Pathophysiology Pathophysiology

Cardiac disease is often associated with a number of other conditions. In many cases, co-morbidities, including ischaemic heart disease, type 2 diabetes, chronic respiratory disease, peripheral vascular disease, arrhythmias and musculoskeletal disorders, may coexist due to similar risk profiles or due to similar pathophysiological pathways. In some cases, the associated condition may precipitate cardiac insufficiency, whilst in other cases they may be the resulting consequence. Atrial fibrillation (AF), for example, may cause heart failure as a tachycardia mediated cardiomyopathy. Conversely, AF may occur as a consequence of heart failure.  Examples of common co-morbidities are summarised below.

Cardiac cachexia is a complication of advanced HF involving depletion of lean body mass (including vital organs such as the heart) leading to a decline in performance status and immune function, and is associated with decreased survival. [#cavey-j.-cardiac-cachexia-2011]

In cardiac cachexia the following are present:

  1. Body wasting of bone, muscle, and fat tissue
  2. Dyspnoea
  3. Malabsorption or loss of nutrients through the gastrointestinal tract
  4. Deconditioning; and anorexia are present in cardiac cachexia[#cavey-j.-cardiac-cachexia-2011]

The cause of cardiac cachexia is multifactorial [#dunn-sp-bleske-b-dorsch-m-et-al.-2009], with complex neurohormonal, metabolic, and immunological factors interacting to cause an anabolic/catabolic imbalance, resulting in negative energy balance. [#anker-s-sharma-r.-2002] This imbalance cannot necessarily be corrected by eating more as with other types of malnutrition, however nutritional assessment is important to support energy, protein and micronutrient needs as much as possible. [#anker-s-sharma-r.-2002] Patients diagnosed with cardiac cachexia should therefore be referred to a Dietitian for individualised dietary counselling and nutrition support.

Diabetes is a chronic metabolic disease associated with an impaired ability to control blood glucose levels. Diabetes is an independent risk factor for the development of cardiovascular disease (CVD) in both men and women, and adults with diabetes are 2-4 times more likely to have heart disease or a stroke than adults without diabetes. Furthermore, diabetic patients who develop clinical CVD have a worse prognosis than CVD patients without diabetes. Myocardial ischaemia secondary to atherosclerosis often occurs in the absence of symptoms in patients with diabetes.

Patients with diabetes have a higher risk of developing heart failure with a prevalence of 12%, rising to 22% in those aged over 64 years. Up to 30% of all patients admitted to hospital with heart failure have diabetes. [#asghar-o-al-sunni-a-khavandi-k-et-al.-2009] This association appears to be bidirectional, as HF is also associated with impaired glucose tolerance and diabetes. The development of HF is associated with worse outcomes for those with diabetes compared to non-diabetic patients, particularly in those with ischemic heart disease. This observation has led to the hypothesis that the diabetic heart is in some way compromised such that it is less able to sustain injury from an exogenous insult such as myocardial infarction.

Sophisticated imaging techniques have demonstrated a reduction of diastolic and systolic function in apparently healthy subjects with type 2 diabetes mellitus. This is a frequent observation, with various manifestations reported in 20% to more than 50% of apparently healthy diabetic subjects. These findings are also present in patients who have similar metabolic diseases, including impaired glucose tolerance and obesity, and a unifying feature may be insulin resistance. This subclinical dysfunction is multifactorial, with contributions from disturbed metabolism, fibrosis, microvascular disease (both structural and functional) and diabetic autonomic neuropathy. [#korczyk-d.-marwick-t.h.-kaye-g] It is further magnified by the presence of hypertension, and occurs most commonly in individuals with poor glycaemic control.

Given the increasing frequency of both obesity and type 2 diabetes mellitus, the subclinical cardiomyopathy associated with these conditions may prove to be extremely important. At present, no clear treatment has been described, although there is evidence that dysfunction is reduced with improved glycaemic control, weight reduction and exercise. The extent to which fibrosis may contribute to uncomplicated diabetes mellitus remains controversial. Inhibitors of the renin–angiotensin–aldosterone system have shown some promise, but a persuasive outcome trial is still awaited.

