july 2015 cardiology newsletter volume 6 no 2 · 6/2/2015 · the important components of the...

Cardiology Newsletter Volume 6 No 2July 2015

Sponsored in the interests of continuing medical education by:

CPD Accredited

• Is Testosterone Cardioprotective?• Cardiac Catheter Ablation for Less Complex Arrhythmias• HIV and Cardiovascular Disease

Volume 6 No 2 July 2015

EditorialDr Mike Bennett

CardiologistWilgers Hospital, Pretoria

Editorial board Dr M. Bennett (Editor)CardiologistWilgers Hospital, [email protected]

Dr D. BlomConsultant PhysicianLipid Clinic, Groote Schuur HospitalHealth Sciences FacultyUniversity of Cape TownCape Town

Dr A.J. DalbyCardiologistMyocardial Ischaemia and InfarctionMilpark Hospital, Johannesburg

Dr J. HarrisbergPaediatric CardiologistSunninghill HospitalJohannesburg

Prof B. JacobsonHaematologistThrombosis and Haemostasis University of WitwatersrandJohannesburg

Dr R. JardineCardiologistArrhythmiasGlynwood HospitalBenoni

Prof J.A. KerCardiologistDepartment of Internal Medicine,University of PretoriaPretoria

Prof. K. Sliwa-HanhleCardiovascular ResearchHatter Cardiovascular Research Institute and Institute of Infectious Disease and Molecular Medicine, University of Cape TownHeart Failure/Translational Research

Dr A. ThorntonCardiologistElectrophysiologySunninghill Hospital, Johannesburg

The views expressed by the authors in this newsletter do not necessarily reflect those of

the sponsor and editorial board.

he recent court case concerning the right to terminate your own life when suffering from a terminal illness provoked a heated debate in newspapers,

social media, coffee shops and in the medical community. Every clinician has had a patient who was terminally ill with no hope of recovering. Some of these people are pain free, reasonably comfortable and they are the fortunate ones. The others are also terminally ill but their quality of life is miserable due to pain, shortness of breath or severe limitation because of trauma, stroke, etc.

The question that arises is not about what my options as a patient are, because they are presently very limited. I can either carry on or ultimately refuse further treatment that will prolong my agony – if able to do so. If I had been anticipating this eventuality, I might have drawn up a living will, with my family being fully aware of my wishes, so that when I am no longer in the position to decline futile treatment and in a hopelessly terminal condition, all life-support systems be switched off. The real question to ask myself, is to what extent can others decide how long I should suffer even when I disagree with them.

In SA the law prohibits assisted dying. Assisted death (euthanasia) is regarded as an act where a doctor deliberately ends a person’s life with drugs to relieve suffering, while assisted suicide is deliberately assisting another person who commits suicide. As for myself, it is against my moral and religious convictions to consider assisted suicide but other colleagues may feel differently. Assisting death under a proper legal and medical framework makes sense to me. Doctors often withhold life-prolonging drugs in patients with terminal disease and no prospect of recovering, while keeping the patient as comfortable as possible. This

is done in consultation with the family and with their approval. This practice is generally accepted although I am not sure if this has been tested in a court of law.

Modern drugs and therapies can prolong many terminal diseases and instead of allowing the disease to run its natural course, the lives of many terminally ill patients are extended unnecessarily. When passing through the ICU’s and seeing the misery, I sometimes wonder if patients and relatives have received adequate information on the prognosis of their loved ones to understand how slim the hope of recovery is. It is important for clinicians to accept the limits of even modern treatment in certain end-of-life situations. I want to believe that the perception by some members of the public that doctors take large amounts of money knowing that there is no other outcome than the passing of a patient, as being devoid of any truth. On the other hand, no doctor should be playing God. A fine line, indeed!

