Sir George W. Pickering was an astute, opinionated observer and highly gifted cardiovascular investigator. He considered the rich history of cardiovascular research, settled on the term “essential hypertension” (although he did not like it much) and left us with two challenges and then outlined three areas of investigation, namely animal models, human translational studies and genetics to pursue. These directives have been largely fulfilled and have resulted in a substantial, albeit imperfect, treatment armamentarium. The essential challenge remains in further scholarship and clinical application.

Aside perhaps from di Paolo's portrait of St. John the Baptist's beheading (Figure 1), the most telling description of blood pressure was conveyed to us by William Harvey, who wrote: “Lastly, as in the cutting of any artery, the blood leaps out sometimes farther, sometimes nearer, you shall find the out‐leaping to be just with the arterial diastole, at which time the heart strikes the breast, and at that time then when it appears that the heart is in its tension and contraction, it is in its systole, and the blood is thrust out with the same motion.”

The fact that elevated blood pressure is lethal is known to us since the 19th century as the result of bedside and “dead‐house” observations, as Pickering observed.1 He commented that high blood pressure can occur in ways. In secondary hypertension, high blood pressure is associated with a specific disease to which it is believed to be secondary, such as pheochromocytoma, unilateral renal disease, Cushing's syndrome, coarctation of the aorta, Conn's syndrome, or acute nephritis. However, Mahomed demonstrated hypertensive patients earlier in whom evidence of a specific underlying disease was wanting.2 The recognition of this condition was slow and a bewildering succession of names was applied. Hyperpiesia was a good one that did not stick.

A name that did survive was Essentielle Hypertonie .3 In 1911, Franka ^a Erich Frank (1884 Berlin‐1957 Istanbul) was a German physician and internist. He was professor of medicine in Breslau, when in 1934, the German authorities released him from his duties because of Jewish parentage. Frank moved to Istanbul, where he continued his highly successful distinguished career.
administered adrenalin (Suprarenin^®; Hoechst) to patients and observed a prompt increase in blood pressure (expressed as cm H₂O), while blood (or plasma) glucose levels hardly changed. Frank recognized the fact that adrenalin‐related blood pressure increases were similar to those observed when the sympathetic chain was stimulated. He noted that the adrenal medulla was sympathetically innervated. Nevertheless, adrenalin worked even if the sympathetic chain was mechanically destroyed. In his discussion, Frank distinguishes between hypertension forms related to underlying renal diseases and hypertension without an obvious cause (similar to Mahomed's conjectures). He concludes that an increase in tone of all small arteries in the body, including those in the kidney, must be responsible and uses the term “primary” to describe this state‐of‐affairs. He then goes on to state that he will use the term “essential hypertension” to describe this condition, to separate it from causes related to renal disease. Renin was known to Frank and the paper by Tigerstedt and Bergmann was cited, although the world would have to wait another 25 years before renin substrate and angiotensin were discovered. Frank does not iterate further on why he selected the term “essentielle Hypertonie,” although he does observe that the reasons for the increased peripheral vascular resistance were unclear. Adrenalin (a problem related to the chromaffin organ) was clearly one of his candidates. Twenty years later, Volhard devoted 142 pages of fine print to the topic but could not really help Frank further.4

Early on, the impact of hypertension on survival was clearly recognized, and not just the accelerated form (malignant hypertension) but also any blood pressure elevation was considered lethal. Schleicher begins her book on hypertension, in 1944, with the statement that hypertension was responsible for more deaths than tuberculosis and cancer put together.5 She cites no references for this interesting statement, although we now know through the Global Burden of Disease Studies that she was absolutely correct. As a matter of fact, elevated systolic blood pressure is the single most important cause for cardiovascular death, the commonest cause of death worldwide, twice as important as smoking, blood sugar, blood lipids, obesity, and environmental influences.

For Pickering, two questions emerged.1 What is the mechanism by which blood pressure increases (in all forms of hypertension)? What is the nature of primary essential hypertension? He outlined three areas of investigation. First, the production of hypertension requires animal models. Second, the circulatory changes must be documented, not only in the animals but also in man. Third, the genetic and environmental factors must be elucidated. Pickering was an ardent taskmaster, but at least he was unequalled as a contributor to all the answers.

Ohm provided the law, and the law is equally applicable to the cardiovascular system as it is to electronic circuitry. Over the entire body, we deal with three variables, electromotive force (pressure), flow, and resistance. Since in established chronic hypertension, cardiac output has invariably been found to be “normal,” we must accept that increased peripheral vascular resistance (as Frank surmised) is responsible for increased blood pressure. Thus, research has focused on what causes vascular alterations to increase peripheral vascular resistance. Animal models have been produced in abundance; the most productive have been gene‐modified rodent models.

