Psychophysiology and the development of Cardiovascular Disease

Question 1

What is cardiovascular disease (CVD)?

Answer 1

It is a class of diseases that involve the heart and/or blood vessels

It has symptoms such as angina, MI, stroke

CVD is the single biggest killer in the UK

Question 2

Describe Coronary Heart Disease (CHD).

Answer 2

• Can be ischaemic (heart is damaged due to oxygen deprivation, caused by restricted blood flow) or nonischaemic (cardiomyopathy)
• Underlying condition is usually coronary atheroschlerosis, a process of arterial wall thickening due to lipid deposition, inflammation and smooth muscle infiltration (Hansson 2005)
• Acute coronary syndromes (ACS). These include myocardial infarction (MI), unstable angina, and sudden cardiac death (SCD).

Question 3

Describe the onset of acute coronary syndrome (ACS)

Answer 3

Chronic risk factors, atherosclerosis –> vulnerable arterial plaque –> plaque disruption, rupture/erosion (also impacted by acute factors - cardiovascular activation, coronary vasoconstriction and prothrombotic blood) –> Myocardial infarction, unstable angina, ventricular tachycardia/arrhythmia

Question 4

What are the chronic, acute and episodic risk factors of CVD?

Answer 4

Chronic: e.g., elevated low-density lipoprotein (LDL) cholesterol, smoking, hypertension

Acute: transient pathophysiologic change (immediate change) resulting from exposure to external physical or psychological factors that can trigger events such as ischaemia, infarction or sudden death.

Episodic: behavioural characteristics that are neither acute nor chronic (e.g., depression)

Question 5

Expand on cardiac arrhythmias.

Answer 5

Approximately 85-90% of sudden cardiac death (SCD) is due to the first arrhythmic event

80% of SCD events are caused by ventricular arrhythmias:
VT: ventricular tachycardia
VF: ventricular fibrillation

Question 6

What does QT interval represent and how does it predict arrhythmic events and SCD?

Answer 6

• Echocardiographic representation of ventricular repolarization time
• Increased variability is a significant predictor of arrhythmic events and SCD
• Difference greatest at 6am

Question 7

What are the triggers of arrhythmic events?

Answer 7

• PHYSICAL - exertion, activity
• time of day/year (peak @ 6am)
• PSYCHOLOGICAL: anger, mental stress, anxiety, mood disturbance, behavioural

Question 8

Describe substrate-trigger interactions.

Answer 8

Increased intensity of stessors (trigger), as well as an increase in severity of personal vulnerability factors, leads to cardiac event

Question 9

What are some behavioural triggers of CVD?

Answer 9

• Poor sleep associated prospectively with risk of CHD mortality (Mallon et al. 2002)
• Smoking increases risk of CHD (increases CA & cortisol levels, heart rate and blood pressure); but little evidence of triggering of ACS
• Alcohol: J-shaped relationship between consumption and mortality; evidence for heavy drinking as trigger lacking
• Vigorous physical activity has been found to trigger MI and SCD. Relative risk estimates of 2.1-5.9 (Mittleman et al 1993; Willich et al 1993)

Question 10

Describe anger as a trigger of CVD?

Answer 10

• Mittleman et al 1995: Elevated reports of anger episodes within 2 hours prior to MI (2.4%)
• SHEEP study (1999) absolute incidence of intense anger in hour before onset was 1.2%
  OR of acute MI in 2 hours after anger episode relative to no anger was 4.0 (1.9-9.4)
• Risk of anger triggering inversely related to SES

Question 11

Describe emotional triggers of CVD.

Answer 11

• Emotional factors can act as triggers of acute cardiac events in susceptible people (see Exercise 1 today and TED talk in Canvas)
• Susceptible because tendency of a heightened psychophysiological response profile
• Death of a partner associated with a range of major CV events in the immediate weeks and months after bereavement (Carey et al., 2014)
• In the month following 9-11, arrhythmic events more likely in ICD population.
• Triggering more common in people of lower SES and undergoing work stress

Question 12

Describe psychobiological processes underlying acute triggering.

Answer 12

• Haemodynamic response: increased BP, HR and cardiac output, regional changes in blood flow
• Autonomic dysfunction: PNS withdrawal (decreased HR variability) /SNS activation
• Neuroendocrine activation: increases in HPA activity and in catecholamine levels (esp noradrenaline)
• Inflammatory processes activated
• Platelet activation can stimulate plaque disruption, promote thrombus formation & induce electrical instability

Question 13

Describe the neurobiological processes underlying acute triggering.

