Obituary: Pietro Cugini (13 December 1936 – 6 April 2020)

ABSTRACT

Chronobiology lost a great and distinguished physician-scientist, Pietro Cugini (Figure 1). He will be dearly missed by his family, his friends, and the field he helped shape and guide as he remained active until the end of his life at 83 years of age. In the middle of the worst pandemic the world has known in recent times, but not from COVID-19, Pietro passed away unexpectedly in front of his Rome apartment, on Via Latina, the same street where he was born and where he spent most of his life. He was buried shortly afterward in the Monumental cemetery of Marino. There was no formal ceremony as funerals were suspended because of the coronavirus. A proper ceremony will take place as soon as travel and congregation are possible. Pietro is survived by his three children, Silvia, Raffaella and Riccardo Cugini.

Keywords:

• Aging
• Ambulatory Blood Pressure Monitoring (ABPM)
• Circadian Rhythm
• Cugini’s minimal–change hypertensive retinopathy
• Renin-angiotensin-aldosterone system (RAAS)
• Sex differences

Pietro Cugini was born in 1936 in Rome, Italy. He graduated cum laude in Medicine and Surgery from “La Sapienza” University of Rome, Italy, in 1962. He held diplomas in Cardiology (1964), Gastroenterology (1966), Hematology (1967), and Endocrinology and Metabolic Diseases (1969). He was a Professor at “La Sapienza” University of Rome, Italy, where he held positions at the Faculty of Medicine and Surgery, which belongs to the Institute of Medical Pathology (1962), at the Institute of Medical Clinic II (1968), and in the Department of Clinical Sciences (1999 to 2001). He taught endocrine biochemistry, endocrine pathophysiology and chronoendocrinology at the Second School of Specialization in Endocrinology, and replacement diseases and kidney and arterial hypertension at the Second School of Specialization in Nephrology. He also lectured at the Chronobiology Clinic at the Faculty of Medicine and Surgery of the University of Florence, Italy. He was a Visiting Professor at the Chronobiology Laboratories of the University of Minnesota, USA, in 1980, 1985, and 1989, and at the Institute of Health Science at Kyushu University, Fukuoka, Japan, in 1988, 1990, and 1996. While Pietro formally retired from teaching in 2001, he continued his research activities in chronobiology until the time of his death.

Figure 1. Pietro Cugini in 1963, shortly after he graduated and had just opened his first private practice in Rome (left), and more recently as a distinguished physician and chronobiologist (right).

Pietro Cugini made numerous important contributions in medicine and basic research. At the beginning of his career, Pietro made use of complex and then-innovative isotopic radiochemistry techniques with which he studied the secretion and metabolic clearance of cortisol in healthy and pathological conditions (obesity, Cushing’s syndrome, cirrhosis of the liver, Stein-Leventhal syndrome, senile diabetes mellitus, ulcerative colitis, collagenopathies). With the advent of radioligand techniques, he completed a series of investigations on the physiology of cortisol secretion by focusing on circadian rhythms in health and disease.

Starting in 1973, Pietro Cugini turned his attention to the renin-angiotensin-aldosterone system, using nascent radioimmunoassay measurement techniques. His work contributed important standardization of the normal values ​​of plasma renin activity and plasma aldosterone in relation to sodium intake, posture, as well as sex, age, pregnancy and race, and had impact in the study of reno-vascular hypertension. His original assessment of the circadian rhythm of prorenin earned him the invitation to Franz Halberg’s Chronobiology Laboratories at the University of Minnesota, where a lifelong cooperation was started by studying the evolution of the circadian rhythm of renin activity and plasma aldosterone as a function of age. Pietro paid special attention to the study of essential arterial hypertension in its normal, high and low renin varieties. Among endocrine aspects of hypertension, Pietro Cugini studied hyper-aldosteronism and primary and secondary pseudo-hyper-aldosteronism. He was first to describe a defect of (Na⁺/K⁺)-ATPase in the membrane of the erythrocytes of pseudo-hyper-aldosteronism patients and carriers.

As Pietro’s results illustrated the importance of circadian (and other) rhythms, his studies focused more directly on the application of chronobiological methods and protocols to medicine in physiological and pathological conditions. Pietro was a prolific writer. He authored nine books and twelve monographs, mostly centered on blood pressure and statistical procedures for assessing blood pressure variability. He also authored or coauthored at least 348 peer-reviewed publications as well as several book chapters. Pietro participated in over 70 scientific meetings, many of them by invitation. He served on the editorial board of journals such as New Trends in Gestational and Perinatal Hypertension, Medicine and Computer Science, Functional Neurology, Methodology and Clinical Didactics (MEDIC), Biological Rhythm Research, Journal of Obstetrics and Gynecology, and Journal of Eating and Weight Disorder. He also served as Editor-in-Chief of several journals and was Scientific Director of “La Clinica Terapeutica”, a testimony of the breadth and depth of his scientific activities. A detailed description of his accomplishments can be found online at https://en.wikipedia.org/wiki/Pietro_Cugini.