I believe that nothing beats honesty and that the wishes and dignity of the patient should be a prime consideration when managing the terminally ill patient with no hope of recovery. We should be compassionate, never forgetting, that relieving pain and discomfort, is much more important than prolonging a life with no hope. I feel that our laws should be revisited to make it easier for those doomed to pain and suffering when there is no hope of recovery. To quote Judge Fabricious: “Each person has the right to life, not an obligation to live (no matter his quality of life)”

Like anybody else, I pray and hope that it will not be my fate but should it be, I demand the right to die with dignity and assisted death should be an option for me.

If you have any suggestions or topics you would like to see published or have articles and/or

case studies for publishing, please email us at: [email protected].

Production Editors: Ann Lake, Helen Gonçalves Design: Jane Gouveia

Enquiries: Ann Lake Publications 011 802 8847 Email: [email protected]

Website: www.annlakepublications.co.za

Volume 6 No 2 July 2015 Page 4

Dr EL Kok MBChB, BA (Hons), DTO (Pret), BA (UNISA), DPD (Cardiff), FECSM.Senior Lecturer, Medical Officer and Sexual Health Specialist, Department of Urology, School of Medicine, Faculty of Health

Sciences, University of Pretoria and Steve Biko Academic Hospital

Is Testosterone Cardioprotective?

lthough testosterone sup-plementation or replace-ment therapy has been available for many years the possible cardiovascular

benefit versus risk of testosterone has always been under discussion. With in-creasing numbers of men taking testos-terone supplementation and contradic-tory safety data this hormone and especially in men with cardiovascular disease has recently come under close scrutiny. Even the European Medicines Agency (EMA) through their Pharma-covigilance Risk Assessment Commit-tee and the US Food and Drug Adminis-tration (FDA) through their Advisory Panel have made statements about the cardiovascular safety of testosterone therapy.

Hypogonadism

DefinitionHypogonadism, also known as Testosterone Deficiency (TD), in adult men is defined as a syndrome where there is a low serum testosterone (biochemical component) accompanied by characteristic symptoms (sexual and non-sexual) and/or signs (clinical component).

Symptoms and signsThe sexual symptoms of hypogonadism are: low sexual desire or libido, erectile dysfunction (ED), decreased frequency of morning erections as well as difficulty in experiencing orgasm and diminished intensity of orgasm.

The non-sexual symptoms of hypogonadism are: fatigue, impaired concentration, depression and a decreased feeling of vitality and/or well-being.

Signs of TD can include anaemia, osteopenia and osteoporosis, abdominal obesity and the metabolic syndrome.

Risk factors and causes The risk factor for hypogonadism are:

chronic illnesses like type 2 diabetes mellitus (T2DM), impaired thyroid gland function, hyperprolactinemia, chronic obstructive lung disease, rheu-matoid arthritis, renal and HIV-related disease, obesity, metabolic syndrome (MetS), stress, hemochromatosis, and vitamin D deficiency. Total testoster-one levels are also lower in men with severe, treatment-resistant depres-sion.

Drugs (glucocorticoids, opiods and antipsychotics) can induce TD. In these conditions the function of the hypothalamic-pituitary-gonadal axis is modified on one or more level, but not irreversibly like in congenital hypogonadism (Kallman or Klinefelter Syndrome) or acquired hypogonadism (anorchia because of trauma/orchiectomy, pituitary lesions/tumors and late-onset hypogonadism).

TestosteroneThe lower limit for a normal male total testosterone (TT) level is 12.1 nmol/L (some recommendations put it at 11 nmol/L). The TT levels should be determined in the fasting state between 07:00 and 11:00. This takes the diurnal variation of testosterone levels into consideration, although it can be markedly blunted in older men.

Testosterone sensitivity may differ in men because of the number of CAG (cytosine-adenine-guanine) repeats in the androgen receptor. A clinical entity exists which is known as the CAG repeat polymorphism (CAGn). The longer the CAGn the less prominent is the androgen effect. This has implications for the level of the TT at which men can present with TD symptoms, but also has implications for success with testosterone replacement therapy (TRT).

There is also an argument that states that the magnitude of the decrease in serum testosterone concentrations might be a better predictor of hypogonadism than the actual total testosterone level itself.

