heart failure in the community (33,34). Major risk factors for heart failure, that is, diabetes (34,35), obesity (36), hypertension (14,15), and parental heart failure (37), were identified in the Original and Offspring FHS cohorts, and later, integrated risk scores estimating the risk of developing heart failure were published based on serial observations (38). The lifetime risk of heart failure in the FHS has been estimated at 20% (39). The FHS has also contributed with seminal work to our current understanding of the epidemiology of heart failure with preserved (HFpEF) versus reduced (HFrEF) LV ejection fraction. As one of the first landmark papers on the topic, FHS data demonstrated that approximately 50% of all individuals in the community who developed clinical heart failure had a preserved LV ejection fraction, and this group of participants with HFpEF experienced a high longterm mortality compared to age-matched control individuals (40). Over time, the proportion of all heart failure cases with a preserved ejection fraction has increased in the FHS, partly reflective of better treatment of select risk factors for HFrEF, such as coronary artery disease and hypertension (41,42). More recently, FHS data demonstrated that heart failure subtype (i.e., HFpEF vs. HFrEF) by itself was not a good discriminant of the risk of hospitalizations and causes of hospitalizations (43). In contrast, among participants with overt heart failure, their comorbidity burden and hospitalization for a specific cause led to frequent recurrent hospitalizations due to the same cause (43).

心房震顫

弗雷明漢心臟研究（FHS）是最早報告心房顫動主要危險因子（瓣膜性心臟病、心臟衰竭、糖尿病、男性和高齡）的研究之一（34 , 44）。隨後，研究人員開發了一種綜合風險函數來評估發生心房顫動的風險（變數包括心電圖PR間期、年齡、性別、收縮壓、高血壓治療、瓣膜性心臟病和心臟衰竭）（45）。最初的心房顫動風險函數最近擴展為CHARGE-AF（基因組流行病學心臟和老化研究隊列-心房顫動）風險評分，FHS是眾多參與其中的研究之一（46）。弗雷明漢心臟研究（FHS）也是最早證實心房顫動會增加人群中中風、心臟衰竭和全因死亡風險的研究之一，其首份報告發表於1978年（47 , 48 , 49）。此外，FHS還提供了心房顫動終生風險的估計值（最新估計值在23%至39%之間，取決於風險因素）（50）。 FHS研究人員報告稱，心房顫動不僅與臨床中風相關，還與認知功能受損和縱向認知衰退相關（51 , 52）。

ATRIAL FIBRILLATION. The FHS was one of the first studies to report the major risk factors for atrial fibrillation (valvular heart disease, heart failure, diabetes, male sex, and advancing age) (34,44), and later, an integrated risk function was developed to estimate the risk of developing the condition (variables included electrocardiographic PR interval, age, sex, systolic blood pressure, treatment for hypertension, valvular heart disease, and heart failure) (45). The initial atrial fibrillation risk function has been expanded more recently into the CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology-atrial fibrillation) risk score, in which the FHS is one of many contributing studies (46). The FHS was also one of the initial studies to show that atrial fibrillation increases the risks of developing stroke, heart failure, and all-cause mortality in the community, with the first report being published in 1978 (47–49). Moreover, the FHS has contributed with estimates of the lifetime risks of developing atrial fibrillation (with most recent estimates ranging between 23% and 39%, depending on risk factor profiles) (50). FHS investigators have reported that atrial fibrillation is associated not only with clinical stroke but also with impaired cognitive performance and longitudinal cognitive decline (51,52).

神經系統結局（中風和癡呆）

弗雷明漢心臟研究（FHS）擁有一套全面的神經流行病學方案，所有FHS參與者均接受積極監測，以觀察其是否發生中風、認知障礙和癡呆（包括阿茲海默症）。 FHS的早期報告已證實高血壓（13）、吸菸（53）、心房顫動（47）和左心室肥厚是中風的關鍵危險因子（54）。這些危險因子後來被證實與磁振造影顯示的較小腦容量以及無中風史個體的認知功能障礙相關（55）。 FHS報告稱，卒中和癡呆的終生累積風險為三分之一（56），父母一方患有卒中會使自身卒中風險增加3倍（57 ）。 FHS也是第一個證實癡呆風險隨血清同型半胱胺酸濃度升高而縱向增加的研究，而血清同型半胱胺酸濃度目前已被公認為失智症的危險因子（58 , 59）。如同過去三十年間心臟衰竭和無症狀左心室收縮功能障礙的發生率趨勢所示，弗雷明漢心臟研究（FHS）參與者的中風和失智症發生率有所下降，部分原因是研究參與者的心血管危險因子狀況隨時間推移而改善（ 60 , 61）。最近，由於參與者（生前同意）慷慨捐贈了死後腦組織，研究表明，中年時期累積的心血管危險因子與皮質和皮質下梗塞相關，但與晚年時期的整體阿茲海默症病理無關（62）。

NEUROLOGICAL OUTCOMES (STROKE AND DEMENTIA). 