Some of us first met Pietro when he first came to Minnesota in 1980 (Figure 2). It was a very interesting time at the Chronobiology Laboratories under the direction of Franz Halberg since circadian rhythms had been found to be ubiquitous and their critical importance had been shown as they could make the difference between life and death in the experimental laboratory (Halberg 1969). Cooperation with colleagues worldwide helped quantify and map the circadian variation of physiological variables in health and disease, and assess differences in circadian parameters as a function of gender and age (Tarquini et al. 1979). New analytical methods were devised to identify disease risk early by entering the physiological range and refining reference values by accounting for their predictable rhythmic variation (Halberg et al. 1978).

Figure 2. Pietro Cugini at the Chronobiology Laboratories of the University of Minnesota in 1980 (pictured with Franz Halberg – right).

In Minnesota, we were completing a very large international study on breast cancer risk in clinically healthy women (Halberg et al. 1981). Pietro’s work confirmed the decrease with age in the circadian amplitude of prolactin in men, while showing that the damped circadian variation in aldosterone seen in women was not observed in men (Cugini et al. 1980). His interest in the renin-angiotensin-aldosterone system (RAAS) brought us to study the circadian variation in circulating renin and aldosterone and to investigate how its circadian parameters might be influenced by different factors. Sodium restriction was found to be associated not only with an increase in both renin and aldosterone but also with an increased circadian amplitude of these hormones (Cugini et al. 1981a), which reached statistical significance in the case of plasma renin activity. A stronger circadian variation on sodium restriction also stemmed from a closer clustering of circadian acrophases among study participants. As compared to 17- to 37-year old women, both the MESOR (rhythm-adjusted mean) and circadian amplitude of renin activity are lower in 60- to 69-year old clinically healthy women and their circadian acrophase is delayed, whereas their MESOR and circadian amplitude of aldosterone are higher (Cugini et al. 1981b). Similar changes were not observed in men (Cugini et al. 1982b, 1981b). Pietro concluded that statistically significant interactions among circadian time, age, and sex establish the adrenocorticopause in women, and suggested that it may occur earlier in women than in men, in keeping with similar results on serum cortisol in the same subjects (Cugini et al. 1982b). By contrast to MESOR-normotensive women, the lower MESOR of plasma renin activity is not accompanied by a concomitant smaller circadian amplitude and the circadian acrophase is advanced rather than delayed in MESOR-hypertensive women (Cugini et al. 1982a). Many more joint publications centered on RAAS and aging followed during the ensuing years, when cooperation also intensified with Professors Terukazu Kawasaki and Keiko Uezono at Kyushu University, Fukuoka, Japan. Teru Kawasaki, who had led the Japanese branch of the breast cancer study, was also focusing his research on RAAS and studying how it is affected by sodium loading or restriction (Uezono et al. 2015).

A close friendship between the three teams in Rome (Pietro Cugini), Japan (Teru Kawasaki), and Minnesota (Franz Halberg) matured during these years, and Pietro visited Kyushu University on several occasions to cooperate with Teru and Keiko. There, Pietro analyzed piles of data and worked until late hours in the evening. During his visits in Fukuoka, Teru and Keiko took him to historical shrines and temples, where he took many pictures, as photography was Pietro’s hobby. Teru spent several months in Rome to work with Pietro on several joint projects, as detailed elsewhere (Uezono et al. 2015). During these visits, Pietro often talked about his children Riccardo, Raffaella, and Silvia.

By the time of Pietro’s third visit to Minnesota (Figure 3), ambulatory blood pressure monitors had become smaller and more readily available. The Chronobiology Laboratories were coordinating international studies aimed at mapping the circadian variation in blood pressure and heart rate in clinical health “from womb to tomb”, a project still ongoing under the name of BIOCOS. Pietro’s work confirmed the presence of a circadian rhythm in blood pressure in newborns monitored shortly after birth (Cugini et al. 1990a, 1991a). The data collected as part of these endeavors served to derive time-specified reference limits for blood pressure that were further qualified by gender and age, as a step toward a “prevention clinic” (Cornelissen et al. 1993; Cugini et al. 1990b). These limits are still used today to identify the presence of vascular variability disorders (VVDs), which describe various abnormal variability patterns of the circadian rhythms in blood pressure and heart rate, and which have been shown to predict cardiovascular disease risk (Halberg et al. 2013). Cooperation in this area intensified with Professor Kuniaki Otsuka of Tokyo Women’s Medical University in Tokyo, Japan.

Figure 3. Pietro Cugini at the Chronobiology Laboratories of the University of Minnesota in 1989 (pictured with Franz Halberg – left).

