COVID-19 pandemic and hypertension: an updated report from the Japanese Society of Hypertension project team on COVID-19.

The number of reported cases with coronavirus disease 2019 (COVID-19) has exceeded 620 million worldwide, still having a profound impact on people's health and daily lives since its occurrence and outbreak in December 2019. From the early phase of the COVID-19 pandemic, there has been a concern that the rapid spread of this communicable disease can negatively influence non-communicable diseases. Accumulating data indicate that the restriction on the access to medical care, psychological distress, and life-style changes triggered by the pandemic have indeed affected blood pressure control in hypertensive patients. Since our previous report in 2020 that summarized the findings of the literature related to COVID-19 and hypertension, there has been a considerable progress in our understanding of the association between these two disorders; nonetheless, there are remaining challenges and emerging questions in the field. In this article, we aim to summarize the latest information on the impact of the pandemic on blood pressure control, the use of the renin-angiotensin system inhibitors in patients with COVID-19, and the blood pressure changes as one of the possible post-acute sequelae of COVID-19 (also known as long COVID). We also summarize the evidence of telemedicine and COVID-19 vaccination in hypertensive subjects, based on data available as of June 2022.

Hypertension management before and under the COVID-19 pandemic: lessons and future directions.

Hypertension is a significant risk factor for cardiovascular diseases. The prevalence of hypertension and its complications is increasing yearly, yet it remains inadequately controlled worldwide. It has already been recognized that self-management, including self-measured blood pressure monitoring at home, is more important than office blood pressure monitoring. The practical application of telemedicine using digital technology was already underway. COVID-19 has promoted the popularization of these management systems in primary care, although the COVID-19 pandemic disrupted lifestyle and healthcare access. At the beginning of the pandemic, we were at the mercy of information on whether certain antihypertensive drugs, for example, might pose a risk of infection in the face of unknown infectious diseases. Over the past three years, however, much knowledge has been accumulated. It has been scientifically proven that there is no serious problem in managing hypertension in the same way as before the pandemic. That is to control blood pressure mainly through home blood pressure monitoring and continuing conventional drug therapy while modifying lifestyle. On the other hand, in the New Normal era, it is necessary to accelerate digital hypertension management and the establishment of new social networks and medical systems to prepare for the re-emergence of future pandemics while continuing to protect against infection. This review will summarize the lessons and future directions we learned from the impact of the COVID-19 pandemic on hypertension management. The COVID-19 pandemic has disrupted our daily life, restricted access to healthcare, and altered some of the conventional management of hypertension.

Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19.

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.

The relationship between changes in exercise habits and psychosomatic activities in older hypertensive patients during the COVID-19 pandemic.

We conducted a one-year follow-up study to determine the temporal change in exercise habits and the related factors during the COVID-19 pandemic in older hypertensive patients. A total of 190 patients were 76.1 ± 5.7 years, and 44.7% (n = 85) were male. One-hundred fifty-one and 138 patients had exercise habits at baseline and a year later, respectively (p = 0.053). We categorized patients based on the change in exercise habits (at baseline/a year later): Group A: +/+ (n = 122); Group B: +/- (n = 29); Group C: -/+ (n = 16); and Group D: -/- (n = 23). In women, the geriatric depression scale and the incidence of falls in a year were higher in group B (n = 18) than (n = 61) in group A. Such a trend was not observed in men. In conclusion, although exercise habit in older hypertensive patients was well-maintained in our survey, reduced physical activity was associated with depression and risk of fall only in women.

Modified DNA vaccine confers improved humoral immune response and effective virus protection against SARS-CoV-2 delta variant.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. New technologies have been utilized to develop several types of vaccines to prevent the spread of SARS-CoV-2 infection, including mRNA vaccines. Our group previously developed an effective DNA-based vaccine. However, emerging SARS-CoV-2 variants of concern (VOCs), such as the delta variant, have escaped mutations against vaccine-induced neutralizing antibodies. This suggests that modified vaccines accommodating VOCs need to be developed promptly. Here, we first modified the current DNA vaccine to enhance antigenicity. Compared with the parental DNA vaccine, the modified version (GP∆-DNA vaccine) induced rapid antibody production. Next, we updated the GP∆-DNA vaccine to spike glycoprotein of the delta variant (GP∆-delta DNA vaccine) and compared the efficacy of different injection routes, namely intramuscular injection using a needle and syringe and intradermal injection using a pyro-drive jet injector (PJI). We found that the levels of neutralizing antibodies induced by the intradermal PJI injection were higher than intramuscular injection. Furthermore, the PJI-injected GP∆-delta DNA vaccine effectively protected human angiotensin-converting enzyme 2 (hACE2) knock-in mice from delta-variant infection. These results indicate that the improved DNA vaccine was effective against emerging VOCs and was a potential DNA vaccine platform for future VOCs or global pandemics.

