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Invited Commentary

The Journal of Cardiopulmonary Rehabilitation and Prevention at 40 yr and Its Role in Promoting Preventive Cardiology: Part 2

Franklin, Barry A. PhD; Brubaker, Peter PhD; Harber, Matthew P. PhD; Lavie, Carl J. MD; Myers, Jonathan PhD; Kaminsky, Leonard A. PhD

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: July 2020 - Volume 40 - Issue 4 - p 209-214
doi: 10.1097/HCR.0000000000000523
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This is part 2 of the third Invited Commentary recognizing the contributions of the Journal of Cardiopulmonary Rehabilitation and Prevention over the past 40 yr. The first two Commentaries provided overviews of the contributions related to cardiac rehabilitation and pulmonary rehabilitation.1,2 This Commentary provides a summary of the importance of the third major area of concentration of JCRP, namely, prevention.3 This second part will focus primarily on risk factors, smoking, cardioprotective medications, and psychological factors.


The multifactorial nature of cardiovascular disease (CVD) has led to the development and application of multivariable risk assessment scores. Risk scores allow clinicians to integrate information from multiple risk factors to quantitatively estimate a person's absolute risk for, or likelihood of experiencing, a cardiovascular (CV) event during a defined period of time (usually 10 yr). The first widely used multivariable CVD risk score was derived from the Framingham Heart Study.4 The Framingham risk score incorporated age, sex, systolic blood pressure (BP), total cholesterol, smoking status, antihypertensive treatment, and diabetes mellitus (DM) to estimate 10-yr risk of coronary heart disease (CHD). Although a number of risk prediction equations are available, the 2018 Cholesterol Clinical Practice Guideline5 recommends the use of the US-derived pooled cohort equations6 (!/calculate/estimate/) to estimate 10-yr risk for hard CVD events (defined as coronary death, nonfatal myocardial infarction [MI], fatal or nonfatal stroke). The pooled cohort equations are designed to be sex- and race-specific for whites and blacks and include stroke (not just CHD) as an end point to better identify modifiable risk in women and blacks. As shown in Figure 1, results of the 10-yr risk estimation should be communicated through a clinician-patient risk discussion to determine appropriate preventive measures, including whether to initiate medical therapy (especially HMG-CoA reductase inhibitors or statins). In the 2018 guidelines,5,7 patients with estimated 10-yr CVD risk of 5% to <7.5% are classified as borderline risk and may be considered for statin therapy under certain circumstances. Those with intermediate (7.5% to <20%) and high (≥20%) 10-yr risk should be considered for initiation of moderate- to high-intensity statin therapy and high-intensity statin therapy, respectively. In those adults with intermediate risk, evaluation of potential of risk-enhancing factors (Figure 1) may be useful in evaluating both short- and long-term CVD risk.

Figure 1.
Figure 1.:
Flow diagram for primary prevention of atherosclerotic CVD (ASCVD). Color corresponds to class of recommendation: green, class I (strong); yellow, class IIa (moderate); orange, class IIb (weak). apoB indicates apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CHD, coronary heart disease; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a). Reproduced from Grundy and colleagues5 , 7 with permission of the American Heart Association/American College of Cardiology.

The 2018 guidelines5 also emphasize quantification of coronary artery calcium (CAC) determined from computed tomography to potentially enhance risk assessments for CVD events in specific patient groups. First reported in 1990,8 CAC levels correlate very highly with the overall atherosclerotic burden.9 Subsequently, multiple studies in asymptomatic individuals have demonstrated the superiority of CAC in predicting CV events10 and that CAC has independent and incremental prognostic value when added to risk scores in asymptomatic subjects.11 In intermediate-risk adults, CAC scores can be helpful in reclassifying MI risk in selected patient subsets. As described in Figure 1, intermediate-risk adults with a CAC score of ≥100 Agatston units (or CAC ≥75th percentile) have CVD event rates indicating that statin therapy would be beneficial. Patients with CAC of 0 appear to have lower 10-yr event rates, suggesting that statin therapy may be of limited value except for those with DM, persistent smoking, and a family history of premature CVD. Cigarette smoking remains a strong risk factor even in the presence of a CAC score of 0.5 In asymptomatic patients with DM, a CAC score of 0 is associated with a favorable 5-yr prognosis. However, after 5 yr, the risk of mortality increases significantly for this cohort, even in the absence of baseline CAC. In patients with a family history of premature CVD, a CAC score of 0 may impart less short-term benefit from statin therapy, but considering a high lifetime risk, long-term benefit cannot be discounted. The same holds for a CAC score of 0 and a high 10-yr risk (eg, ≥20%). While CAC is an inexpensive, safe, and easy-to-obtain measure, uncertainty exists about the predictive value of intermediate CAC scores.5 Moreover, for patients with a CAC score of 0, it is currently uncertain when and whether follow-up CAC measurements should be obtained to reassess risk status.