A large international network of physicians and scientists participated in the monitoring of blood pressure, and several meetings were held to disseminate knowledge acquired in this then-fledging area. The 1990 meeting on Chronobiology and Chronomedicine in Tokyo, Japan, organized by Haruo Watanabe and Kuniaki Otsuka (Figure 4) was the precursor of much still ongoing work devoted to health surveillance by means of physiological monitoring and to the effects of the broad environment on human physiology. Focus on heart rate variability was added to the circadian variation of blood pressure, and nonlinear methods of analysis, including those related to chaos theory, complemented cosinor rhythmometry and conventional statistical and time series analyses (Cugini et al. 1992, 1991b; Halberg et al. 1992; Otsuka et al. 1995). Under the leadership of Kuniaki Otsuka, 7-day/24-hour ABPM started in two Japanese cities to monitor the health of residents, with focus on the health of the elderly (Otsuka et al. 2016).

Figure 4. Some participants of the 1990 meeting on Chronobiology and Chronomedicine in Tokyo, Japan. From left to right: Kuniaki Otsuka, Yoichi Hata, Yuji Kumagai, Takashi Yanaga, Franz Halberg, Haruo Watanabe, Kohji Tamura, Guiseppe Germano, Pietro Cugini, Germaine Cornelissen, and Yoshihiko Watanabe.

Two aspects of Pietro Cugini’s research deserve particular attention. One relates directly to blood pressure and abnormal patterns of blood pressure variability. The other relates to aging.

Conventionally, pre-hypertension is defined based on repeated single measurements of blood pressure taken at office visits. Only in special cases is a 24-hour ambulatory blood pressure monitoring (ABPM) record performed. Even in such cases, the diagnosis often relies on no more than mean values over 24 hours, during daytime and during nighttime, for comparison with fixed thresholds. By contrast, Professor Cugini formulated what we called “Cugini’s minimal-change hypertensive retinopathy” (Cornelissen et al. 2007a, 2009), based on elevations of both the MESOR and circadian amplitude of blood pressure, compared to control subjects without retinopathy, using chronobiologic methodology applied to 24-hour records interpreted in the light of conventional guidelines (Cugini et al. 1999, 1998, 1997) (Figure 5). Of note, in Cugini’s study, patients with retinopathy were dippers, while those without retinal involvement were non-dippers. An elevated circadian amplitude of blood pressure beyond a gender- and age-specified threshold, and an acrophase outside the 90% prediction limits when the acrophase of heart rate is within anticipated limits are VVDs predicting cardiovascular disease risk when the classification in terms of dipping failed (Cornelissen et al. 2007b).

Figure 5. “Cugini’s minimal-change hypertensive retinopathy”. TNS: “Truly Normotensive Subjects”; PNS: “Putatively Normotensive Subjects”. © Halberg Chronobiology Center.

Pietro Cugini’s interest in aging throughout his career culminated with the work he did in the small town of Campodimele, so well described in Tracy Lawson’s book (Lawson 2011). The question asked in this book is “To what, if any, extent do the purity and range of foods eaten here contribute to the enviable well-being and long lives of the Campomelani?” Through his work, Pietro helped answer some of the many facets this question entails (Cugini et al. 1994, 2011). He mapped biological rhythms of blood pressure of three generations of longevous families, and examined lifestyle elements like their working and walking habits, while also paying attention to meal timing. He recorded the dietary habits, notably salt intake and alcohol consumption, of the entire population, from ten-year-olds to those aged over one-hundred. Pietro estimated that genetic traits accounted for 30% of their long life expectancy, much of the remaining 70% likely attributed to their lifestyle: strong synchronization with the geophysical cycles; physical exercise; beneficial climate amid the Aurunci Mountains; and good nutrition (Pietro called it “hyper-Mediterranean”), which all contributed to blood pressure values below the Italian average. While other communities around the globe boast longevity levels higher than that of Campodimele, the village is ideal as a model because such a high proportion of its residents share a homogeneous lifestyle, including diet.

For his work, Professor Pietro Cugini received several awards and accolades, including the “Portico d’Onofrio Award for research on longevity in Campodimele” in 1994, and in 2002, Pietro became an Honorary Citizen of the Municipality of Campodimele. In 1998, the “Honor of Commendatore of the Italian Republic” was bestowed upon him. Pietro Cugini was elected to the Lancisian Academy in 2009, and to the Academy of Physiocritics in 2011. Pietro’s work on minimal retinal alterations was also praised by his receiving the Nosographic recognition of the “Initial Tensive Damage of Target Organ/Monitoring Prehypertension Syndrome” in 2007–2009, also known as “Cugini’s Syndrome” (1997–2002).

Pietro Cugini was not only a talented educator, a passionate researcher and seasoned scholar, and a well-respected Academician; he was also a very dear friend, a real gentleman, who will be missed by so many relatives, friends and his extended scientific family. He leaves a rich legacy for the next generations to build upon. His contributions will remain part of history on how chronobiology evolved to become a discipline in its own right. For this, and for your friendship, we thank you Pietro.