Clinical considerations are important and clinicians should ensure that:

  • All patients with coronary heart disease are screened for diabetes
  • Treatment of other risk factors, including dyslipidaemia, hypertension, overweight/obesity and smoking, are addressed
  • Glycaemic control is optimized
  • Management of microvascular (e.g. retinopathy, nephropathy, neuropathy) and macrovascular (e.g., CHD, stroke, peripheral vascular disease) complications are optimized

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increasing age. The prevalence of AF in people over the age of 65 years is up to 5.5% and increases up to 15% in those aged over 80 years. [#ball-j-carrington-m-mcmurray-j-et-al.-2013]

Hospitalisations frequently result from AF associated heart failure and stroke. AF is also associated with obesity, valvular disease, coronary artery disease, hypertension, obstructive sleep apnoea and hyperthyroidism.

Patients with heart failure (HF) are 6 times more likely to develop AF than those without HF and the incidence increases with the severity of HF (i.e., 50% incidence of AF in those with NYHA heart failure grade IV). The mechanisms associated with this response involve atrial dilation (opportunity for localised circuits to develop), neurohormonal dysregulation (alteration in intracellular calcium and conduction properties) and activation of the rennin-angiotensin aldosterone system (associated with atrial fibrosis and interference with cardiac conduction).

AF is classified as follows:

  • Paroxysmal: Self terminating within 24-48 hrs
  • Persistent: Lasting longer than 7 days or requiring cardioversion
  • Long standing persistent: Persisting more than 1 year despite attempted rhythm control
  • Permanent

Physiologically, ventricular response may be exaggerated and ventricular filling time is decreased, leading to a reduction in cardiac output. Fatigue and decreased exercise tolerance are therefore common. Additionally, turbulent blood flow within the cardiac chambers may also predispose the individual to thromboembolic events.

Management of AF is achieved through:

Pharmacological approaches

  • Rhythm control – aim for sinus rhythm
  • Rate control –aim to improve symptoms
  • Anticoagulation for prevention of stroke

Non pharmacological approaches

  • Rhythm control e.g., AF ablation
  • Weight loss, reduce alcohol consumption
  • Exercise

Sleep disordered breathing is very common in patients with cardiac disease and can affect 40-70% of patients with HF. It is also strongly associated with AF. Sleep disordered breathing is associated with a number of significant physiological changes, caused by large intra-thoracic pressure swings and overnight hypoxaemia.  Physiological effects include increased sympathetic activity, systemic hypertension, endothelial dysfunction, oxidative stress, tissue ischaemia, platelet activation and increased coaguability. Ventricular ectopics, brady-arrhythmias and decreased heart rate (HR) variability may also occur. The effect of sleep-disordered breathing on the cardiovascular system has been an area of intense recent research.

See Sleep disturbances for more information.

Anaemia is defined as Hb <130g/L in males and <120g/L in females.  It is a risk factor for IHD and occurs in approximately 37% of patients with heart failure.  Heart failure patients with anaemia have poorer outcomes and increased mortality, however it is unknown whether the anaemia represents a marker of disease severity (and therefore a prognostic tool) or whether it is the trigger for poorer outcomes (and thus a target for treatment). [#tang-y.-katz-s.-d]

Treating anaemia in patients with HF has been shown to improve symptoms and quality of life.

The risk of anaemia in this population is associated with[#tang-y.-katz-s.-d]:

  • Older age
  • Female gender
  • Chronic kidney disease
  • Cachexia
  • Use of ACE inhibitors
  • Increased JVP
  • Peripheral oedema

Potential causes of anaemia in patients with heart failure include[#korczyk-d.-marwick-t.h.-kaye-g]:

  • Iron deficiency (associated with reduced absorption due to gut oedema, uraemic gastritis, GI bleed)
  • Vitamin B12 and folic acid deficiencies
  • Anaemia of chronic disease (associated with systemic inflammation)
  • Impaired erythropoietin production (associated with renal dysfunction, angiotensin converting enzyme activation and inhibition and angiotensin receptor blockade)

Severe reductions in haemoglobin may lead to fluid retention, impaired renal perfusion and neurohormonal activation, which may contribute to disease progression. Conversely, haemodilution may also contribute to worsening anaemia. In this latter group, aggressive diuresis which reduces plasma volume may aid in correcting the anaemia. Impaired exercise tolerance is another consequence of anaemia in these patients.