Phase I Study to Assess the Safety and Immunogenicity of an Intradermal COVID-19 DNA Vaccine Administered Using a Pyro-Drive Jet Injector in Healthy Adults.

We conducted a nonrandomized, open-label phase I study to assess the safety and immunogenicity of an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19) administered using a pyro-drive jet injector at Osaka University Hospital between Yanagida November 2020 and December 2021. Twenty healthy volunteers, male or female, were enrolled in the low-dose (0.2 mg) or high-dose (0.4 mg) groups and administered AG0302-COVID19 twice at a 2-week interval. There were no adverse events that led to discontinuation of the study drug vaccination schedule. A serious adverse event (disc protrusion) was reported in one patient in the high-dose group, but the individual recovered, and the adverse event was not causally related to the study drug. In the analysis of the humoral immune response, the geometric mean titer (GMT) of serum anti-SARS-CoV-2 spike glycoprotein-specific antibody was low in both the low-dose and high-dose groups (246.2 (95% CI 176.2 to 344.1, 348.2 (95% CI 181.3 to 668.9)) at the 8 weeks after first vaccination. Regarding the analysis of the cellular immune, the number of IFN-γ-producing cells responsive to the SARS-CoV-2 spike glycoprotein increased with individual differences after the first dose and was sustained for several months. Overall, no notable safety issues were observed with the intradermal inoculations of AG0302-COVID19. Regarding immunogenicity, a cellular immune response was observed in some subjects after AG0302-COVID19 intradermal inoculation, but no significant antibody production was observed.

Factors Related to Preventive Behaviors against a Decline in Physical Fitness among Community-Dwelling Older Adults during the COVID-19 Pandemic: A Qualitative Study.

Older adults face the concern of developing frailty and sarcopenia due to an inactive lifestyle during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to reveal the preventive behaviors taken by older adults who perceived a decline in physical fitness during COVID-19 and analyze the background factors which promoted such behaviors using a qualitative study design in 2020. The participants were recruited through the cohort study of Japanese older adults who were aged 79-81 and had not been diagnosed with sarcopenia previously in 2019 and perceived their physical fitness to have declined during the pandemic. The interviews of 19 participants were analyzed using thematic analysis. The participants engaged in five types of preventive behaviors to counter declining physical fitness: "walking", "exercising at home", "improving daily diet", "maintaining a daily routine", and "taking a good rest". Four themes were extracted pertaining to backgrounds of such preventive behaviors: "feeling anxiety and mental pressure", "available networks with family and neighbors", "prior experiences of behaviors", and "access to information". Anxiety due to lifestyle changes during the pandemic was the primary reason for the behaviors. This study can be a useful guide for undertaking possible measures to prevent frailty during future pandemics.

Preclinical study of a DNA vaccine targeting SARS-CoV-2.

To fight against the worldwide COVID-19 pandemic, the development of an effective and safe vaccine against SARS-CoV-2 is required. As potential pandemic vaccines, DNA/RNA vaccines, viral vector vaccines and protein-based vaccines have been rapidly developed to prevent pandemic spread worldwide. In this study, we designed plasmid DNA vaccine targeting the SARS-CoV-2 Spike glycoprotein (S protein) as pandemic vaccine, and the humoral, cellular, and functional immune responses were characterized to support proceeding to initial human clinical trials. After intramuscular injection of DNA vaccine encoding S protein with alum adjuvant (three times at 2-week intervals), the humoral immunoreaction, as assessed by anti-S protein or anti-receptor-binding domain (RBD) antibody titers, and the cellular immunoreaction, as assessed by antigen-induced IFNγ expression, were up-regulated. In IgG subclass analysis, IgG2b was induced as the main subclass. Based on these analyses, DNA vaccine with alum adjuvant preferentially induced Th1-type T cell polarization. We confirmed the neutralizing action of DNA vaccine-induced antibodies by a binding assay of RBD recombinant protein with angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, and neutralization assays using pseudo-virus, and live SARS-CoV-2. Further B cell epitope mapping analysis using a peptide array showed that most vaccine-induced antibodies recognized the S2 and RBD subunits. Finally, DNA vaccine protected hamsters from SARS-CoV-2 infection. In conclusion, DNA vaccine targeting the spike glycoprotein of SARS-CoV-2 might be an effective and safe approach to combat the COVID-19 pandemic.