Unquestionably, cigarette smoking remains the most common cause of death and disabilities in the United States (US) and worldwide. Although important advances have been made in tobacco control, the smoking rate varies considerably among population subsets and is concentrated disproportionately in lower socioeconomic classes. For example, the self-reported smoking rate is 1% among US physicians but >30% in some blue-collar workers.12 Interestingly, a retrospective cohort study that included 2306 consecutive patients from Olmstead County, Minnesota, who underwent percutaneous coronary intervention at the Mayo Clinic, revealed that the 12-mo smoking cessation quit rate following coronary revascularization did not change significantly over the past decade (48% in 1999-2001 vs 56% in 2007-2009), despite the enactment of smoke-free ordinances and improved treatment interventions.13

The smoking prevalence among US adults (≥18 yr) now hovers at 20%, >8 million people are sick or disabled as a result of tobacco use, and smoking kills an estimated 480 000 Americans each year.12,14 However, the grim reality is that this widely cited estimate of the mortality burden of smoking may be an underestimate. Using pooled data from 5 contemporary US cohort studies, researchers reported that approximately 17% of the excess mortality among smokers was due to associations with causes that are not currently established as attributable to smoking, including renal failure, intestinal ischemia, hypertensive heart disease, infections, various respiratory diseases, breast cancer, and prostate cancer.15 These corresponded to relative risks of 2.0, 6.0, 2.4, 2.3, 2.0, 1.3, and 1.4, respectively. Collectively, these data15 and other reports14 now suggest that at least 60 000 and perhaps as many as 120 000 additional deaths each year among US men and women may be caused by cigarette smoking.

A landmark study of 50 yr of observation of 34 439 male British physicians found that, on average, cigarette smokers die approximately 10 yr younger than nonsmokers. Stopping at age 60, 50, 40, or 30 yr, gained about 3, 6, 9, or 10 yr of life expectancy, respectively.16 Similarly, using data from the US National Health Interview Survey, researchers reported that life expectancy was increased from 4-10 yr among smokers who quit, depending on their age at the time of smoking cessation.17 Moreover, a relevant report showed that weight gain following smoking cessation was not associated with a reduction in the benefits of quitting smoking on CV outcomes.18 Three important messages emerged from these reports. Physicians and allied-health professionals in general, and especially those who care for patients with smoking-related illnesses, should be more proactive in urging quit attempts. Second, the importance of smoking as a health hazard needs to be elevated. Third, these data support a net CV benefit of smoking cessation, despite the often associated subsequent weight gain.


Secondhand smoke increases the risk of CHD by approximately 30%.19,20 In other words, individuals who live with an indoor smoker or spend considerable time in smoke-filled environments are at a 30% higher risk for an acute cardiac event than their matched counterparts without this exposure. Despite what would be expected from a comparison of the doses of toxins delivered, the effects of even brief (minutes to hours) passive smoking are, on average, 80-90% as large as those from chronic active smoking.19 Such exposures can lead to acute vascular injury characterized by mobilization of dysfunctional endothelial progenitor cells with blocked nitric oxide production, increased endothelial microparticles and vascular endothelial growth factor levels, and decreased flow-mediated dilation using ultrasonography.21 Although the latter returned to baseline at 2.5 hr, markers of vascular injury persisted for > 24 hr. Collectively, these data suggest that even brief exposure to real-world levels of secondhand smoke can have adverse acute (Table) and chronic effects on the CV system,19,21,22 including the triggering of acute cardiac events and ischemic stroke.23 According to a widely cited retrospective analysis of data from 192 countries, in 2004, secondhand smoke was responsible for an estimated 603 000 deaths worldwide in adult nonsmokers, and approximately 63% of these deaths were due to ischemic heart disease.24