Chronic kidney disease (CKD) is strongly associated with the development of cardiovascular disease (CVD), and patients in the early stages of CKD are more likely to develop CVD than to progress to end stage renal failure. [#sarnak-mj-levey-as-schoolwerth-ac-et-al.-2003]

The risk of developing CVD increases with decreasing estimated glomerular filtration rate (eGFR) and increased proteinuria. CKD is also associated with increased mortality following ACS, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) surgery.

CKD is also common in patients with HF and is strongly associated with increased morbidity and mortality in these patients. Up to 50% of ambulatory patients with stable HF have some degree of renal dysfunction. Moderate to severe renal dysfunction in patients with HF increases the relative risk of mortality by 100% (absolute risk > 50% at 5 years). In patients with baseline eGFR < 50 mL/min/m2 a further drop of 10 mL/min/m2 increases mortality by 7%.

It is generally accepted that renal dysfunction is a marker of progressive HF. However, it has also been postulated that renal dysfunction may directly affect the biology of HF by upregulating the renin–angiotensin–aldosterone and sympathetic nervous systems, increasing production of pro-inflammatory factors and worsening anaemia, leading to LV hypertrophy and impaired myocardial contractility. [#korczyk-d.-marwick-t.h.-kaye-g]

The existence of both HF and renal dysfunction in an individual is called cardiorenal syndrome (CRS), which is divided into five types, according to the presentation (acute versus chronic) and primary cause of the syndrome (cardiac versus renal):

  • CRS type 1 (acute) – acute decompensated HF leading to acute kidney injury (AKI)
  • CRS type 2 (chronic) – chronic HF leading to chronic kidney disease
  • CRS type 3 (acute renocardiac syndrome) – AKI leading to acute cardiac dysfunction (HF, arrhythmia or coronary ischemia)
  • CRS type 4 (chronic renocardiac syndrome) – chronic kidney disease contributing to cardiac dysfunction
  • CRS type 5 (secondary CRS) – combined heart and kidney dysfunction due to an acute (e.g., sepsis) or chronic (e.g. diabetes mellitus) systemic disorder.

Therapy differs for the different types. As medications used to treat HF (eg., diuretics and ACE inhibitors), may contribute to renal impairment, careful patient selection and monitoring are crucial.

In patients with HF, congestive hepatopathy (cardiac cirrhosis) is relatively common and may occur as a consequence of elevated right atrial pressure. This may be the result of right heart failure, pulmonary hypertension, tricuspid valve disease or constrictive pericarditis. Transient abnormalities of liver function tests most commonly include elevated aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH).  Ascites is common in these patients.

Acute ischaemic hepatitis may occur in patients with new or decompensated chronic HF when hepatic perfusion is rapidly reduced due to poor cardiac output and venous congestion.

Improving cardiac function is the primary focus of treatment for these conditions.

COPD and CVD frequently coexist. Pathology may include right ventricular dysfunction, pulmonary hypertension, CAD, arrhythmias and HF. Whilst smoking is implicated as a causative factor in many, recent literature suggests systemic inflammation may be a key factor in the pathogenesis of these conditions. Since low-grade systemic inflammation is common in both COPD and vascular disease, coexistence of these conditions likely accelerates atherosclerosis and contributes to the increase in adverse cardiovascular events. Oxidative stress is also a likely contributor. In those with COPD, the incidence of CAD is significantly higher (~33% vs 27%) when compared to matched individuals without COPD. [#mapel-dw-dedrick-d-davis-k.-1991-1999]  Similarly, a reduction in FEV1 in those with COPD, independently predicts cardiovascular mortality even after adjusting for conventional cardiovascular risk factors such as age, cigarette smoking, hypertension, cholesterol and obesity.

In patients with HF, COPD is more common in males than females and is an independent predictor of mortality and HF hospitalisation. Cigarette smoking increases the risk of developing HF by 50%.  Up to 20% of patients with COPD may have undiagnosed HF and up to 40% may have evidence of some LV systolic dysfunction. [#korczyk-d.-marwick-t.h.-kaye-g] Recent studies suggest an increasing prevalence of the two conditions co-existing, which is most likely representative of an aging population.[#hawkins-nm-petrie-mc-jhund-ps-et-al.-2009]

Respiratory infections are associated with HF decompensation in 10–16% of admissions. Pneumococcal and influenza A vaccinations of elderly patients with HF reduce the rate of hospitalization and associated costs. In general, concomitant pulmonary and HF therapy is safe, although short-acting β2-adrenoreceptor agonists and digoxin have potentially negative effects on cardiac and pulmonary function, respectively.

