Ageing Heart and Heart Failure Notes

Ageing Heart and Heart Failure

Notes from a presentation by Guy MacGowan, Dept of Cardiology, Freeman Hospital, Biosciences Institute, Newcastle University.

Effects of Normal Ageing on Heart Function

• Cellular and organ function are affected by normal aging.
• Hypertension significantly impacts the aging heart.

Types of Heart Failure

• Heart failure with preserved ejection fraction (HFpEF).
• Heart failure with reduced ejection fraction (HFrEF).

Pathophysiology of Heart Failure with Reduced Ejection Fraction

• Discussion of the rationale for medical therapies.
• Heart Failure is a disease of the elderly – as shown by the National Heart Failure Audit.

Calcium Transients and the Pressure Waveform

• A graph shows pressure in mmHg over time (s) relating to fluorescence. MacGowan et al, Am J Physiol 2006

Cellular Mechanism of Cardiac Contraction

• Diagram illustrating the cellular mechanism of cardiac contraction, involving:
  • Sarcoplasmic Reticulum
  • $[Ca^{2+}]i$
  • SERCA2a + Phospholamban
  • Sarcolemma
  • Troponin C
  • Myofilament
  • L-type $Ca^{2+}$ channel
  • $[Ca^{2+}]o$

Age-Related Changes in Excitation-Contraction in Rats

• Cytosolic [Ca] changes with age:
  • Action Potential graph showing mV over time (msec) for 6-month and 24-month old rats. Lakatta and Sollott, Mol Interv 2002
  • Twitch force (g/mm²) over time (msec) for 6-month and 24-month old rats.
  • Velocity of $[Ca^{2+}]$ accumulation (nM/mg X min) vs. $[Ca^{2+}] \mu M$ for adult and senescent rats.

Integration of the ATP Synthesizing and Utilizing Reactions

• Reference to Ingwall, J. S. et al. Circ Res 2004;95:135-145. Copyright ©2004 American Heart Association

Cardiac MRI

• Cardiac MRI can measure several components of cardiac function and metabolism, providing high resolution and unique information.
• MR tagging provides non-invasive myocardial labelling.
• $^{31}P$ spectroscopy allows measurements of PCr/ATP ratios.

MR Imaging Details

• Specific imaging parameters are listed, including:
  • Sc 9.1/8 B-TFE/FFE/M Td 000 ms [350] AP 45° FH-31 A 38 L 48 F 22 W 1608 L 801
  • Sc 7.10 B-TFE/FREM nl 000 ms [20] AP 7° RL 44° FH-6° A 39 L 43 F 26 W 1834 L 872
• Accurate measures of left ventricular mass, blood pool volumes, ejection fractions can be obtained.

The Cardiac Cycle: Ejection Fraction and Diastolic Function

• Graph illustrating pressure changes (mmHg) during systole and diastole over time (ms).

Key Parameters

• Early filling volume
• Stroke volume
• End-diastolic volume
• End-systolic volume
• Late filling volume
• Equations:
  • Cardiac Output = Stroke Volume * Heart Rate
  • Ejection Fraction = (Stroke Volume / End-diastolic Volume) * 100

Cardiac Output and Diastolic Function in Normal Human Ageing

• r = -0.72, p = 2 x $10^{-8}$
• E/A ratio (Early/Late filling) – measure of diastolic function

High Energy Phosphate Metabolism

• ATP, PCr
• Cardiac $^{31}P$ spectrum acquired from a normal heart acquired on NMRC 3T scanner.
• ATP α β γ
• PDE
• PCr
• 2,3-DPG+Pi

Energetics: PCR/ATP Ratio from $^{31}P$ MRS in Normal Human Ageing

• Graph showing PCr/ATP ratio (-) for different age groups (18-40 y, 40-60 y, 60+ y).
• r = -0.52, p = 0.0004

How does Hypertension Effect Ageing in the Heart?

• Systolic Blood Pressure increases with age in both normal and hypertensive individuals, but is significantly higher in hypertensive individuals. *P<0.05 Nml vs HPTN

Hypertension and the Heart

• Impact on Systolic Blood Pressure:
  • Data comparing normal (Nml) vs. hypertensive (Hptn) groups over different age ranges.
• Impact on Diastolic Function:
  • EFP (%), comparing Nml vs. Hptn groups.
  • *P<0.05 Nml vs HPTN
• LV Mass: g/m^2 *P<0.05 Nml vs HPTN
• Energetics: PCr/ATP *P<0.05 Nml vs HPTN

Heart Failure

• A reduction in the heart's ability to contract or relax.
• Heart failure with reduced ejection fraction (HF rEF).
• Heart failure with preserved ejection fraction (HF pEF).