Answer 13

• natural disasters are good to look at acute cardiac events
• Earthquake studies have shown (see Dar et al 2020):
  
  • increased risk for acute cadriovascular complications such as MI, left ventricular dysfunction, and arrhythmias
  • relative increase in SNS activity; increases in heart rate, low-frequency/high-frequency heart rate variability ratio, and risk of thromboembolism
• Coronary microvascular constriction during acute mental stress is hypothesized to be important mechanism behind stress-induced MI
• CAD patients with high peripheral vasoconstriction show increased stress activation (vs.low vasoconstrictors) in insula/parietal cortices and decreased activation in prefrontal cortex (Shah et al 2019).

Question 14

Summarise acute triggering

Answer 14

• Converging evidence for supporting role of acute mental stress and heightened (negative) emotional processing in the acute triggering of cardiac events, may be moderated by SES
• Include processes that may promote plaque rupture, vascular environment encouraging thrombus formation, and neuroendocrine /autonomic processes that stimulate rhythmic disturbances
• Brain areas involved in fear inhibition and visuospatial processing of threat likely to be involved in stress-related vascular function, particularly coronary microvascular constriction
• Suggests the critical role of management techniques intended to reduce exposure to triggers and precautions in high-risk situations (e.g., natural disasters) in reducing the risk of acute cardiac events

Question 15

What are risk factors?

Answer 15

• Risk factor in epidemiological terms is a variable associated with an increased risk of disease; disease often results from multiple risk factors (act as confounders; need to control for)
• Confer an independent risk on prognosis
• Have a direct dose-dependent relationship; increase in risk factor associated with concomitant increase in mortality (gradation effect)
• Established operational pathway (plausibility)
• Reduction in the risk factor leads to a concomitant improvement in survival

Question 16

What are risk markers?

Answer 16

A variable that is quantitatively associated with a disease (or outcome) however direct manipulation of the marker does not necessarily alter the risk of the outcome

Lie somewhere on the causal pathway between a third pathway and cardiac prognosis

Question 17

Give examples of psychological factors as potential risk factors for CVD.

Answer 17

Depression
Anxiety
Acute and chronic stress
Anger & hostility
Personality
Psychosocial variables:
Social support
Socioeconomic status

Question 18

Describe depression.

Answer 18

• Depression characterised by melancholic mood and symptoms such as changes in appetite, sleep patterns, diminished interest/pleasure in usual activities
• Distinguish between Adjustment Disorder (resolves quickly with appropriate support) with Depressed Mood and Major Depressive Disorder:
  
  • – Between 30% and 50% of cardiac patients may have depressive symptoms (compared to 13% in population) – can resolve with psychoeducation, social support etc.
  • – Major depressive disorder rates are higher in cardiac patients esp post MI (16-23%); maladaptive response, needs targetted intervention

Question 19

What is the role of depression with CVD?

Answer 19

• Affects morbidity and mortality in CVD patients
• Independently associated with a more than threefold increased risk of sudden cardiac death in coronary artery disease (CAD; Lahtinen et al 2018)
• Depression diagnosis following CAD diagnosis associated with 2-fold higher risk of death (May et al 2017).
• More severe symptoms of depression predict shocks for VF/VT in ICD patients (TOVA cohort)
• Frequency of laughter independently associated with CVD incidence (HR=1.62 for low frequency laughers) after adjusting for multiple risk factors (Sakurada et al 2019)

look at ppt for table linking depression and CVD

Question 20

Describe anxiety and CVD.

Answer 20

• Anxiety is common in cardiac patients, associated with poor health status and QoL
• Evidence that anxiety is independently associated with increased mortality in CVD
• Anxiety and depression tend to co-occur in post-MI patients
• Many studies have found a relationship between anxiety and adverse clinical events

Question 21

Describe studies linking anxiety and CVD

Answer 21

Shen et al (2008) in a study of 735 older men (60+) without a history of CHD found that anxiety characteristics independently and prospectively predicted MI incidence after controlling for confounders (e.g., age, education, marital status, fasting glucose, BMI, systolic BP)

• These relationships remained significant after controlling for health behaviours, as well as depression, anger and hostility
• 2016 meta-analysis of 37 studies (n=1565699); Anxiety was associated with a 52% increased incidence of CVD (HR = 1.52; Batelaan et al)

look at ppt for table on depression & anxiety

Question 22

Describe stress and its link with CVD.