[Decrease in activity and its related factors under COVID-19 crisis in community-dwelling older people].

AIM: To prevent the transmission of the novel coronavirus [COVID-19] and stop its spread, a state of emergency was declared from April to May 2020. People were encouraged to refrain from outings and reduce their contact with people. The purpose of this study was to examine the subjective changes in the amount of activity under COVID-19 crisis among the elderly and the factors related to this decrease in activity. METHODS: This study was part of the SONIC study, an ongoing prospective cohort study targeting community dwelling older people in their 70, 80, 90s, and over 100 years old in different regions (urban and suburban) of Japan. Subjective changes in the amount of activity during the state of emergency were assessed via a mail questionnaire. RESULTS: The percentage decrease in activity for the subjects in their 70s, 80s, and 90s were 68.1% (513/753), 65.3% (324/496), and 56.0% (164/293), respectively. By region, 69.4% in urban, while 57.7% in the suburbs. In the 70- and 80-year-old cohorts, the decrease in activity was more frequent among those in urban areas than in suburban areas. In the 90-year-old cohort, the differences between the regions were attenuated, while the economic status and walking speed were significantly associated with a decrease in activity. CONCLUSIONS: The decrease in activity varied by age group and region, suggesting that approaches to preventing the adverse health effects associated with inactivity due to the COVID-19 crisis are more important in urban areas than in suburban ones.

Therapeutic vaccine for chronic diseases after the COVID-19 Era.

There is currently a respiratory disease outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After rapid development, RNA vaccines and adenoviral vector vaccines were approved within a year, which has demonstrated the strong impact of preventing infectious diseases using gene therapy technology. Furthermore, intensive immunological analysis has been performed to evaluate the efficiency and safety of these vaccines, potentially allowing for rapid progress in vaccine technology. After the coronavirus disease 2019 (COVID-19) era, the novel vaccine technology developed will expand to other vaccines. We have been developing vaccines for chronic diseases, such as hypertension, for >10 years. Regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. Therefore, the epitope vaccine approach has been proposed to induce antibody production in response to a combination of a B cell epitope and exogenous T cell epitopes through major histocompatibility complex molecules. When these vaccines are established as therapeutic options for hypertension, their administration regimen, which might be a few times per year, will replace daily medication use. Thus, therapeutic vaccines for hypertension may be a novel option to control the progression of cerebrovascular diseases. Hopefully, the accumulation of immunological findings and vaccine technology advances due to COVID-19 will provide a novel concept for vaccines for chronic diseases.

A pressor dose of angiotensin II has no influence on the angiotensin-converting enzyme 2 and other molecules associated with SARS-CoV-2 infection in mice.

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19.

Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin-angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

Phase I / II study of intracutaneous inoculation of COVID-19 DNA vaccine (AG0302-COVID19)

The Japan Geriatrics Society consensus statement "recommendations for older persons to receive the best medical and long-term care during the COVID-19 outbreak-considering the timing of advance care planning implementation".

Since the end of 2019, a life-threatening infectious disease (coronavirus disease 2019: COVID-19) has spread globally, and numerous victims have been reported. In particular, older persons tend to suffer more severely when infected with a novel coronavirus (SARS-CoV-2) and have higher case mortality rates; additionally, outbreaks frequently occur in hospitals and long-term care facilities where most of the residents are older persons. Unfortunately, it has been stated that the COVID-19 pandemic has caused a medical collapse in some countries, resulting in the depletion of medical resources, such as ventilators, and triage based on chronological age. Furthermore, as some COVID-19 cases show a rapid deterioration of clinical symptoms and accordingly, the medical and long-term care staff cannot always confirm the patient's values and wishes in time, we are very concerned as to whether older patients are receiving the medical and long-term care services that they wish for. It was once again recognized that it is vital to implement advance care planning as early as possible before suffering from COVID-19. To this end, in August 2020, the Japan Geriatrics Society announced ethical recommendations for medical and long-term care for older persons and emphasized the importance of conducting advance care planning at earlier stages. Geriatr Gerontol Int 2020; 20: 1112-1119.