The FHS has a comprehensive neuroepidemiology program where all FHS participants are under active surveillance for developing stroke, cognitive impairment, and dementia (including Alzheimer’s disease). Early reports from the FHS established hypertension (13), smoking (53), atrial fibrillation (47), and LV hypertrophy as key risk factors for stroke (54). These risk factors were later shown to be related to smaller brain volumes on magnetic resonance imaging and to impaired cognitive function in individuals without a history of stroke (55). The cumulative lifetime risks of stroke and dementia was reported to be 1 in 3 in the FHS (56), and having a parent with stroke was reported to increase the risk of stroke by 3-fold (57). The FHS was also the first study to demonstrate that the risk of dementia increased longitudinally with higher levels of serum homocysteine, which is now a wellacknowledged risk factor for dementia (58,59). As noted for trends in frequencies of heart failure and asymptomatic LV systolic dysfunction, over the past 3 decades, the FHS participants have experienced a decline in the incidence rates of stroke and dementia, partly as a result of improvement of the cardiovascular risk factor profiles over time among study participants (60,61). More recently, because of the generous donation of brains postmortem by participants (who consent when they are alive), the cumulative burden of cardiovascular risk factors at midlife was shown to be associated with cortical and subcortical infarcts but not with overall Alzheimer pathology at late life (62).

亞臨床和臨床血管疾病

弗雷明漢心臟研究 (FHS) 是最早證實吸菸與間歇性跛行之間存在關聯的研究之一( 63 )。在隨後的幾十年裡，FHS 隊列接受了全面的、最先進的表型分析，以研究各種血管床的亞臨床血管疾病和功能，這有助於我們理解動脈粥狀硬化、動脈硬化和內皮功能障礙的病理生物學，以及亞臨床血管疾病進展為嚴重心血管事件的過程。可用的測量指標包括主動脈大小、主動脈及主動脈瓣和二尖瓣的動脈粥樣硬化和鈣化負荷；超音波檢查測量的頸動脈內膜中層厚度；冠狀動脈鈣化可透過電腦斷層掃描、超音波心動圖和心血管磁振造影進行評估，頸動脈-股動脈脈搏波速度的測量以及肱動脈超音波介導的血管張力可用於評估也可用於心血管的血管張力測量。例如，弗雷明漢心臟研究（FHS）的數據表明，動脈僵硬是首次發生心血管事件的強烈獨立危險因子（64），即使高血壓控制良好，由於持續存在的血管僵硬，仍存在心血管事件的殘餘風險（65）。動脈僵硬也與目標器官損傷有關，包括蛋白尿和左心室肥厚（66）、認知障礙、亞臨床腦損傷和癡呆（67 , 68 , 69 , 70），以及心房顫動（71）和心臟衰竭（72）。在弗雷明漢心臟研究（FHS）中，基於心血管磁振造影的亞臨床主動脈粥樣硬化盛行率較高（約50%）。與本期雜誌專題中發表的其他基於人群的研究一樣，FHS的數據證實了電腦斷層掃描冠狀動脈鈣化評分能夠重新分類冠心病中等風險人群，並表明不同血管床的鈣化對未來心血管疾病風險具有獨立的預後意義（73 ）。最近，FHS數據還表明，主動脈尺寸增大（主動脈瘤的前兆和主動脈剝離的危險因子）是一種遺傳特徵（74）。

SUBCLINICAL AND CLINICAL VASCULAR DISEASE. 