Answer 22

• Conceptual issues in defining stress
• Can trigger events but less clear that it ‘causes’ events (at least for low-level stressors)
• Can be acute or chronic
• Excessive ‘stress reactivity’ may be a risk factor for CAD
• Permanent ‘stress’ (high levels of chronic stress) at work or home was associated with >2.1 times the risk of MI (Interheart study 2004)
• Whitehall II study (1998) found a 2.15 x increased risk for new CHD in men who experienced a mismatch between effort and reward at work
• Swedish cohort followed for 5 yrs (Orth-Gomer et al 2000) studied impact of work & marital stress on subsequent incidence of CV events in Stockholm women. Marital stress was associated with a 2.9 x increased risk of coronary events but work stress did not predict subsequent coronary events

Question 23

Describe Chida & Steptoe’s study linking anger & hostility with CVD.

Answer 23

Chida & Steptoe meta-analysis(2009):
- reported a 20% increased risk of both incident CHD in initially healthy people and poor prognosis in CHD patients

• harmful effects of (trait) anger & hostility in healthy pops was greater in men
• when behavioural covariates (smoking, physical activity, BMI, SES) are controlled for effects no longer significant

Question 24

What are the challenges with anger & hostility?

Answer 24

Not all anger the same: Anger-Out tendencies to express aggression outwardly; Anger-In tendencies to suppress or withhold anger

Correlations among anger measures tend to be low-to-moderate, which partly reflects multi-dimensional nature of anger

Self-reported ‘cynical hostility’ and intensity/frequency of anger more frequently show effects (Suls, 2013)

Question 25

What is socioeconmic status (SES) & social support and its link with CVD?

Answer 25

• SES defined as an individual’s occupation, economic resources, social standing and education (Kaplan et al 1997)
• Powerful predictor of CV risk
• Social gradient affecting CAD risk factors and CV disease (Whitehall study; Marmot et al 1984)
• Epidemiological studies have confirmed an association between low social support and the risk of CV disease;
  
  • • correlates with SES, medication use, medical compliance
  • • Social isolation

Question 26

Describe cardiovascular reactivity as a model inking stress to CVD.

Answer 26

• One model linking stress to CVD
• Refers to changes in CV activity that are related to psychological stress
• Exaggerated reactivity to psychological stressors may play a role in development of hypertension and/or CVD
• Reactivity hypothesis provided framework for the Whitehall study (Carroll et al 1995, 2001)

Question 27

Describe the Whitehall study in more detail.

Answer 27

• Prospective study (5 & 10 yrs)
• Examining BP reactivity to a mental stressor in middle-aged men as a predictor of subsequent BP level & hypertension development
• Reactivity was a sig predictor of BP 5 yrs later but accounted for only <1% of the additional variance after inclusion of 3 overlapping predictors: age, initial screening BP & resting baseline BP
• Phase II: found essentially the same

Question 28

What are the 3 models for comorbidity and depression as found by Mosovich et al (2007)?

Answer 28

A - CVD –> depression
B - Depression –> CVD
C - Common underlying factor (cytokine and inflammatory response to stress) –> Depression and CVD

Question 29

Describe some biological mechanisms of CVD.

Answer 29

• HPA axis dysregulation potentially explains link between depression and CVD/poor CAD prognosis
• Autonomic imbalance favouring sympathetic activation is a risk factor for cardiac prognosis and death
• HPA axis dysregulation is associated with CV risk factors such as coronary artery stenosis, visceral obesity, high blood pressure and heart rate and hypercholesterolemia
• Decreased HR variability due to vagal withdrawal which in turn may increase the risk for ventricular arrhythmias
• Depression, or exposure to chronic stress; HPA axis may deregulate resulting in excessive cortisol secretion and cytokine production
• Both anxiety & depression linked to abnormalities in the duration of ventricular repolarization (ie. long QT intervals)
• Depression without CVD associated with reduced HRV - decreases with increasing depression severity (Kemp et al 2010)
• Increased metabolic activity of amygdala (neural centre of stress perception) is an independent predictor of CVD events within 5 yrs (mediated by increased bone-marrow activity and arterial inflammation; Tawakol et al. 2017).

Question 30

What are the physiological responses of stress?

Answer 30

• Stimulates SNS
• Increased HPA axis
• Vasoconstriction
• Increased CAs
• Increased platelet aggregation
• Increased HR
• Increased BP
• Increased QT variability
• Increased inflammatory cytokines

Question 31

What are the physiological responses of depression?