Table - Effects of Secondhand Smoke on the Cardiovascular Systema,b
  • Increased platelet aggregability

  • Endothelial dysfunction

  • Impairment in coronary artery dilatation

  • Increased inflammation and infection

  • Accelerated atherosclerosis

  • Decreased antioxidant defense

  • Decreased vagal stimulation to the heart

  • Increased arterial stiffness

  • Decreased heart rate variability

  • Increased malignant ventricular arrhythmias

  • Increased infarct size

aThese mechanisms, rather than isolated stressors, presumably interact with each other to disproportionately increase the risk of atherosclerotic cardiovascular disease and its clinical manifestations.
bAdapted from references 19, 21, and 22.


Reductions in acute CV event rates, approximately 16-40%, have been reported in several large US cities and countries that have banned smoking in public places.25–29 More recently, investigators reported that initial implementation of a smoke-free law (which exempted casinos) in Gilpin County, Colorado, was followed by a 23% drop in ambulance calls from locations other than casinos but no significant change in calls from casinos.28 Two years later, when the law was expanded to casinos, a 19% drop in ambulance calls from casinos was observed, with no changes in calls originating outside casinos. Another study, using the Bremen, Germany, ST-segment elevation MI (STEMI) Registry, examined the effect of a public smoking ban on hospital admissions due to STEMIs.29 A significant decrease (16%; P < .01) in hospital admissions due to STEMIs was observed after the smoking ban was implemented. The decline in hospital admissions due to STEMIs was exclusively found in nonsmokers (26%; P < .01), whereas in smokers the incidence of STEMIs was essentially unchanged.29 Investigators suggested that their novel findings may be explained by the protection of nonsmokers from passive smoking and the absence of such an effect in smokers.


Cannabis Smoking

Using data from the Determinants of Myocardial Infarction Study, researchers reported that the risk of MI onset was elevated 4.8 times over baseline (95% CI, 2.4-9.5) in the 60 min after marijuana use.30 More recently, relative to triggers of acute MI, researchers used this heightened risk and its prevalence in the population to calculate the population attributable fraction for marijuana smoking at 0.8%.31 Finally, during the 2006-2010 period, of all cannabis-related disorders reported to the French Addictovigilance Network, 35 of 1979 (1.8%) were CV complications and 20 of these involved acute coronary syndrome, primarily in men (86%) whose average age was 34 yr.32 Although the authors acknowledged that these events were likely underreported, they concluded that cannabis may be a trigger of CV complications in young people.


Electronic cigarettes (or e-cigarettes), which heat a nicotine solution to generate an aerosol that is inhaled without combustion of tobacco and its toxic constituents, have been touted as a healthier smoking alternative and even a potential smoking cessation aid. However, e-cigarettes remain largely unregulated, and the possible health risks remain unclear. Although the cardiorespiratory responses to e-cigarettes need additional clarification, a preliminary report noted that these acutely increased aortic stiffness and systolic BP in young smokers.33 In addition, a just-published population-based longitudinal analysis found that current e-cigarette use increased the odds of developing incident respiratory disease by a factor of 1.29 (95% CI, 1.03-1.61).34 Accordingly, both population studies and clinical trials suggest that there is insufficient evidence to support the marketing messages of e-cigarettes.35 It has become increasingly clear that e-cigarette emissions are not merely harmless water vapor, that many persons employ dual use of e-cigarettes with conventional cigarettes, and that these offer no proven cessation benefits. Also alarming is the rapidly increasing youth initiation of e-cigarette vaping. Moreover, no long-term studies evaluating safety are available because of the limited market presence of e-cigarettes, leaving many critical questions unanswered. Thus, providers should consider these preliminary data when responding to patient queries regarding the safety and effectiveness of cigalike devices.