The FHS was one of the first studies to establish an association of smoking with intermittent claudication (63). In later decades, the FHS cohorts have undergone comprehensive, state-of the-art phenotyping for subclinical vascular disease and function in a variety of vascular beds that have contributed to our understanding of the pathobiology of atherosclerosis, arteriosclerosis, and endothelial dysfunction, as well as the progression of subclinical vascular disease to hard CVD events. Available measures include aortic size and atherosclerotic and calcification burden in the aorta and aortic and mitral valves; carotid intimal-medial thickness on ultrasonography; and coronary artery calcifications based on computed tomography, echocardiography, and cardiovascular magnetic resonance, as well as tonometry-derived measures of carotid-femoral pulse wave velocity and ultrasound-guided measures of brachial artery flow– mediated dilation. For instance, the FHS data demonstrated that arterial stiffness is a strong, independent risk factor for a first CVD event (64) and that there is a residual risk of cardiovascular events even with well-controlled hypertension because of persistent increased vascular stiffness (65). Arterial stiffness has also been shown to be associated with target end-organ damage, including albuminuria and LV hypertrophy (66), cognitive impairment, subclinical brain damage, and dementia (67–70), as well as with atrial fibrillation (71) and heart failure (72). The prevalence of subclinical aortic atherosclerosis based on cardiovascular magnetic resonance was reported to be high (approximately 50%) in the FHS. Like other population-based studies presented in this theme issue of the Journal, data from the FHS have confirmed the ability of coronary calcification scores on computed tomography to reclassify individuals at intermediate risk of CHD and have shown an independent prognostic importance of calcification across the different vascular beds for the future risk of CVD (73). More recently, the FHS data also demonstrated that increased aortic size, a precursor of aortic aneurysms and a risk factor for aortic dissection, is a heritable trait (74).

心臟影像

在社區隊列研究中，弗雷明漢心臟研究（FHS）是最早採用心臟影像學技術的機構之一，並在1970年代末將超音波心動圖引入其常規參與者追蹤中。心臟超音波檢查引入後不久，便建立了心室質量和左心室肥厚危險因子（例如，年齡增長、肥胖和高血壓）的正常範圍（75 , 76），以及社區人群左心室壁厚度、左心房大小和主動脈根部大小的正常參考值（ 77 , 78）。 FHS對於闡明社區無症狀個體中左心室肥厚和其他異常超音波表現的預後意義至關重要（79 ）。 FHS也強調了無症狀左心室收縮功能障礙和擴張的不良預後意義，並證實其會增加長期發展為顯性心臟衰竭的風險（80 , 81）。由於其縱向設計並進行了重複的超音波心動圖測量，弗雷明漢心臟研究（FHS）也描述了心臟重塑在成年期和正常老化過程中的發生情況。左心室收縮期射血分數、主動脈根部和左心房大小隨年齡增加而增加，而左心室舒張末期內徑則減少（82）。此外，左心室舒張功能往往會隨著年齡增長而惡化，但良好的心血管代謝風險因子可以部分緩解這種與年齡相關的左心室舒張功能下降（83）。在FHS研究中，1985年至2014年間無症狀左心室收縮功能障礙的盛行率有所下降，部分原因是風險因子控制得更好（冠心病患病率降低和血壓控制不佳的情況減少）（41）。近年來，弗雷明漢心臟研究（FHS）還提供了與心肌應變（斑點追蹤超音波心動圖）、左心房排空分數和左心房功能指數相關的參考值和臨床心血管疾病風險（84、85、86、87、88 ）。最後，FHS基於心臟磁振造影（目前評估心室結構的黃金標準方法）建立了一般人群心室質量、心腔容積和收縮功能指標的正常值（89）。

CARDIAC IMAGING. The FHS was an early adopter of cardiac imaging modalities among community-based cohort studies and introduced echocardiography to its routine participant study visits in the late 1970s. Normal ranges for ventricular mass and risk factors for LV hypertrophy (i.e., advancing age, obesity, and high blood pressure) were established shortly after the introduction of cardiac ultrasonography (75,76), along with normal reference values for LV wall thickness, left atrial dimension, and aortic root size in the community (77,78). The FHS has been important for describing the prognostic importance of LV hypertrophy and other abnormal sonographic findings in asymptomatic individuals in the community (79). The FHS also highlighted the adverse prognostic significance of asymptomatic LV systolic dysfunction and dilation by documenting an increased long-term risk of developing overt heart failure (80,81). Given its longitudinal design with repeated echocardiographic measures, the FHS has also described how cardiac remodeling occurs over the adult life course and with normal aging. LV systolic ejection fraction, aortic root, and left atrial size increase with age, whereas the LV end-diastolic dimension decreases (82). Further, LV diastolic function tends to worsen with age, but the age-related decrements in LV diastolic function can be partially attenuated by favorable cardiometabolic risk profiles (83). The prevalence of asymptomatic LV systolic dysfunction declined between 1985 and 2014 in the FHS, partly as a result of better risk factor control (lower prevalences of CHD and poorly controlled blood pressures) (41). More recently, the FHS has also contributed reference values for and clinical CVD risks associated with myocardial strain (on speckled tracking echocardiography), left atrial emptying fraction, and left atrial function index (84–88). Finally, the FHS has established normative values of ventricular mass, cavity volumes, and systolic function measures in the general population based on cardiac magnetic resonance imaging (the current gold standard modality to assess ventricular structure) (89)

