key: cord-0771642-ft843b68
authors: Lau, Darren; McAlister, Finlay A.
title: IMPLICATIONS OF THE COVID-19 PANDEMIC FOR CARDIOVASCULAR DISEASE AND RISK FACTOR MANAGEMENT
date: 2020-11-16
journal: Can J Cardiol
DOI: 10.1016/j.cjca.2020.11.001
sha: 8ee08514f2c41e8815a029e02bfa68619719dafc
doc_id: 771642
cord_uid: ft843b68

COVID-19 and our public health responses to the pandemic may have far-reaching implications for cardiovascular risk affecting the general population and not just survivors of COVID-19. In this narrative review, we discuss how the pandemic may impact general cardiovascular risk for years to come, and explore the mitigating potential of telehealth interventions. From a health care perspective, the shift away from in-person office visits may have led many to defer routine risk factor management and may have had unforeseen effects on continuity of care and adherence. Fear of COVID-19 has led some patients to forego care for acute cardiovascular events. Curtailment of routine outpatient laboratory testing has likely delayed intensification of risk-factor modifying medical therapy, and drug shortages and mis-information may have negatively impacted adherence to antihypertensive, glucose-lowering, and lipid-lowering agents. From a societal perspective, the unprecedented curtailment of social and economic activities has led to income loss, unemployment, social isolation, decreased physical activity, and increased frequency of depression and anxiety, all of which are known to be associated with worse cardiovascular risk-factor control and outcomes. We must embrace and evaluate measures to mitigate these potential harms to avoid an epidemic of cardiovascular morbidity and mortality in the coming years that could dwarf the initial health impacts of COVID-19.

Since first emerging in the Hubei province of China, the novel coronavirus SARS-CoV-2 has spread globally, with 223297 cases of COVID-19 and 10,023 reported deaths in Canada as of October 28, 2020. 1 Acute cardiovascular complications of COVID-19 are more common than initially thought and can include myocarditis, pericarditis, myocardial infarction, decompensated heart failure, stroke, and pulmonary embolus. 2 In addition, a number of the antiviral therapies and immune response modulators currently being investigated for treatment of Covid-19 have cardiovascular side effects and/or potentially interact with cardiovascular medications. 3 Nothing is known about the potential long-term cardiovascular complications of COVID-19 infection at this early stage of the pandemic. However, the cardiovascular implications of COVID-19 will definitely extend beyond direct infection-related cardiovascular damage. The public health response to the pandemic, meant to mitigate morbidity and mortality from acute COVID-19, may have the unintended consequence of increasing cardiovascular risk in much broader swaths of the general population, including those uninfected with SARS-CoV-2. In this review, we explore potential mechanisms by which COVID-19 and our responses to the pandemic may affect future cardiovascular risk. We then discuss some of the factors that might mitigate this risk if successfully harnessed in these challenging circumstances.

including the inhibition of pro-inflammatory cytokines and reduced thrombus formation via nitric oxide and prostacyclin pathways. Down-regulation of the ACE2 receptor induced by SARS-CoV-2 binding and endocytosis may lead to an imbalance of angiotensin II and angiotensin 1-7 with consequent alterations of normal circulatory homeostasis, particularly in the endothelium of the pulmonary capillaries, where this imbalance may contribute to the immune-thrombotic microvascular coagulopathy associated with respiratory compromise in COVID-19. 4 -7 ACE2 and Angiotensin 1-7 have been proposed as potential therapies for COVID-19. 8, 9 Other mechanisms of cardiovascular injury include direct infection of endothelial cells, as well as damage mediated by release of inflammatory mediators and by other aspects of the immune response to COVID-19. 7, 10, 11 Extensive coronary microvascular thrombi may lead to myocardial infarctions even in patients with non-obstructive coronary arteries 12 , and up to one third of patients hospitalized with COVID-19 have elevated troponins. 13 However, COVID-19 may adversely impact cardiovascular risk in many more than just those who were infected and survived, by various mechanisms related to our individual and collective pandemic responses as will be outlined below. It is probable that the footprint of these J o u r n a l P r e -p r o o f secondary and tertiary impacts on cardiovascular health may far outweigh that related to primary SARS-CoV-2 infection and/or its treatment (see included Figure and Table) .

