Ageing Heart and Heart Failure

Ageing Heart and Heart Failure

  • Presented 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.

  • Effects of hypertension are relevant.

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

  • 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 illustrates the relationship between pressure (mmHg) and fluorescence over time (s).

Cellular Mechanism of Cardiac Contraction

  • Sarcoplasmic Reticulum:

    • [Ca2+]i[Ca^{2+}]_i

    • SERCA2a + Phospholamban

  • Sarcolemma:

    • Troponin C

    • Myofilament

    • L-type Ca2+Ca^{2+} channel

    • [Ca2+]o[Ca^{2+}]_o

Age-related changes in excitation-contraction in rats

  • Cytosolic [Ca2+][Ca^{2+}] changes with age.

  • Action potential duration varies with age.

  • Twitch force decreases with age.

  • Velocity of [Ca2+][Ca^{2+}] accumulation changes with age.

Integration of the ATP synthesizing and utilizing reactions

Cardiac MRI

  • Measures components of cardiac function and metabolism with high resolution.

  • MR tagging: non-invasive myocardial labeling.

  • 31P spectroscopy: measurements of PCr/ATP ratios.

MR Imaging

  • Accurate measures of left ventricular mass, blood pool volumes, ejection fractions.

The Cardiac Cycle: Ejection Fraction and Diastolic Function

  • Illustrates systole and diastole phases.

The Cardiac Cycle: Ejection Fraction and Diastolic Function

  • Early filling volume.

  • Stroke volume.

  • End-diastolic volume.

  • End-systolic volume.

  • Cardiac Output = Stroke Volume * Heart Rate

  • Ejection Fraction = (StrokeVolume/End−diastolicVolume)∗100(Stroke Volume / End-diastolic Volume) * 100

  • Late filling volume.

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 31P 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 31P MRS in Normal Human Ageing

  • PCr/ATP ratio decreases with age.

  • r = -0.52, p = 0.0004

  • Age groups: 18-40 y, 40-60 y, 60+ y.

How does Hypertension Effect Ageing in the Heart?

  • Systolic Blood Pressure increases with age in hypertensive individuals compared to normal.

  • *P<0.05 Nml vs HPTN

How does Hypertension Effect Ageing in the Heart?

  • Diastolic Function decreases with age in hypertensive individuals compared to normal.

  • EFP, %

  • *P<0.05 Nml vs HPTN

How does Hypertension Effect Ageing in the Heart?

  • LV Mass increases with age in hypertensive individuals compared to normal.

  • g/m2

  • *P<0.05 Nml vs HPTN

How does Hypertension Effect Ageing in the Heart?

  • Energetics decreases with age in hypertensive individuals compared to normal.

  • PCr/ATP

  • *P<0.05 Nml vs HPTN

Heart Failure

  • A reduction in ability of heart to contract or relax.

  • Heart failure with reduced ejection fraction (HF rEF).

  • Heart failure with preserved ejection fraction (HF pEF).

  • Approx 900K people have heart failure in UK.

  • 5% emergency hospital admissions.

  • 2% NHS spending.

  • Symptoms of shortness of breath, peripheral oedema, and fatigue.

Ageing and the Types of Heart Failure

  • Age predisposes to CAD causing myocardial infarction, along with risk factors (smoking/DM/FHx).

  • Longstanding: HPTN/DM/ Obesity causing diastolic dysfunction.

  • Ageing leads to HF pEF (Diastolic Dysfunction) or HF rEF (Systolic Dysfunction).

  • Sudden Onset vs Gradual Onset over Years.

  • CAD: Coronary artery disease.

  • Symptoms for HFpEF and HFrEF are the same: Dyspnoea/odema.

Pathophysiology of HF rEF

  • Sir William Osler (1849-1919).

  • Progression from MI to Terminal Decline in Cardiac Function over Time, with a Period of Stabilisation and CHF.

Why does the heart fail several years after the initial insult?

  • LV Dysfunction leads to Neurohormonal Stimulation and Peripheral Resistance, causing LV Remodeling and HF reduced EF.

Neurohormonal Activation in Heart Failure with Reduced Ejection Fraction

  • Increased levels of Plasma Norepinephrine, Plasma Renin Activity, Arginine Vasopressin, Atrial Natriuretic Peptide, and Endothelin-1 in HF compared to NL.

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

  • 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.

  • Higher concentrations of plasma norepinephrine are associated with increased mortality.

HF reduced EF

  • Progression of Heart Failure with Reduced Ejection Fraction.

  • Left Ventricle: INCREASING NEUROHUMORAL ACTIVATION.

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

  • Renin-Angiotensin-Aldosterone System activation.

HF reduced EF

  • Pharmacological intervention points within the Renin-Angiotensin-Aldosterone System.

Angiotensin Converting Enzyme Inhibitors

  • Inhibits conversion of angiotensin I to angiotensin II.

  • Used to treat hypertension and congestive heart failure.

  • Consistently have been shown to reduce mortality in heart failure patients.

Effect of ACEi in Patients with HFrEF

  • CONSENSUS and SOLVD trials showed reduced mortality with Enalapril treatment.

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.

Effects of ß-Blockers on Mortality in HFrEF

  • COPERNICUS, MERIT-HF, CIBIS II, and US CARVEDILOL trials showed reduced mortality with b-blocker treatment.

Effect of Aldosterone Antagonist Spironolactone on Mortality in HFrEF

  • The RALES trial demonstrated a 30% reduction in mortality with Spironolactone.

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.

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

  • HFPEF vs HFrEF: Outcomes are probably equally poor.

HF preserved EF/HF reduced EF

  • SGLT2 Inhibitors in HFpEF + HFrEF: Main Mechanisms of Action.

  • Reduction of risk of heart failure.

National Heart Failure Audit

  • Age Distribution and Length of Stay in Hospital.

  • Mean age = 78 years.

  • Median age = 80.4 years.

  • Mean age men = 76.1 years.

  • Mean age women = 80.2 years.

Age and Treatment and Heart Failure Service Referrals

  • Prescription rates of ACEI, ARB, Beta blockers, Loop diuretics, and MRA vary with age.

  • Follow-up services utilization varies.

Aetiology and Echo Diagnosis

  • Comparison of HF-REF and HF-PEF.

  • Significant differences in prevalence of IHD, Myocardial Infarction, Valve disease, Hypertension between HF-REF and HF-PEF.

Outcomes

  • Mortality after discharge is influenced by specialist input and age.

Outcomes 2

  • Survival post-discharge is influenced by medication and care setting.

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.

Conclusions

  • There are 2 main types of heart failure – heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

  • The neurohumoral hyopthesis 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.