生物標誌物

弗雷明漢心臟研究（FHS）一直處於社區風險預測生物標記研究的前沿。例如，一些早期生物標記研究表明，由10種蛋白質（血漿利鈉肽、C反應蛋白、腎素、醛固酮、纖維蛋白原、D-二聚體、1型纖溶酶原激活物抑製劑、同型半胱氨酸和尿白蛋白/肌酐比值）組成的多標誌物組合與發生重大心血管事件和死亡的風險相關，但其對這些事件的標準顯著性（ 90 微因子，遠低於其貢獻因素， 90 微因子對這些事件的標準微因子，遠低於其對這些事件的標準風險，遠比其貢獻 90 微因子，其對這些事件的標準微因子，遠低於其對這些事件的標準風險，遠低於其對這些事件（90 微因子），遠低於其對這些事件（ 90微因素對這些事件）的風險都遠低於其貢獻。基於FHS的重要研究也證實了肥胖相關的利鈉功能障礙，並表明血液利鈉肽濃度不足以用於篩檢社區人群的左心室收縮功能障礙和左心室肥厚（ 91 , 92）。

BIOMARKERS. The FHS has been at the forefront of biomarker research for risk prediction in the community. For instance, some of the early biomarker research showed that a multimarker panel of 10 proteins (plasma natriuretic peptides, C-reactive protein, renin, aldosterone, fibrinogen, D-dimer, plasminogen-activator inhibitor type 1, homocysteine, and urinary albumin-to-creatinine ratio) was associated with the risk of developing major cardiovascular events and deaths but contributed only minimally to incremental prediction of these events beyond standard risk factors (90). Important work based on the FHS also demonstrated a natriuretic handicap associated with obesity and showed that blood natriuretic peptide concentrations were suboptimal to screen for LV systolic dysfunction and LV hypertrophy in the community (91,92).

心血管疾病及其危險因子的遺傳學和基因組學

弗雷明漢心臟研究 (FHS) 的遺傳學發現得益於其基於家庭的抽樣方法，該方法能夠分析相關臨床性狀的遺傳力、連鎖關係以及全基因組關聯研究。自 2007 年起，FHS 參與者開始使用基於晶片的基因分型平台進行基因分型，最初採用的是 100K 計畫（100K Affymetrix [加州聖克拉拉]），之後又採用了密度更高的平台（500K Affymetrix 晶片加上 50K Affymetrix補充晶片）、外顯子定序和全基因組定序平台，其中全基因組定序是透過美國國家心肺血液研究所的 TOP-Med（精準醫學跨組學）計畫完成的。 FHS 隊列也進行了全血DNA 甲基化、microRNA和基因表現譜的高通量檢測。大多數參與者已同意進行遺傳學和基因組學分析，具有可用生物標記的個體數量已在其他文獻中公佈（93）。這些遺傳學和基因組學資料為深入了解心血管疾病（CVD）（94 , 95）、血壓（ 96 , 97）、冠狀動脈疾病（98 , 99 , 100 , 101）、中風（, 103 動脈（主動脈1033）、血脂水平（ 99 1033） 103動脈（ 1033） 1034 103 動脈（3033 ） 103動脈（ 10333 ）、血脂）和體重指數（106）的分子流行病學做出了重要貢獻，並闡明了超音波心動圖特徵和心臟衰竭的基因組結構（ 107 , 108 , 109 , 110）。許多研究都得益於多隊列合作，包括 CHARGE（基因組流行病學心臟和衰老研究隊列）、EchoGen（Echo Genetics）、DIAGRAM（糖尿病遺傳學複製和薈萃分析）、MAGIC（葡萄糖和胰島素相關性狀薈萃分析聯盟）、CARDIoGRAM（冠狀動脈疾病全基因組複製和薈萃分析）以及 HERMES分析）以及 HERMES（冠狀動脈疾病107、111、112、113、114、115） 。這些研究以及其他全基因組關聯研究（[ SNP間關聯全基因組資料庫]）的匯總統計估計值表明，Johnson 等人 [ 116 ] 編製的 Phenotypes 資料庫 ( 117 , 118 ) 繼續作為探索基於孟德爾隨機化原理的因果推論研究的重要工具 ( 119 , 120 , 121 )。