Secondary Impacts due to pandemic-related health care restrictions and the infodemic:

Although the frequency of virtual visits has grown exponentially since the pandemic began, it has not fully made up for the marked decline in outpatient visits due to restrictions imposed after 

Routine laboratory testing is an important part of cardiovascular risk reduction. Medical therapy for diabetes, hypertension, and dyslipidemia involves the routine measurement of laboratory parameters, both for safety, and to guide appropriate intensification. In March-May 2020, many outpatient laboratories suspended or limited routine or non-essential bloodwork to protect patients and staff from acquiring COVID-19. 47 Choosing Wisely Canada recommended delaying non-essential care and laboratory testing when possible. 48 While most outpatient laboratories have since resumed routine bloodwork, albeit at lower volumes due to measures put in place for physical distancing and increased personal protective equipment precautions, many patients continue to express anxiety about attending. 49 No studies have been published yet on rates of laboratory testing and therapeutic intensification during the COVID-19 pandemic, but we believe it has undoubtedly led to deferred cardiovascular risk factor management for many patients, J o u r n a l P r e -p r o o f particularly those with multiple comorbidities who are both more likely to need routine lab work and also more likely to experience severe COVID-19. 50

Even before the Covid-19 pandemic, drug shortages were becomingly an increasingly common problem in health care, and the therapeutic turbulence caused by switching between drugs even within the same class has been shown to negatively impact patient adherence and outcomes. 51

Over Canadian pharmacies have restricted prescription refills to 30 day intervals to preserve stocks during the pandemic, the potential negative consequences for patient adherence (due to increased costs, inconvenience, and patient fear of going to a pharmacy multiple times over 3 months rather than once 55 ) and clinical outcomes have yet to be revealed. This is a research priority given that even brief periods of abstinence from antihypertensive or lipid lowering therapy can be associated with cardiovascular events. 56-58

J o u r n a l P r e -p r o o f "Infodemic" is a term coined by Dr. Tedres Adhanom Ghebreyesus, Director-General of the World Health Organization, to refer to inaccurate, decontextualized, misleading, biased, or otherwise "fake" information disseminated on social, and sometimes conventional, media. 59, 60 The term may also include legitimate information, but accompanied by premature calls to action, as exemplified by the early enthusiasm for hydroxychloroquine, whose benefits were later disproved by higher quality studies. 61, 62 Regarding cardiovascular risk, widespread speculation on social media and in the mainstream media that angiotensin converting enzyme inhibitors and angiotensin receptor blockers could increase susceptibility to COVID-19 and worsen prognosis created sufficient concern in the public that many organizations, including Hypertension Canada and the Canadian Cardiovascular Society issued specific policy statements in print and social media encouraging patients treated with these agents not to discontinue therapy. 63 The concerns about these agents were subsequently shown to be unfounded in human studies 3 , but the potential adverse effects of this misinformation on patient adherence with antihypertensive therapy remains a concern.

The infodemic is not just a phenomenon in the lay press. In the scientific literature there has also been a proliferation of COVID-related papers on pre-print servers which lack the safe-guard of peer review. 64, 65 The rush to publication has now been documented in peer-reviewed journals, with articles being published at extraordinary speeds in the early phases of the pandemic 65 , and several notable instances of articles being later retracted, withdrawn, or having an expression of concern issued. 66 The situation is unlikely to change in the near future, as a arguably, should not, contribute meaningfully to clinical practice.

Tertiary Impacts due to pandemic-related social and economic restrictions:

The unprecedented economic upheaval generated by COVID-19 and mitigation measures aimed at reducing spread of disease will likely worsen cardiovascular risk factor control and outcomes in the upcoming years. Canadian companies have had to implement substantial activity reductions and layoffs in the face of diminished demand for services and products due to stay-at-home orders, fear of COVID-19, and travel restrictions. As a result, unemployment in Canada increased to 13.7% in May 2020, and remained 12.3% in June 2020, more than double the rates for the same months the year before. 69 In the US, 19.6% of respondents in one national survey were not working, and a third described moderate-to-high levels of food insecurity. 70