Numerous medications, including aspirin (ASA), β-adrenergic blockers (BBs), statins, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), and most recently, the pro-protein convertase subtilisin kexin type-9 inhibitors (PCSK9Is) and new medications for DM, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose transport protein 2 inhibitors (SGLT2Is), have varied roles in the primary and especially, the secondary prevention of CVD. For all of these agents, there is substantial concern about compliance, related to the cost of medications and/or associated symptoms, and the large and increasing pill count for many patients, frequently 5-10 and sometimes >10 prescription medications for multimodality treatment and prevention.


Clearly, except when contraindicated because of excessive bleeding risks or allergies, ASA is a first-line therapeutic agent for all patients for the secondary prevention of CHD. Recently, however, the routine use of ASA for low- and moderate-risk primary prevention has been challenged.7 New guidelines emphasize that between ages 40 and 70 yr, low-dose ASA is indicated for primary prevention only among those at high-risk for atherosclerotic CVD, and higher doses of ASA are no longer recommended for primary prevention. The use of ASA is also no longer recommended for primary prevention in those with high bleeding risk, and routine use of low-dose ASA for primary prevention is now proscribed for those <40 yr or >70 yr. However, ASA may be considered for selected high-risk patients, based on strong family history, inability to obtain lipid, BP and glucose goals, or a high CAC score.


The BBs have been mainstay therapy for secondary prevention for patients following acute MI and for heart failure (HF) with reduced ejection fraction (HFREF), as well as for patients with CHD and symptoms of angina pectoris. Some recent studies, however, have questioned the routine use of BBs for modern day patients with MI and preserved left ventricular function,36 especially in the era of dual antiplatelet therapy and high-intensity statins. Although generally BBs are treated as a class, the agent carvedilol seems to be especially efficacious in patients with HFREF and post-MI settings.37


There is substantial evidence to support the use of statins in the primary and, especially, secondary prevention of CHD. In primary prevention, statins are indicated only for patients with DM and other high-risk patients between the ages of 40 and 75 yr and for individuals with low-density lipoprotein cholesterol (LDL-C) > 190 mg/dL.38 However, in secondary prevention, the evidence of statins is stronger, with high-intensity statins (40-80 mg of atorvastatin or 20-40 mg of rosuvastatin) for the majority of patients with high-risk atherosclerotic CVD. In those at very high risk of CVD, lipid guidelines now suggest goals for LDL-C <70 mg/dL, with consideration of adding ezetimibe or PCSK9Is to high-intensity statins when appropriate.


The use of ACEIs/ARBs is considered to be first-line therapy for hypertension, along with diuretics and calcium channel blockers, except for African Americans with hypertension, who do not have chronic kidney disease, when ACEIs/ARBs are preferred over these other classes in patients with hypertension and chronic kidney disease.39 The ACEIs/ARBs for decades have been first-line therapy for patients with symptomatic HFREF, although now sacubitril/valsartan has replaced this class as first-line therapy.40 However, with the new hypertension guidelines to treat BP at levels 130/80 mm Hg, except in low-risk patients, many patients will require not only ACEIs/ARBs but also calcium-channel blockers and/or diuretics and even other agents to reach current BP goals.


Recently, the use of the injectable monoclonal antibodies, PCSK9Is, has been introduced into clinical practice, where evolocumab and alirocumab can provide nearly 60% reductions in LDL-C.41 These agents are indicated for patients with familial hypercholesterolemia, who need additional LDL-C lowering and for patients with atherosclerotic CVD. Recent trials with these agents have produced additional clinical event reductions in patients with CVD, leading to these agents being indicated in the US and European lipid guidelines to evoke incremental lowering of LDL-C in patients with very high-risk CVD.41,42 In the US, the costs of these agents was recently lowered by nearly 60%, making them more accessible to many of our patients.