GENETICS AND GENOMICS OF CVD AND ITS RISK FACTORS. Genetic discovery in the FHS is facilitated by the family-based sampling, which enables analyses of heritability, linkage, and genome-wide association studies for relevant clinical traits. Starting in 2007, FHS participants have been genotyped with array-based genotyping platforms, initially with the 100K Project (100K Affymetrix [Santa Clara, California]) and, later, with more dense platforms (500K Affymetrix plus 50K Affymetrix supplement), exome sequencing, and whole-genome sequencing platforms, the last of these through the TOP-Med (Trans-Omics for Precision Medicine) project of the National Heart, Lung, and Blood Institute. The FHS cohorts have also undergone high-throughput assays for whole-blood DNA methylation, microRNA, and gene expression profiling. The majority of participants have consented for genetics and genomics analyses, and the numbers of individuals with available biomarkers are available elsewhere (93). These genetic and genomic data have contributed to important insights into the molecular epidemiology of CVD (94,95), blood pressure (96,97), coronary artery disease (98–101), stroke (102), lipid levels (99,103), aortic stenosis (104), atrial fibrillation (105), and body mass index (106), and they have elucidated the genomic architecture of echocardiographic traits and heart failure (107–110). Many of the investigations have been facilitated by multicohort collaborations, including the CHARGE (Cohort of Heart and Aging Research in Genomic Epidemiology), EchoGen (Echo Genetics), DIAGRAM (Diabetes Genetics Replication and Meta-analysis), MAGIC (Meta-analyses of Glucose and Insulin-Related Traits Consortium), CARDIoGRAM (Coronary Artery Disease Genome-Wide Replication and Meta-analysis), and HERMES (Heart Failure Molecular Epidemiology for Therapeutic Targets) consortia (107,111–115). The summary statistics estimates from these and other genomewide association studies (exemplified by the GRASP [Genome-Wide Repository of Associations Between SNPs and Phenotypes] database compiled by Johnson et al. [116]) (117,118) continue to serve as important tools for exploring causal inference studies based on mendelian randomization principles (119–121) MULTIOMICS STUDIES OF CVD AND ITS RISK FACTORS. The FHS has implemented several initiatives in the fields of molecular epidemiology and is at the forefront of discovering clinical correlates and disorders associated with metabolomic, lipidomic, and proteomic profiling. More recently, the FHS participants have also contributed stool microbiome data, which will be an important resource to understand the influence of the gut microbiome on health and disease risks. Indeed, all of these multiomics data will yield additional important insights into various pathophysiological states in the years to come and have already highlighted biological pathways involved in the development of, for example, diabetes (122–124), high body mass index (125), renal disease (126,127), longevity (128), heart failure (129,130), atrial fibrillation (131), dyslipidemia (99), atherosclerotic disease (132,133), and acute exercise (134). In addition, microbiome data recently solved a long unanswered question, that is, why certain people absorb cholesterol from the intestines, while others do not, by discovering that certain bacteria subtypes metabolize cholesterol to the unabsorbable coprostanol and that individuals whose gut is rich with select bacterial species had higher levels of fecal cholesterol and lower levels of blood cholesterol in the FHS (with the magnitude of variation being comparable to that carried by common genetic variants of lipid homeostasis) (135).

心血管疾病及其危險因子的多組學研究

弗雷明漢心臟研究（FHS）在分子流行病學領域開展了多項舉措，並處於代謝組學、脂質組學和蛋白​​質組學分析與臨床相關性和疾病發現的前沿。近期，FHS參與者也貢獻了糞便微生物組數據，這將成為了解腸道微生物組對健康和疾病風險影響的重要資源。事實上，所有這些多組學數據將在未來幾年為各種病理生理狀態提供更多重要的見解，並且已經突出了與糖尿病（ 122、123、124）、高體重指數（125）、腎臟疾病（ 126、127 ） 、長壽（128）、心臟衰竭（腎臟疾病（ 126、127 ） 、長壽（128）、心臟衰竭（腎臟疾病（129、130 130 房）、血脂異常（99）、動脈粥狀硬化性疾病（ 132、133）和急性運動（ 134）等疾病發展相關的生物學途徑。此外，微生物組數據最近解決了一個長期未解的問題，即為什麼有些人能從腸道吸收膽固醇，而有些人卻不能。研究發現，某些細菌亞型會將膽固醇代謝成無法吸收的糞甾醇，而腸道中富含特定細菌種類的個體在FHS研究中糞便膽固醇水平較高，血液膽固醇水平較低（變異幅度與脂質穩態常見遺傳變異所攜帶的變異幅度相當）（ 135）。