Metabolic syndrome and Type 2 diabetes mellitusThe important components of the metabolic syndrome (MetS), namely obesity (waist circumference in males > 94 cm), hypertension, dyslipidemia, impaired glucose regulation and insulin resistance are observed in men with hypogonadism.

Men with T2DM show a high prevalence of low serum testosterone levels as well as symptoms of hypogonadism. Kapoor (2007) reported TT levels of < 8 nmol/L in 17%, and TT of between 8 and 12 nmol/L in a further 25% of type 2 diabetic men with symptomatic hypogonadism.

Cardiovascular diseaseThe major cause of death in men with T2DM is cardiovascular disease (CVD). Low testosterone has been linked with CVD in several studies. Carotid intimal media thickness (CIMT) assesses the degree of atherosclerosis and is inversely related with testosterone levels. TD is also associated with a greater progression of atherosclerosis. This was seen over a 4-year follow-up period.

It is well-known that inflammation plays a major role in cardiovascular disease. A low grade systemic inflammation is furthermore associated with a low testosterone. Total testosterone and several pro-inflammatory cytokines are inversely associated with coronary artery disease and T2DM. The mediators of the inflammatory response that comes into play are: high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Testosterone replacement therapy will suppress circulating cytokines.

It is currently unknown if low testosterone causes coronary artery disease (CAD) or if it is a consequence of CAD. An inverse relationship exists between the degree of TD and the severity of the CAD.


The TIMES2 study has shown that TRT improved the following cardiovascular risk factors: insulin resistance, cholesterol, lipoprotein, body fat composition and sexual function in men with T2DM and/or the MetS.

In men with angiographically proven coronary disease there are at a greater risk for mortality in those with a low testosterone.

Hypogonadism and ED are seen as biomarkers for cardiovascular disease.Major cardiovascular events (MACE) is defined as the composite of cardiovascular death, non-fatal acute myocardial infarction, acute coronary syndromes, stroke and cardiac failure. TRT has been around for many years and thus far there has been no clinical study reporting concern with regards to increased MACE, except heart failure.

In a study by Tan et al (2014) men who received TRT over a 5-year period had a 7-fold lower risk for MI and a 9 times lower risk for a stroke, compared with samples from the general population. There was also no worsening of pre-existing MI or Stroke in patients on TRT.

According to the European Association of Urology (EAU) 2015 guidelines on male hypogonadism it is a contra-indication to give a man TRT with a haematocrit > 0.54% or severe chronic cardiac failure (New York Heart Association Class IV).

It is further recommended (level 1b, grade A): “Men with hypogonadism and either pre-existing cardiovascular disease, venous thromboembolism or chronic cardiac failure who requires TRT should be treated with caution, monitored carefully with clinical assessment, haematocrit (not exceeding 0.54) and testosterone levels maintained as best possible for age within the mid-normal healthy range”.

Observational data show an increased risk of all-cause and cardiovascular disease related mortality in men with low levels of endogenous testosterone. TD does not only influence the quality of life in men, but also their life span.

Oskui et al (2013) states: “The concept that testosterone replacement therapy improves angina has yet to be proven wrong”. Animal studies show that testosterone induces coronary vasodilatation by modulating the activity of ion channels (potassium and calcium) on the surface of vascular smooth muscle cells. The effect of testosterone on coronary arteries is independent of vessel endothelium.

It is suggested that testosterone plays a role in the regulation of the QTc interval. TRT plays a role in ventricular repolarization by shortening the QTc interval. Prolongation of the QTc interval as seen in obese hypogonadal men could theoretically lead to an increased incidence of ventricular arrhythmias, including Torsade de Pointe.

Studies have showed that men with congestive heart failure (CHF) have reduced levels of total and free testosterone. Reduced testosterone levels in men with CHF are associated with a poor prognosis and increased mortality. It is further negatively correlated with exercise capacity in CHF patients.