The majority of Canadians (59%) have private health insurance for drug benefits 71 , most of which is provided in the form of extended health benefits as part of their employment. 72 Over half of these individuals (53%) would not be eligible for public drug benefits, which are accessible only for those older than 65 years, on social assistance, or under unique circumstances (e.g.: catastrophic costs, cancer therapies, etc.). 73 The loss of employment, for many, will lead to loss of insurance benefits and difficulty affording glucose lowering, antihypertensive, and lipid-lowering medications. 74, 75 A significant body of literature has examined the effect of reduced income, unemployment, and job stress on cardiovascular risk factors. Lower income has been consistently associated with J o u r n a l P r e -p r o o f higher rates of diabetes in both cross-sectional 76, 77 and longitudinal studies. 78 Lower income has been consistently associated with increased rates of hypertension. 79 Unemployment has only sometimes been associated with increased diabetes 80 and hypertension 81 ; most studies have instead found that being employed in a job with a high degree of "job strain" (i.e.: a combination of high job demands, and low job control) increased the risk of hypertension. 79 The exact role of unemployment / employment in cardiovascular risk factor control is complicated, and may differ by sex-and age-strata. 81 In terms of cardiovascular outcomes, the consensus observation across multiple studies has been more consistent: unemployed persons have a higher risk of major adverse cardiovascular events. 82-84

The best evidence for increased cardiovascular risk following COVID-19 job losses may come associated with a decline in medication use and treatment intensity. 85 We therefore have good reason to expect the economic fallout from COVID-19 to manifest as worsening cardiovascular risk factor control in years to come. 

The COVID-19 pandemic has been associated with an unprecedented increase in rates of depression and anxiety across the general population. In initial surveys from China during the period of mandatory stay-at-home orders, over half of patients reported a moderate-to-severe psychological impact of the outbreak, with 16.5% reporting moderate-to-severe depressive symptoms, and 28.8% reporting moderate-to-severe anxiety symptoms. 90 Reasons for this include social isolation due to fear of contagion and stay-at-home orders 94 ;

intrinsic fear of COVID-19 95 ; food insecurity and other economic deprivation due to job loss 70 ;

and false or misleading information, i.e.: the "infodemic" 60 , that has accompanied COVID-19 on J o u r n a l P r e -p r o o f media and social media platforms. In addition, even before COVID-19, social isolation and loneliness were recognized risk factors for mortality with odds ratios of 1.29 and 1.32, consistent with many more traditional "medical" mortality risk factors. 96 Many, though not all 97 105 , has similarly been associated with a 1.4-fold increased risk of hypertension. 106 Anxiety has also been associated with unhealthy behaviours which increase the risk of hypertension 107 and cardiovascular disease, such as tobacco use, physical inactivity, and unhealthy food choices. 107, 108 Both anxiety and depression have been associated with lower rates of medication adherence. [109] [110] [111] [112] Other potential pathways linking depression and anxiety to cardiovascular risk have been proposed, including systemic chronic inflammation, HPA axis dysfunction, and autonomic dysregulation as causal mechanisms. 113

We have so far sketched a variety of pathways by which the COVID-19 pandemic and our individual and collective responses to it may unintentionally worsen cardiovascular risk in the general population. For health care providers, efforts to continue routine cardiovascular risk reduction via virtual means in this challenging landscape will be critical. 19, 114 Virtual visits may create new challenges, yet telehealth technologies offer key means of communicating with and engaging patients during the pandemic. Here, we briefly review some of the evidence for telemonitoring and telecare in cardiovascular risk factor management.

J o u r n a l P r e -p r o o f

Digital health interventions (DHI) span a spectrum from generic web-based strategies, to text messaging and/or email interactions between patients and health care providers, to the use of mobile phone health-related applications, and to telemonitoring with the use of wearable biometric sensors by patients. All have the goal of "watching over the 5000 hours per year when patients are not in direct contact with healthcare providers … and are deciding whether to take prescribed medications or follow other medical advice, deciding what to eat and drink and whether to smoke, and making other choices about activities that can profoundly affect their health". 115 Numerous systematic reviews have confirmed that DHI can successfully improve specific CV risk factors such as smoking cessation 116 , physical activity 117 , and weight loss 118 .

Importantly, a systematic review of 9 trials in 2263 patients (2 primary prevention trials, 2 in heart failure, and 5 secondary prevention studies) reported a 40% relative reduction in CV disease outcomes (CV events, hospitalizations, and all-cause mortality) from DHI in secondary prevention patients both via risk factor reduction but also by increasing adherence to evidencebased preventive therapies such as aspirin or statins. The pooled absolute risk reduction of 7.5% implied a Number-Needed-to-Treat of 16 patients. 119 Although there was no statistically significant difference in CV outcomes with DHI in the primary prevention studies, there were statistically significant benefits on weight, systolic blood pressure, total and LDL cholesterol, and

Framingham risk scores. 119 However, a Cochrane review of 93 DHI studies highlighted that much of the published evidence is of poor quality, there is evidence of publication bias, and the results are inconsistent across studies with effectiveness influenced by numerous factors including the type of patients studied, the type and frequency of interactions between patients and healthcare providers, and the healthcare system in which the intervention is embedded. 120