Recently, 2 classes of medications for DM have been shown to reduce clinical events. The GLP-1RAs and, especially, the SGLT2Is class now have substantial clinical event data.43–45 Several but not all GLP-1RA trials have demonstrated significant reductions in major CVD end points. However, the data for the SGLT2Is class have been even more impressive, with substantial evidence particularly for the primary and secondary prevention of HF events and the secondary prevention of major CVD. In fact, there is recent evidence that SGLT2Is reduce HF events in HFREF patients without DM.46 Considering the epidemic of DM and the difficulty that primary care physicians and endocrinologists have in effectively implementing comprehensive risk reduction interventions in this escalating patient population, current evidence suggests that specialists in CVD may need to become more involved in the treatment of DM, including the use of new DM agents that provide concomitant CVD protection.


There is considerable evidence that psychological risk factors and psychological stress, including anxiety, hostility, and especially, depression, are risk factors for the development of CVD and may adversely impact prognosis in patients with established CVD.47–49 Besides having a significant role in chronic CVD, psychological stress can also trigger the onset of acute CVD events.48 Sympathetic nervous system stimulation emanating from acute psychological stress can lead to a cascade of physiologic responses, including increases in heart rate, BP and pro-arrhythmogenic states, vasoconstriction, worsening endothelial function and injury, platelet activation, and hemostatic alterations. Clinical consequences of acute psychological stress may include myocardial ischemia, ventricular arrhythmias, more vulnerable coronary plaques, and the potential for thrombus, potentially triggering acute MI and sudden cardiac death.

Indeed, numerous studies have reported an acute increase in CVD events with psychological stress, including during earthquakes, following sleep deprivation, sporting events, acute anger and anxiety, stock market declines, and hurricanes, among other acute psychological stressors.48 Clearly, associations between psychological risk factors, especially depression, and CVD are well established.47,49

There is accumulating evidence to suggest that positive psychological well-being, which includes positive feelings and thoughts, such as optimism, happiness, and passion for life, has potential independent associations with lower CVD risk and can be utilized potentially to improve overall health.47 In fact, feelings of positive psychological well-being have been directly associated with the 7 major metrics of CV health and improved outcomes in CVD. Individual-level interventions, including mindfulness-based programs and other positive psychological-based interventions, including programs at workplaces, have potential to improve CV health and reduce CVD.47


Aggressive risk factor reduction, including lifestyle modification (eg, regular physical activity, cardioprotective dietary practices, smoking cessation) and more intensive efforts to control hyperlipidemia and DM with pharmacotherapies, can reduce the incidence of plaque rupture and improve coronary artery vasomotor function. These prevention approaches, along with psychologic and stress management interventions, are individually associated with improved CV outcomes and impressive mortality reductions (Figure 2).50 When selectively combined, even greater survival benefits are likely to be achieved (Figure 3).51

Figure 2.
Figure 2.:
Prevalence of depression and subsequent mortality based on changes in o 2peak during exercise-based cardiac rehabilitation. a P < .001 compared with o 2 loss. NS indicates not significant. Reproduced with permission from Milani and Lavie.50
Figure 3.
Figure 3.:
Cumulative time-to-event curves for clinical events in the cardiac rehabilitation + stress management training (CR + SMT), CR alone, and no CR groups. Clinical events included all-cause mortality, myocardial infarction, cardiac or peripheral vascular intervention, stroke/transient ischemic attack, or unstable angina requiring hospitalization. Participants in the CR + SMT group were at a significantly lower risk of clinical events compared with the CR-alone group (HR, 0.47; 95% CI, 0.24-0.91; P = .025). Both CR groups had lower event rates than a nonrandomized matched No-CR control group (HR, 0.35; 95% CI, 0.22-0.56; P < .001). Number at risk represents participants with follow-up data for clinical events who had not yet had an event at years 0, 2, and 4. Adapted with permission from Blumenthal et al.51

As CV health care providers, we need to become champions of promoting preventative strategies including healthy lifestyle overhauls in our patients to prevent the development and progression of CVD. Achieving these goals will, no doubt, involve a paradigm shift in the practice of medicine, which embraces an interprofessional approach. The value of the Journal of Cardiopulmonary Rehabilitation and Prevention in promoting these preventative strategies over the past 40 yr is apparent.


The authors thank Brenda White for her meticulous preparation of this manuscript and for carefully checking the accuracy of their references throughout the text and in the citations listed at the conclusion of this commentary.


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preventive cardiology; prevention

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