Testosterone replacement therapyBecause of three very weak and flawed studies (Bassario et al, 2010; Vigen et al, 2013 and Finkle et al 2014) published in reputable journals in the past 4 years, suggesting possible cardiovascular (CV) risk and safety concerns with TRT, the public media have caused a scare, fear and reluctance in hypogonadal men to use testosterone supplementation.

Morgentaler (2014) calls this reaction to TRT and possible CV risks, according to him, fuelled by antipharma sentiment, anger against aggressive marketing, and antisexuallity: “hormonophomia”. He compares it to the negative reactions to female hormonal replacement therapy after the publication of the Women’s Health Initiative (WHI) in 2002.

Corona et al (2014) in a systematic review and meta-analysis on CV risk associated with TRT concludes that testosterone supplementation (TS) is not related to any increase in CV risk even when composite or single adverse events were considered.

When studies in subjects with metabolic derangements were analysed separately a protective effect of testosterone supplementation on CV risk was observed. They could not find a causal role between TS and CV events studying the present data and further conclude that TS could be a valuable strategy to improve metabolic profile, reducing body fat and increasing lean muscle mass that would ultimately reduce the risk of heart disease.

Morgentaler et al (2015) in reviewing the literature on testosterone therapy and CV risk conclude that they could find no scientific basis for the suggestion that testosterone therapy increases CV risk. They go as far as to say that research evidence rather clearly indicates that higher levels of testosterone are associated with amelioration of CV risk factors and reduce the risk of mortality.

ConclusionCardiovascular health in men is maintained by a normal testosterone level. Testosterone replacement therapy in hypogonadal men improves their obesity, T2DM, myocardial ischemia, exercise capacity, and QTc length.

References available on request.


Figure 1: schematic of the anatomy of AVNRT. (SP – slow pathway, FP – fast pathway, IAS – interatrial septum, IVS – interventricular septum, TV – tricuspid valve, MV – mitral valve, RB – right bundle, LB – left bundle).

Cardiac Catheter Ablation for Less Complex Arrhythmias

n 2012 I wrote an article for this journal entitled “What is catheter ablation of atrial fibrillation and why is it important?” in which I outlined the reasoning behind

ablation of atrial fibrillation, and explained how this is done, and discussed the results and complications. In atrial fibrillation an ablation is performed in order to improve quality-of-life, with no clear evidence, at least at present, that mortality and stroke risk are significantly affected, although there is some early evidence to suggest that this might be the case. In atrial fibrillation ablation, the success rate is generally quoted at around 80%, but many patients will need more than one procedure, and the risk of serious complications is relatively high at between 2 and 6%. Other complex arrhythmias such as ventricular tachycardia associated with ischaemic heart disease, and scar related atrial re-entry rhythms are very similar in terms of the complexity of the procedure, the outcomes, and the potential risks and complications.

In comparison, in other arrhythmias such as supraventricular tachycardias, so-called “normal heart” ventricular tachycardia where there is no overt heart disease, and ventricular ectopy, the results are generally significantly better, with success rates in excess of 85%, with multiple procedures required much less frequently, and with lower complication rates, in the order of 1%. The complications are similar to those mentioned in the previous article and include local complications in the groin, aside from minor bruising and discomfort, such as haematoma formation, the formation of arteriovenous fistulae, and deep-vein thrombosis, complications in the heart such as perforation and pericardial tamponade, valvular damage, damage to the vascular tree, either arterial or venous, and damage to the normal conducting system, as well as endocarditis, more systemic complications such as systemic emboli, and obviously death. In the ablation of these less complex arrhythmias the risk of any major complication is low

and the mortality risk extremely low. Specific success rates, recurrence rates and complication rates will be discussed when necessary under each type of arrhythmia.

In the next few paragraphs I will discuss the pathophysiology of some of these arrhythmias, briefly describing how ablation of these is performed, with the indications for ablation, and the risks and complications.