Answer 31

• Stimulates SNS activity
• Increased CAs esp NE
• Platelet aggregation
• Increased HR
• Increased HR responses to physical and psychological stressors
• Decreased HR variability
• Increased QT variability
• Significant predictor of VT
• Increased inflammatory cytokines

Question 32

What are the neurobiological mechanisms of CVD?

Answer 32

From Dar et al 2020 (Curr Treat Options Cardiovasc Med. ; 21(5): 23):

Fig. 1 Proposed neurobiological mechanism linking psychosocial stress to cardiovascular disease, with imaging examples, and potential therapies targeting involved tissues. BBs beta blockers, CBT cognitive behavioral therapy, MACE major adverse cardiovascular events, RR relaxation response, SNS sympathetic nervous system, SSRIs selective serotonin reuptake inhibitors.

see figure on ppt

Question 33

What are the behavioural mechanisms of CVD?

Answer 33

• Non-compliance; Psychological factors such as depression & anxiety may interfere with medication adherence
• Depression is associated with a 2-to-3-fold increased risk of non-compliance to treatment
• Reluctance to make lifestyle changes
• Low participation in cardiac rehab
• Linked with traditional risk factors for CVD such as smoking and alcohol consumption

Question 34

Why should we assess and manage psychological factors of CVD?

Answer 34

• Common in cardiac patients
• Impact adversely on quality of life
• Affect the adoption of lifestyle changes
• Can interfere with adherence to treatment
• Linked to behavioural & cardiovascular risk factors
• They tend to cluster together within individual patients

Question 35

What are cardiac rehabilitation programmes?

Answer 35

• Post MI, surgery or procedure
• Designed to improve physical and psychological health and QoL
• Only 40% of heart attack survivors participate
• Have elements of health education, exercise and lifestyle change

Question 36

Give examples of techniques used in intervention studies?

Answer 36

• Relaxation training
• Cognitive behavioural stress management
• Mindfulness-based intervention
• Meditation
• Group emotional support
• Cognitive therapy

Question 37

What did Lewin et al., find out?

Answer 37

Lewin et al (2009) UK study
- 192 patients (8 ICD centres)

• Prospective, multi-centre trial
• At 6 months post-surgery, intervention group had:
  
  1. better physical health
  2. fewer limitations in physical activity
  3. greater reduction in proportion of patients with a borderline diagnosis of anxiety and depression
  4. 50% fewer unplanned admissions

Question 38

Describe the ENRICHD trial.

Answer 38

• Enhancing recovery; Post MI patients
• 2,481 patients enrolled
• Psychosocial intervention group
• Used CBT (began 2 weeks post-MI)
• Secondary endpoint HRQoL
• Improved psychosocial outcomes but no effect on event-free survival

Question 39

What did studies specific to anxiety and depression find?

Answer 39

Depression:
ENRICHD trial (2001) the intervention of CBT reduced depression but failed to positively affect the incidence of major adverse cardiac events or death

Anxiety:
Intervention studies in ICD patients usually small-scale. They seem to be successful in reducing anxiety with CBT showing the strongest and most stable reductions

Question 40

What does stress management use?

Answer 40

• Uses specific cognitive behavioural strategies to help patients reduce stress levels
• Meta-analyses show that if intervention is successful in reducing psych stress then the risk of <2yr mortality is reduced by 28%; Sig benefit only for men, not women
• Cardiac rehabilitation (CR) enhanced by stress management training produced significant reductions in stress and greater improvements in psychological stress and adverse clinical events compared with standard CR (Blumenthal et al 2016).

Question 41

Give examples of some psychosocial intervention trials.

Answer 41

2017 Cochrane review: psychological interventions for CHD

• 35 RCTs with 10,703 participants
• Only psychological interventions by health care workers with training in psychological techniques
• Small-to-moderate reductions in anxiety/depression levels
• 21% reduction in cardiac mortality (RR 0.79, 95% CI 0.63- 0.98)
• No evidence of a statistically significant effect of the intervention on all-cause mortality (RR=0.90, 95% CI 0.77-1.05) or risk of revascularisation (RR=0.94, 95% CI 0.81-1.11)
• 2019 review of mindfulness-based interventions demonstrated favourable effects on psychological and physiological outcomes among adults with CVD (Scott-Sheldon et al 2019)