Epidemiology of Heart Failure in the UK

• Approximately 900K people have heart failure in the UK.
• Accounts for 5% of emergency hospital admissions.
• Represents 2% of NHS spending.

Symptoms of Heart Failure

• Shortness of breath.
• Peripheral oedema.
• Fatigue.

Ageing and the Types of Heart Failure

• Age predisposes to CAD (coronary artery disease) causing myocardial infarction, along with risk factors (smoking/DM/FHx).
• Longstanding HPTN/DM/Obesity causing diastolic dysfunction
• Ageing HF pEF: Diastolic Dysfunction. Gradual Onset over Years
• HF rEF: Systolic Dysfunction. Sudden Onset
• Symptoms for HFpEF and HFrEF are the same: Dyspnoea/odema

Pathophysiology of HFrEF

• Sir William Osler (1849-1919) - MI leads to Terminal Decline in Cardiac Function and ultimately CHF (Congestive Heart Failure) after a Period of Stabilisation. HF reduced EF

Progression of Heart Failure

• Why does the heart fail several years after the initial insult?
• LV Dysfunction leads to Neurohormonal Stimulation, which increases Peripheral Resistance and causes LV Remodeling, ultimately leading to HF reduced EF.

Neurohormonal Activation in Heart Failure with Reduced Ejection Fraction

• Elevated levels:
  • Plasma Norepinephrine
  • Plasma Renin Activity
  • Arginine Vasopressin
  • Atrial Natriuretic Peptide
  • Endothelin-1
  • HF reduced EF

Acute and Chronic Effects of Neurohumoral Activation

• ACUTE:
  • Increases BP;
  • Preserves perfusion to vital organs
• CHRONIC:
  • Increases Afterload;
  • Reduces Stroke Volume;
  • Myocyte Necrosis and Apoptosis;
  • Sodium Retention
  • HF reduced EF

Evolutionary Perspective

• Man has not developed an evolutionary strategy to counteract long term reduction in cardiac output.
• Instead, man uses the neurohumoral responses evolved to cope with acute reduction in cardiac output (blood loss etc).
  • HF reduced EF

Plasma Noradrenaline (Norepinephrine) and Outcome in Heart Failure with Reduced Ejection Fraction

• Graphs showing cumulative mortality (%) over months, stratified by concentrations of plasma norepinephrine.
  • >5.32 nmol/l
  • >3.55 nmol/l and <5.32 nmol/l
  • <3.55 nmol/l
  • HF reduced EF

Progression of Heart Failure with Reduced Ejection Fraction

• Left Ventricle: INCREASING NEUROHUMORAL ACTIVATION. HF reduced EF

Aetiology of Heart Failure with Reduced Ejection Fraction

• Myocardial Infarction
• Hypertension
• Valvular Heart Disease
• Idiopathic Dilated Cardiomyopathy
• Secondary Cardiomyopathy (Alcohol, chemotherapy)
• Myocarditis HF reduced EF

Neurohormonal Pathways

• Diagram of the Renin-Angiotensin-Aldosterone System (RAAS) and Sympathetic Activity.

Therapeutic Targets

• Diagram showing points of intervention: b-Blockers, ACEi, ARB, Aldo Inhibitors.
  HF reduced EF

Angiotensin Converting Enzyme Inhibitors

• Inhibits conversion of angiotensin I to angiotensin II.
• Used to treat hypertension and congestive heart failure.
• Consistently shown to reduce mortality in heart failure patients. HF reduced EF

Effect of ACEi in Patients with HFrEF

• CONSENSUS*: Severe CHF
• SOLVD Treatment†: Moderate CHF
  • Placebo (n = 126)
  • Enalapril (n = 126)
  • Enalapril (n = 1285)
  • Placebo (n = 1284)
• Mortality (%) over Months.
• HF reduced EF

b-Blockers in Congestive HFrEF

• Inhibit b-adrenergic receptors on myocytes.
• Produces negative chronotropic and inotropic effects.
• Previously thought to be contraindicated in heart failure due to acute negative inotropy.
• However, long term inhibition of neurohumoral activation produces significant benefits on survival and cardiac function. HF reduced EF

Effects of ß-Blockers on Mortality in HFrEF

• Data from multiple studies:
  • COPERNICUS (n=2289) Risk ¯ 34 % P=.006
  • MERIT-HF (n=3991) Risk ¯ 34 % P<.0001
  • CIBIS II (n=2647) Risk ¯ 65 % P=.00013
  • US CARVEDILOL (n=1094) Risk ¯ 35 % P<.0001
• HF reduced EF