Atrioventricular nodal reciprocating or re-entry tachycardia (AVNRT)In this tachycardia patients are born with 2 functionally and anatomically distinct AV nodal pathways (Figure 1), known as the fast and slow pathways, with the fast pathway situated superiorly in what is known as Koch’s triangle and the slow pathway inferoposterior to the compact AV node and along the septal margin of the tricuspid annulus slightly superior to the coronary sinus ostium. In the typical form the slow pathway acts as the anterograde limb of the circuit and the fast pathway as the retrograde limb. Other forms can occur. Targeting of

the slow pathway with either complete ablation or significant modification is associated with an acute success rate, with no further inducible tachycardia, in excess of 95%, although there is a small chance that the slow pathway is only oedematous and that the patient may develop recurrent tachycardia in approximately 3 to 7% of cases. The complication rates are similar to those generally mentioned, with a slightly higher incidence of heart block, due to the anatomic proximity of the pathology to the normal conducting system. The risk of heart block is generally quoted at around 1%. Radio-frequency is the usual form of energy used for this procedure, but cryoablation can also be used, because of the decreased risk of heart block, although this is countered by an increased recurrence rate of up to 25%.

Ablation should be considered for poorly tolerated AVNRT with haemodynamic compromise, in patients who have not responded to reasonable medical therapy, and in patients who desire complete control of their arrhythmia, as medication is rarely totally effective.

Dr Andrew Thornton MBBCh, PhD, FCP(SA)Cardiologist (specializing only in arrhythmias and cardiac implantable electronic devices)

Sunninghill Hospital, Johannesburg


intolerance and rapid atrioventricular conduction, in poorly tolerated AVRT, as an alternative to medical therapy, and in some cases who are asymptomatic and with high-risk properties of the pathway. The acute success rate of accessory pathway ablation is on average 95%, being somewhat better in left free wall accessory pathways, than in the rest. As is the case in AVNRT, there is a possibility that the pathway is only oedematous and not destroyed, and again this is associated with a recurrence rate of approximately 5%. All the usual complications can occur, but the quoted complication rate for accessory pathway ablation is less than 2%, with an extremely low mortality rate.

Atrial flutterAn atrial flutter is any macro re-entrant atrial arrhythmia, and atrial flutters are generally divided into those which are isthmus dependent, passing through the isthmus between the tricuspid valve and the inferior vena cava (Figure 3), and the non-isthmus dependent atrial flutters. I will only discuss the isthmus dependent flutters in this piece.

Isthmus dependent atrial flutters can either go in an anticlockwise direction through this isthmus, or in a clockwise direction, with the former being more common. The rate of the flutter circuit is typically between 250 and 350 beats per minute and often there is 2-to-1 or 3-to-1 atrioventricular conduction giving a fairly regular pattern to ventricular conduction and the pulse rate. However, on many occasions conduction is variable with an irregular ventricular response and pulse, and this is often misinterpreted as being atrial fibrillation. Equally atrial fibrillation can often be fairly organised, and is then misinterpreted as atrial flutter. It is important to look at each individual “flutter wave” and ensure that each one looks like all of the others, bearing in mind that there may be some interference from the QRS complexes and T waves.

Unfortunately the recurrence rate of isthmus dependent atrial flutter, even in the presence of medical therapy, is extremely high. In addition a major problem is that rate control during atrial flutter is extremely difficult and patients are often extremely symptomatic, and

Atrioventricular reciprocating or re-entry tachycardia (AVRT) utilising extra nodal accessory pathways.Accessory pathways connect the myocardium of the atrium and ventricle directly. These pathways can allow conduction only from atrium to ventricle or in both directions, or only from ventricle to atrium. Accessory pathways that allow conduction from atrium to ventricle are generally associated with the presence of Delta waves on the surface ECG known as overt or manifest pre-excitation. Accessory pathways that conduct only from the ventricle to atrium have no visible signal on the normal 12 lead ECG, and are called concealed accessory pathways. The amount of pre-excitation seen when manifest accessory pathways are present depends on the relative amount of conduction through the AV node, and through the accessory pathway and can vary depending on the physiological status of the patient. Conduction can also be intermittent especially when the accessory pathway refractoriness is long.