Pickering was well aware of the kidney's putative role in blood pressure regulation and gives Goldblatt full credit.6 Oddly, Pickering does not appear to ascribe to the idea that pressure natriuresis is the most important of all long‐term regulators of arterial pressure. Guyton et al reasoned that an increase in extracellular fluid volume, which usually accompanies sodium accumulation, is responsible for increases in arterial pressure.7 If the increase in fluid volume is prevented, hypertension will not occur despite marked sodium retention. They argued that long‐term autoregulation in hypertension plays a very important role for two reasons. First, it greatly increases the total peripheral resistance, while the cardiac output increases only a small amount; second, when it promotes arteriolar constriction, capillary pressure is reduced, which in turn allows a very large proportion of the extracellular fluid to remain in the blood rather than to leak into the interstitium. Even more remarkable is the fact that the systems analysis by Guyton et al, an idea with methodology far ahead of its time, is not cited or even mentioned by Pickering, who was surely familiar with the concept. Guyton's model is accepted by many, although it continues to draw substantial discussion including the introduction of alternative models, and may require subsequent modification. Pickering never warmed up to the salt‐hypertension idea and publicly teased Dahl (salt‐sensitive and salt‐resistant rats) for his conclusions and his low‐salt diet. Pickering's data suggested that angiotensin actually promoted natriuresis rather than sodium retention.

Genetics has undergone a revolution that would have delighted Pickering. Have we “closed the loop” and if not, where are we now? Perhaps we should begin with “bottom up.” Are we just born with it? Weitz initially studied monozygotic twin subjects and observed that their blood pressures invariably were similar, while dizygotic twins were not quite so similar. Weitz next addressed this notion in 82 patients with hypertension (without renal disease) and 267 other patients attending his clinic for other reasons. He found a family history of stroke and heart failure (cardiovascular disease) in 77% of his patients but in only 30% of his controls. Weitz subsequently measured blood pressure in siblings of patients and controls. The results at the time suggested that hypertension is inherited in a Mendelian fashion (autosomal dominant). Platt ascribed to that view and also made observations in twins and families.8 What Pickering and associates did was to accrue evidence from population samples (Figure 2). In this figure, we can see the blood pressure distributions of subjects in women and men, corrected for age, across a wide range of blood pressures. The Pickering investigators studied three groups of patients, the population at large, the first‐degree relatives of persons known to be hypertensive and the first‐degree relatives of patients known to be not (normal) hypertensive.1 The frequency distributions made the point. The Gaussian distributions are merely shifted according to the genetic risk. The data approximated Galton's data for height and more recent findings to this end. Pickering loved being right; but was he?

The closest we can come to genetically addressing Pickering's distributions is the genome‐wide genetic association study (GWAS). These studies examine >1 million genetic markers across the >3 billion long base‐pair genome. In the largest such studies, a million affected (hypertensive persons) have been compared to a similar number of controls. The idea here is to find those sites on the genome that are (far) more common in the hypertensives, compared to the normotensives. Cabrera et al recently reviewed the large numbers of GWAS performed and reported on 1000 genetic loci influencing blood pressure.9 Each locus predicts far less than 1 mm Hg blood pressure. The number would have surely flabbergasted Pickering who was hardly prone to becoming rattled. Nonetheless, the 1000 genes explained only a part of the expected genetic variance. Many of the genes are expressed in the vascular tree. They are involved in signal transduction, receptor regulation, cell proliferation, structural morphogenesis, filament‐based processes and organelle organization. The authors performed a “multi‐trait” association of the blood pressure loci plotted against numerous phenotypes associated with hypertension, as a “heat map.” The results could represent “finding what you knew had to be there.”

Nevertheless, Platt does not leave the arena empty handed. Numerous families with Mendelian hypertension have been identified and the relevant mutations cloned.10 Each mutation has a profound effect on blood pressure, explaining the entire genetic effect within each family. Most have involved sodium (chloride) transport in the distal nephron, implying agreement with Guyton et al, although the phenotyping of the putative dietary salt‐related effects was not rigorous. Some involve mutations relevant to vascular function, directly implicating smooth muscle cells as the mediators.

Currently, primary essential hypertension is interpreted as instances of blood pressure increases where we do not know the cause. However, that criticism is unjust since we know a vast amount about the vascular tree in hypertension. Good clinicianship coupled with >1000 genetic loci, a vast array of animal models, and effective pharmacological (and even non‐pharmacological) treatments have pointed out that the essential aspect of essential hypertension is getting the systolic blood pressure down, preferably <130 mm Hg, even in older patients.