Effect of Aldosterone Antagonist Spironolactone on Mortality in HFrEF

• Pitt B, et al. N Engl J Med. 1999;341:709-717.
• 30% reduction p<0.001
• HF reduced EF

Difficulties with Heart Failure Therapies

• Most heart failure therapies reduce BP - you can only reduce the BP so much
• The multiple medications are complex for both doctors and patients
• Electrolytes and renal function need to be monitored closely
• Close follow-up is often required
• There is a need for co-ordinated care between primary care nurses and physicians and hospital specialists for efficient heart failure management. HF reduced EF

Heart Failure with Preserved Ejection Fraction

• Proportion of patients with heart failure with preserved ejection fraction is increasing.
• Prevalence of rates of hypertension, atrial fibrillation, and diabetes amongst heart failure patients are increasing.
• Similar survival to HF rEF
• Most proven therapies for HF rEF do not improve outcomes in HF pEF HF preserved EF

Causes of Death in Heart Failure by Ejection Fraction

• Reference to Toru Kondo et al. JACC 2024; 2024 American College of Cardiology Foundation

SGLT2 Inhibitors in HFpEF + HFrEF

• FIGURE 1 Main Mechanisms of Action of SGLT2 Inhibitors:
  • SGLT2 inhibitors promote Natriuresis/Diuresis and Glucosuria/Uricosuria.
  • Leading to Blood pressure ↓ and Plasma volume ↓
  • Also decreases Insulin resistance and Body weight↓
  • Ketones ↑
  • Hemodynamic effects and Metabolic effects, Reduction of risk of heart failure

Outcomes with SGLT2 Inhibitors

• Primary Outcome: Hazard ratio, 0.74 (95% CI, 0.65-0.85) P<0.001
• Hospitalization for Heart Failure: Hazard ratio, 0.70 (95% CI, 0.59-0.83)
• Death from Cardiovascular Causes: Hazard ratio, 0.83 (95% CI, 0.71-0.97)

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes

• A Change in KCCQ-CSS
  • Estimated difference, 7.3 points (95% CI, 4.1 to 10.4) P<0.001
    ` B Change in Body Weight
  • Estimated difference, -6.4 percentage points (95% CI, -7.6 to-5.2) P<0.001

National Heart Failure Audit: Age Distribution and Length of Stay in Hospital

• Graphs showing number of patients and Mean length of stay (days) by age group.
  • Mean age = 78 years; Median age = 80.4 years
  • Mean age men = 76.1 years; Mean age women = 80.2 years
• Data from 2012/13 to 2015/16
• No specialist care vs Specialist care shown

Age and Treatment and Heart Failure Service Referrals

• Graphs showing Prescribed at discharge (%) by age.
• ACEI
• ACEI and/or ARB
• ARB
• Beta
• Loop
• MRA
• Follow-up services (%):
  • Cardiology Ward
  • General Medical Ward
  • Cardiac rehabilitation
  • Cardiology follow-up
  • Heart failure nurse follow-up
  • Heart failure nurse follow-up (LVSD only)

Aetiology and Echo Diagnosis

Outcomes

• Survival post-discharge (%).
• Mortality (%).
• Specialist input vs No Specialist Input.
• Age<75 vs Age≥75

Outcomes 2

• Survival post-discharge (%) by medication.
  • ACEI inhibitor/ARB
  • ACEI inhibitor/ARB and beta blocker
  • ACEI inhibitor/ARB, beta blocker or MRA
  • No ACEI/ARB, beta blocker or MRA
• Survival post-discharge (%) by Care Type.
  • Cardiology
  • Care of the elderly
  • General Medicine
  • Other

Conclusions

• Ageing in the heart is associated with impaired function – such as diastolic function, reduced cardiac output and energetics.
• Risk factors for heart failure in the elderly such as hypertension accentuate the ageing phenotype, and can eventually lead to heart failure with preserved ejection fraction.
• Heart failure is a disease of elderly, is common, and costs the health service a significant proportion of its total budget

Final Conclusions

• There are 2 main types of heart failure – heart failure with reduced ejection fraction and heart failure with preserved ejection fraction
• The neurohumoral hypothesis of heart failure progression underscores evidence-based medical treatment of HFrEF
• Most proven therapies for heart failure with reduced ejection fraction do not work in HF pEF, with the exception of SGLT2 inhibitors
• The role of obesity treatments in the treatment of heart failure is likely to become very important in the next few years.