The circuit of AVRT can either be orthodromic (as in Figure 2), where conduction to the ventricle is through the AV node and back to the atrium through the accessory pathway, or antidromic where conduction to the ventricle is through the accessory pathway and back

to the atrium through the AV node (the reverse of orthodromic). Orthodromic tachycardias have a regular, narrow QRS complex appearance, and antidromic tachycardias have a regular, broad QRS complex appearance. In the case of multiple accessory pathways, other variants can be present. Atrial fibrillation and the presence of a manifest accessory pathway which has a short refractory period can allow for rapid repetitive conduction to the ventricle which can result in ventricular fibrillation and sudden death.

The risk of sudden death has not been well quantified, but has been estimated to be between 0.15 and 0.39%, and can unfortunately be the first presenting symptom.

It is generally suggested that an electrophysiological study should be performed for most patients with manifest pre-excitation. This allows for assessment of the conduction properties, and consequently the risk of sudden death, induceability of re-entry arrhythmias, and the exact position of the accessory pathway. Depending on the findings an ablation can be performed at the same time. There is a class I indication for an ablation in the presence of manifest pre-excitation and the presence of re-entry arrhythmias, the presence of manifest pre-excitation and atrial fibrillation with haemodynamic

Figure 2: Schematic of the circuit of orthodromic AVRT utilising a left lateral acces-sory pathway (RA – right atrium, LA – left atrium, AVN – atrioventricular node, RV – right ventricle, LV – left ventricle, RB – right bundle, LB – left bundle, AP – accessory pathway).


are at very high risk of developing a tachycardia induced cardiomyopathy.

For any recurrent isthmus dependent atrial flutter, catheter ablation is seen as acceptable first-line therapy, and even with a first documented episode is seen as a reasonable alternative to medical therapy in the long term. The acute success rate is in the region of 90 to 95%, unfortunately with a 10 to 15% recurrence rate after a single procedure. The procedure can be repeated to find where the gaps in the line of conduction block are, with a long-term success rate of 90 to 95% in prevention of atrial flutter. The complication rates from an atrial flutter ablation are similar to those for AVNRT and AVRT. Unfortunately patients with atrial flutter often have associated atrial myocardial disease and have the same risk factors for atrial flutter as atrial fibrillation, and therefore, in the longer term, these patients are at risk for developing atrial fibrillation. In the short-term, over a period of 18 to 24 months, this risk is probably in the region of 8 to 10%, but in the longer term may increase further. In the event of recurrent arrhythmias, as is the case after any apparently successful ablation, ECG documentation during further symptoms is essential to document what arrhythmia the patient is experiencing.

Premature ventricular complexesAlthough previously thought to be completely benign in the absence of underlying heart disease, and causing only symptoms on occasions, it has been more recently recognised that a PVC burden of 15 to 25%, and possibly even as low as 10%, may be associated with progressive left ventricular dysfunction and a cardiomyopathy. In many cases though the PVCs are related to an underlying cardiomyopathy. There should always be concern with PVCs where the coupling interval between the preceding normal QRS complex and the PVC is extremely short, which could suggest the short QT syndrome, where malignant ventricular arrhythmias are possible. The majority of patients with normal hearts and PVCs will have beats with a left bundle branch block type appearance and a normal or right axis suggesting an origin in the outflow tract, or ectopy with a relatively narrow QRS complex, right bundle branch block appearance and a leftward axis suggestive of an origin in the left posterior hemi-fascicle of the conducting system. Both of these can be considered for ablation, and the 2014 expert consensus on ventricular arrhythmias, mentioned in the references, would suggest that it be considered for ablation where there is a single dominant morphology

of the ectopy, when medical therapy has failed, the patient is intolerant of medical therapy, or has refused medical therapy, and also when left ventricular dysfunction is present. The efficacy of ablation of PVCs is between 75 and 100% in published studies, but is dependent on the ectopy being present at the time of the procedure so that the focus can be targeted. The complication rates are generally quoted as being approximately 1%. Ablation of ectopic beats is often undertaken using what are called 3-D mapping systems. These enable the operator to make a 3-D map of the area of interest by sweeping the ablation catheter around this area, and also allow one to make what is called an activation map based on the electrical signals present in that area, with the earliest electrical signal obviously originating from the ectopic focus. This has improved both the efficacy and the safety of ablation in general, and especially with regard to ventricular ectopic beats.