Further research is clearly needed to determine the most effective DHI modalities in specific populations and to better understand the patient, provider, health system, and program factors which influence effectiveness. Until then we can expect to see both positive 121 and negative 122, 123 trials published in the literature. 124 

While a number of trials have demonstrated that patient self-monitoring has a small but statistically significant effect on improving BP control 125, 126 , a Canadian study reported that only 16% of patients complied with all recommended procedures when measuring their BP at home and less than one-third reported at least 80% of their home measurements to their physician. 127 On the other hand, the addition of telemonitoring, whereby clinicians review BP readings submitted by patients over the internet or via short message service (SMS) and titrate therapy as required, is associated with much larger reductions in BP, in the order of 5mmHg for systolic blood pressure [128] [129] [130] , and has been shown to be cost-effective. 129, 131 However, telemonitoring trials have generally recruited small samples of often highly selected individuals, followed for relatively short periods. There are numerous potential barriers to scaling such interventions up to accommodate large numbers of patients 132 and thus such efforts should be accompanied by robust evaluation plans.

Telehealth interventions in diabetes care have usually involved self-monitoring of blood glucose and communication back to the clinician via a variety of means (text message, web portal, smartphone apps, and telephone), with feedback offered to the patient ranging from none, to generic messages generated by automated processes, to nurse, pharmacist, or physician feedback with or without concrete medication changes; with or without diet and lifestyle coaching; communicated either synchronously or asynchronously. 133, 134 Critical appraisal of the field is complicated by the high degree of heterogeneity of interventions but a recent systematic review of 111 randomized trials identified a pooled mean HbA1c reduction of 0.57% (95% CI J o u r n a l P r e -p r o o f 0.40%-0.74%) 135 , consistent with other reviews. [136] [137] [138] Other reported benefits of telehealth in diabetes include increased patient satisfaction, knowledge, and self-efficacy outcomes. 139 However, one broad theme appears consistently: Interventions involving personal feedback from a health care provider -whether a specialist nurse, pharmacist, or physician does not appear to matter -with the ability to make medication changes appear to be critical to achieving reductions in HbA1c. 135 

The COVID-19 pandemic is likely to have a wide and long-lasting impact on cardiovascular risk factor control and outcomes for the general population and not just for COVID-19 survivors. The threat of an "impending tsunami" 45 of cardiovascular morbidity and mortality in the coming years is real. Many of the challenges to cardiovascular risk management caused by the pandemic will require forward-looking social and economic policies to address. New messaging from public health authorities, who have until now been focused on preventing acute COVID-19 infections, will be needed -messaging that considers the overall health needs of the population, including primary and secondary prevention of cardiovascular disease, as the pandemic stretches out over time. 19, 114 As clinicians we also need to rise to this challenge, by finding ways of remodelling care delivery and improving the effectiveness and efficiency of cardiovascular risk management during the COVID-19 pandemic. In doing so, we are likely to find ourselves innovating during the most unlikely of times. J o u r n a l P r e -p r o o f

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Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic

COVID-19: ACE2centric Infective 57

The risks associated with short-term placebocontrolled antihypertensive clinical trials: a descriptive meta-analysis

Withdrawal of statins increases event rates in patients with acute coronary syndromes

UN tackles 'infodemic' of misinformation and cybercrime in COVID-19 crisis

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Socioeconomic status and hypertension: a metaanalysis

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Psychosocial predictors of hypertension in men 93

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Psychosocial impact of COVID-19

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Type 2 diabetes does not increase

Depressive symptoms, insulin resistance, and risk of diabetes in women at midlife

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Depression increases the risk of hypertension incidence: a meta-analysis of prospective cohort studies

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Adherence to Medication, Physical Activity and Diet in Older Adults With Diabetes: Its Association With Cognition, Anxiety and Depression

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J o u r n a l P r e -p r o o f

Acute CV morbidity/mortality due to SARS-CoV-2 infection and/or treatments

Deferred/delayed CV management due to health care restrictions and the infodemic

Influence of pandemic-related social and economic factors Time COVID-related cardiovascular morbidity and mortality J o u r n a l P r e -p r o o f

Acute CV morbidity/mortality due to SARS-CoV-2 infection and/or treatments

Deferred/delayed CV management due to health care restrictions and the infodemic

Influence of pandemic-related social and economic factors Time COVID-related cardiovascular morbidity and mortality