乔治·W·皮克林爵士是一位机敏，有见识的观察员，也是一位非常有天赋的心血管研究者。他考虑了心血管研究的悠久历史，选择了“基本高血压”一词（尽管他不太喜欢），给我们带来了两个挑战，然后概述了三个研究领域，即动物模型，人类转化研究和遗传学。追求。这些指令已基本实现，并导致了一个重要的，尽管不完美的治疗武器库。根本的挑战仍然在于进一步的学术研究和临床应用。

也许除了迪保罗（Di Paolo）对施洗者圣约翰的斩首的肖像（图1）以外，威廉·哈维（William Harvey）向我们传达了最有说服力的血压描述，他写道：有时，有时甚至更近，您会发现出流与动脉舒张期正好有关，此时心脏撞击乳房，而此时似乎心脏处于紧张和收缩状态，处于收缩期，血液以相同的运动被推出。”

正如Pickering观察到的那样，血压升高具有致命性，这是19世纪以来我们在床边和“死屋”观察到的结果。1他评论说，高血压可能以多种方式发生。在继发性高血压中，高血压与被认为是继发性的特定疾病有关，例如嗜铬细胞瘤，单侧肾脏疾病，库欣综合征，主动脉缩窄，康氏综合征或急性肾炎。但是，Mahomed较早地证明了高血压患者，他们想要某种特定的基础疾病的证据。2这种情况的识别速度很慢，并且使用了一系列令人困惑的名称。增生是一种很好的持久性。

幸存下来的一个名字是Essentielle Hypertonie。3 1911年，弗兰卡 ^一个 埃里希·弗兰克（1884年柏林- 1957年伊斯坦布尔）是一位德国医生和内科医生。他曾在布雷斯劳（Breslau）担任医学教授，1934年，由于犹太人的血统，德国当局将他免职。弗兰克（Frank）移居伊斯坦布尔，继续他非常成功的杰出职业生涯。
施用肾上腺素（Suprarenin ^® ; Hoechst公司）对病人和观察到血压迅速增加（表示为厘米水柱₂O），而血液（或血浆）的葡萄糖水平几乎不变。弗兰克（Frank）认识到，肾上腺素相关的血压升高与刺激交感神经链时的血压升高相似。他指出，肾上腺髓质被神经支配。然而，即使交感神经链被机械破坏，肾上腺素也起作用。在他的讨论中，弗兰克区分了与潜在肾脏疾病相关的高血压形式和没有明显原因的高血压（类似于马默德的猜想）。他得出结论，体内所有小动脉（包括肾脏中的小动脉）的音调升高都必须负责，并使用“主要”一词来描述这种情况。然后他继续声明，他将使用“原发性高血压”一词来描述这种情况，将其从与肾脏疾病相关的原因中分离出来。弗兰克（Frank）知道了肾素，并引用了Tigerstedt和Bergmann的论文，尽管在发现肾素底物和血管紧张素之前，世界还需要再等25年。弗兰克（Frank）不再重复为什么选择“雌性高渗”这个词，尽管他确实注意到尚不清楚外周血管阻力增加的原因。肾上腺素（与嗜铬菌素器官有关的问题）显然是他的候选人之一。二十年后，沃哈德（Volhard）为该主题投入了142页精美的画册，但并不能真正帮助弗兰克进一步发展。弗兰克（Frank）不再重复为什么选择“雌性高渗”这个词，尽管他确实注意到尚不清楚外周血管阻力增加的原因。肾上腺素（与嗜铬菌素器官有关的问题）显然是他的候选人之一。二十年后，沃哈德（Volhard）为该主题投入了142页精美的画册，但并不能真正帮助弗兰克进一步发展。弗兰克（Frank）不再重复为什么选择“雌性高渗”这个词，尽管他确实注意到尚不清楚外周血管阻力增加的原因。肾上腺素（与嗜铬菌素器官有关的问题）显然是他的候选人之一。二十年后，沃哈德（Volhard）为该主题投入了142页精美的画册，但并不能真正帮助弗兰克进一步发展。4

早期，人们清楚地认识到了高血压对生存的影响，不仅是加速形式（恶性高血压），而且任何血压升高都被认为具有致命性。Schleicher于1944年开始撰写有关高血压的书，其中指出高血压比结核病和癌症加在一起造成的死亡更多。5尽管我们现在通过全球疾病负担研究得知她是绝对正确的，但她并未引用这一有趣的陈述。实际上，收缩压升高是导致心血管死亡的最重要原因，也是全世界最常见的死亡原因，其重要性是吸烟，血糖，血脂，肥胖和环境影响的两倍。

对于皮克林，出现了两个问题。1血压升高（各种形式的高血压）的机制是什么？原发性原发性高血压的本质是什么？他概述了三个调查领域。首先，高血压的产生需要动物模型。第二，必须记录循环变化，不仅在动物中，而且在人类中。第三，必须阐明遗传和环境因素。皮克林（Pickering）是一位热心的任务负责人，但至少他是所有答案的贡献者。