Pulmonary hypertension (PHT) may occur as a primary elevation of pressure in the pulmonary arterial system (PAH) or as a consequence of other identifiable causes.

Classification is based upon aetiology and mechanism and includes 5 main groups, whereby group 1 is PAH and groups 2-5 include all other identifiable causes of PHT. Group 2 constitutes PHT secondary to left sided heart disease, which occurs secondary to chronic left atrial hypertension in patients with heart failure as a result of myocardial and valvular disease.

The pathophysiology of Group 2 PHT is characterized by a cascade of events that occur, leading to changes in pulmonary arterial, capillary, and venous circulation and ultimately causing right ventricular dysfunction and right heart failure. These changes occur in patients with HF with reduced ejection fraction (HFREF) as well as those with HF with preserved ejection fraction (HFPEF). Multiple organ systems are affected, leading to increased morbidity and mortality in these patients.

The prevalence of PHT in patients with chronic heart failure increases with the progression of functional class impairment. Up to 60% of patients with severe left ventricular systolic dysfunction and up to 70% of patients with heart failure with HFPEF may present with PHT. [#badesch-bd-champion-hc-gomez-sanchez-ma-et-al, #vachiery-jl-adir-y-barbera-ja-et-al.-2013] When present, PHT results in more severe symptoms and worse exercise tolerance and exerts a negative impact on outcome. Patients with PHT (especially in the case of HFPEF) are often older, female, with a higher prevalence of cardiovascular co-morbidities and most, if not all, of the features of metabolic syndrome.

Depression and anxiety are very common in people with cardiovascular disease and heart failure.  These conditions are associated with poor prognosis, increased mortality and hospital readmissions.  See Psychosocial issues for more specific information.

Venous thromboembolism is common in patients with HF and occurs in approximately 10-22% of hospitalised patients.  Increased risk in these patients is related to impaired ventricular function, chronic inflammation and a higher propensity for developing AF. [#dean-sm-abraham-w.-2010]

Common cardiovascular risk factors such as obesity, diabetes, hypertension, low HDLs and high triglycerides have also been shown to be associated with an increased risk of venous thromboembolism. [#ageno-w-becattini-c-brighton-t-et-al.-2008]

Gout is common in patients with HF as plasma urate levels are frequently elevated in these patients.  Another reason for this high incidence is that common treatments such as diuretic therapy also elevate plasma urate levels.  Since anti-inflammatory medications are contra-indicated in these patients and corticosteroids are often avoided, colchicine is the preferred treatment for acute management with allopurinol recommended for chronic therapy if required.

Peripartum cardiomyopathy (PPCM) is a rare cause of dilated cardiomyopathy that occurs in approximately 1 in 2,500 to 4,000 live births. It is often difficult to diagnose as the symptoms of HF mimic those of pregnancy (e.g., fatigue, shortness of breath (SOB), swollen ankles, weight gain).

PPCM is diagnosed when the following 3 criteria are met:

  1. HF develops in the last month of pregnancy or within 5 months of delivery
  2. Heart pumping function is reduced, with an ejection fraction (EF) less than 45%
  3. No other cause for HF with reduced EF can be found

The specific cause of PPCM is unknown, however, it is thought to perhaps relate to a viral illness or abnormal immune response.

Other potential causes of PPCM include:

  • Genetic mutation
  • Coronary artery spasm
  • Small vessel disease
  • Nutritional deficiencies
  • Defective antioxidant defences

Older maternal age, multiparity, multifoetal pregnancies (e.g., twins), high blood pressure and African descent appear to incur a higher risk.

Outcomes for patients with PPCM have improved in recent years, with survival rates as high as 90% to 95% with appropriate therapy. [#givertz-m.-2013] Although early improvement in EF (i.e., within the first 3-6 months) predicts a good outcome, some women will have slow, gradual improvement in EF over a number of years.

These patients as well as those with cardiomyopathy from other causes who become pregnant, require specific advice relating to:

The Pregnancy and cardiomyopathy booklet is a useful resource that addresses these issues for the patient.

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