ConclusionIn summary then, less complex arrhythmias such as AVNRT, AVRT with either manifest or concealed accessory pathway conduction, atrial flutter and ventricular ectopy and non-sustained ventricular tachycardia, are extremely common. Medical therapy is usually not able to completely control these arrhythmias, and medication is often associated with some degree of side effects. In addition many patients are relatively young, and will need medical therapy lifelong if they choose to pursue this option. Cardiac catheter ablation of these less complex arrhythmias is associated with an excellent outcome, exceeding 80%, and often 90% after single procedures, and with a low risk of significant complications. It is important that patients with all of the above-mentioned arrhythmias are offered the opportunity to undergo curative therapy with a high risk of success and low-risk. In some circumstances it is not unreasonable for patients to refuse to consider catheter ablation, or to delay this, but patients should be offered the necessary information so as to allow them to make their own decision with regard to long-term therapy.

References available on request.Figure 3: Schematic of the circuit of isthmus dependent flutters. (RALW – right atrial lateral wall, TA – tricuspid annulus, SLTV – septal leaflet of the tricuspid valve, IVC – inferior vena cava, CS – coronary sinus ostium, AVN – atrioventricular node).


Dr Friedrich ThienemannClinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine

Faculty of Health Sciences, University of Cape Town

HIV and Cardiovascular Disease

ombination antiretroviral ther-apy (cART) has dramatically improved survival of patients with human immunodeficien-cy virus/acquired immunode-ficiency syndrome (HIV/AIDS).

When HIV infection is diagnosed early and cART is initiated in time, most pa-tients experience acceptable immune recovery and can reach normal life ex-pectancy. With the decline of HIV-related morbidity and mortality and increased life expectancy, non-HIV-related condi-tions and comorbidities continue to rise in this cohort.

Cardiovascular disease (CVD) is the leading comorbidity and cause of death in this population. Some antiretroviral agents may also contribute to this increased rate of CVD in HIV and therefore require careful selection according to the underlying cardiovascular risk factors. In general, antiretroviral agents causing dyslipidemia or diabetes should be avoided in patients at risk. Nonetheless, in most parts of the world, including developed countries, HIV is often diagnosed at advanced stages of immunosuppression leading to severe opportunistic infections which can involve the heart and are associated

with high mortality rates. Also, immune recovery in those patients remains incomplete despite long-term successful viral suppression after initiating cART and patients remain at a higher risk of AIDS or death.

Epidemiology of HIV and cardiovascular diseaseHIV/AIDS is a global pandemic affecting approximately 34 Million people (Figure 1). Africa carries the highest burden with almost 70% of all HIV-infected individuals worldwide. Other regions with high HIV/AIDS prevalence rates are South-East Asia and countries of the former Soviet Republic. It has been recognised that the incidence of opportunistic infections involving the heart has increased since the advent of the epidemic, but systematic data remain scarce. The most commonly reported cardiac manifestations in HIV/AIDS are pericardial disease (often related to tuberculosis), cardiomyopathy, and pulmonary hypertension (Figure 2 and 3).

HIV pericarditisWorldwide, pericarditis is one of the most common cardiac disorders in HIV. Presentations can vary from

small and asymptomatic pericardial effusion to cardiac tamponade. Causes of pericardial effusion can be manifold ranging from opportunistic infections with mycobacteria, bacteria, viruses and fungi to AIDS-related malignancies; aetiology is thus largely dependent on the degree of immunosuppression and exposure to infection. The incidence of pericardial effusion in patients with advanced HIV has been described at 11% per annum. The diagnostic yield of pericardial fluid cultures and biopsies lies between 24-37%, suggesting that HIV itself may be a the primary contributor.