欧姆提供了定律，该定律同样适用于心血管系统和电子电路。在整个身体上，我们处理三个变量，电动势（压力），流量和阻力。由于在已建立的慢性高血压中，人们总是发现心输出量“正常”，因此我们必须接受外周血管阻力增加（如弗兰克（Frank）推测的）是血压升高的原因。因此，研究集中在引起血管改变以增加周围血管阻力的原因上。动物模型已经大量产生；生产力最高的是基因修饰的啮齿动物模型。

Pickering非常了解肾脏在血压调节中的假定作用，并给予Goldblatt充分的信誉。6奇怪的是，Pickering似乎并未归因于压力钠尿是所有长期动脉压调节器中最重要的想法。Guyton等人认为，通常伴随钠积累的细胞外液量增加是动脉压升高的原因。7如果防止液体量增加，尽管钠despite留明显，也不会发生高血压。他们认为，高血压的长期自动调节起着非常重要的作用，原因有两个。首先，它大大增加了总的外周阻力，而心输出量仅增加了少量。第二，当它促进小动脉收缩时，毛细血管压力会降低，从而使很大一部分细胞外液保留在血液中而不泄漏到间质中。更引人注目的是，Guideton等人的系统分析（一种方法论早于其思想）却没有被皮克林引用或提及，因为皮克林肯定熟悉该概念。盖顿的模式为许多人所接受，尽管它继续引起包括引入替代模型在内的大量讨论，并且可能需要随后进行修改。皮克林从不热衷于盐高血压的想法，并公开嘲弄达尔（他对盐敏感和耐盐的大鼠）的结论和低盐饮食。皮克林（Pickering）的数据表明，血管紧张素实际上促进了利钠而非钠retention留。

遗传学经历了一场使皮克林高兴的革命。我们是否“闭环”了，如果没有，我们现在在哪里？也许我们应该从“自下而上”开始。我们刚出生吗？Weitz最初研究了单卵双胞胎受试者，发现他们的血压始终相似，而双卵双胞胎并非如此相似。韦茨接下来针对82位高血压患者（无肾脏疾病）和其他267位因其他原因就诊的患者谈到了这一概念。他在77％的患者中发现了中风和心力衰竭（心血管疾病）的家族病史，但在他的对照组中却只有30％的患者。韦茨随后测量了患者和对照兄弟姐妹的血压。当时的结果表明，高血压以孟德尔方式遗传（常染色体显性遗传）。8 Pickering及其同事所做的是从人群样本中收集证据（图2）。在此图中，我们可以看到在广泛的血压范围内，按年龄校正的男女受试者的血压分布。Pickering研究人员研究了三类患者，即总体人群，已知患有高血压的人的一级亲属和已知不是（正常）高血压的患者的一级亲属。1频率分布很重要。高斯分布只是根据遗传风险而变化。该数据近似于高尔顿的身高数据，并为此提供了更多最新发现。皮克林爱正确。但是他呢？

我们可以用遗传学方法解决皮克林分布的最接近方法是全基因组遗传关联研究（GWAS）。这些研究在超过30亿个碱基对长的基因组中检查了超过100万个遗传标记。在最大的此类研究中，将一百万受影响的人（高血压患者）与相似数量的对照进行了比较。此处的想法是在基因组中发现与正常血压相比在高血压中较常见的那些位点。Cabrera等人最近回顾了执行的大量GWAS，并报告了影响血压的1000个遗传基因座。9每个场所预测的血压远低于1毫米汞柱。这个数字肯定会让皮克林大吃一惊，而皮克林几乎不容易发rat。尽管如此，这1000个基因仅解释了预期遗传变异的一部分。许多基因在血管树中表达。它们参与信号转导，受体调节，细胞增殖，结构形态发生，基于细丝的过程和细胞器组织。作者对与高血压相关的许多表型绘制的血压位点进行了“多特征”关联，作为“热图”。结果可能表示“找到您所知道的内容”。

尽管如此，普拉特仍不会空手而归。已经鉴定出许多孟德尔高血压家庭，并克隆了相关的突变。10每个突变都会对血压产生深远影响，这说明了每个家庭的整个遗传效应。尽管假定的饮食盐相关作用的表型并不严格，但大多数涉及远端肾单位中的氯化钠运输，这表明与盖顿等人的观点一致。一些涉及与血管功能有关的突变，直接牵涉平滑肌细胞作为介体。

当前，原发性原发性高血压被解释为我们不知道原因的血压升高情况。但是，这种批评是不公正的，因为我们对高血压中的血管树了解很多。良好的临床表现以及超过1000个基因位点，大量动物模型以及有效的药理（甚至非药理学）治疗方法已指出，原发性高血压的主要方面是使收缩压降低，最好是<130 mm Hg ，甚至在老年患者中也是如此。