An independent association between pericardial effusion and survival could be found. Survival of AIDS patients with pericardial effusion on echocardiography was significantly shorter compared to AIDS patients without pericardial effusion. The epidemiology of pericardial effusion seems to change dramatically in patients on cART. Within the HIV-HEART study 802 HIV-positive outpatients underwent echocardiography screening of which 85% were receiving cART at the time. Pericardial effusion was only present in 0.25% of patients.

Figure 1: Global adult human immunodeficiency virus prevalence 2009. Source: UNAIDS Report on the Global AIDS Epidemic 2009.


HIV pericarditis in the context of a high tuberculosis burdenEven though the most common cause of pericarditis in HIV in developed countries is idiopathic, tuberculosis probably remains the most common cause of pericarditis in HIV worldwide. In some African regions up to 80% of patients with tuberculosis are also infected with HIV. In this epicentre of two epidemics, Mycobacterium tuberculosis is the cause of pericardial disease in 86-100% of HIV-infected patients.

HIV-associated cardiomyopathyIn autopsy studies myocarditis has been reported in up to 52% of HIV patients with biventricular involvement in 10% of cases. An opportunistic pathogen other than HIV could only be detected in 19-26%. In countries with high tuberculosis/HIV-coinfection rates, HIV-associated tuberculosis pericarditis has been associated with the development of concomitant myopericarditis. However, in about 80% of cases the aetiology remains uncertain and direct infection of myocytes and autoimmune

processes triggered by HIV have been implicated.

The estimated incidence of HIV-associated dilated cardiomyopathy (HIV-DCM) pre-cART is 15.9/1,000 per annum. HIV-DCM is considered WHO Clinical Stage IV (AIDS) and is associated with a poor prognosis with an adjusted mortality hazard ratio of 4.0 when compared with HIV-uninfected controls with idiopathic DCM; the median survival of HIV-DCM is 101 days compared to 472 days in HIV-infected controls without DCM. Data from Africa revealed an HIV-

Figure 2: Cardiac manifestations of human immunodeficiency virus infection. HIV-PH, HIV-associated pulmonary hypertension, HIV-DCM, HIV-associated dilated cardiomyopathy. Source: Thienemann et al. Eur Heart J 2013.

Figure 3: Primary cardiovascular diagnosis of all HIV patients (%) presenting with de novo heart disease at a tertiary cardiac service in South Africa (n=518). Abbreviations: CAD=coronary artery disease, CVD= cardiovascular disease. Source: Sliwa et al. Eur Heart J 2012.

Pulmonary arteries: HIV-PH

Coronary arteries: Ischaemic heart disease

Left atrium and ventricle: HIV-DCM

Pericardium: HIV pericarditis

Right atrium and ventricle: HIV-DCM (bilateral manifestation) HIV-PH

CardiacManifestationsofHIVinfection

HIV-related cardiomyopathy 37.8%

Congenital heart disease 0.4%Post-partum cardiomyopathy 3.3%CAD 2.7%

Other CVD 1.7%

Cerebrovascular disease 3.5%

Hypertensive heart failure 6.2%

Right heart failure 6.2%

Other heart disease 6.9%

Hypertension 7.1%

Valve disease 11.2%Pericarditis/pericardial effusion12.5%


DCM prevalence of 18-32%. A study in China found HIV-infection to be independently associated with cardiac diastolic dysfunction. 42.8% of HIV patients had diastolic dysfunction, with similar results found in India. These studies were performed before cART became available in 1996, in cART-naive patients at advanced stage of disease, or in regions where cART is not widely available. In the latter, malnutrition has been described as contributor to the frequent occurrence of HIV-DCM within the African context. With the introduction of cART, the prevalence of HIV-DCM dropped by about 30% in developed countries, but in developing countries where cART roll-out is delayed and penetration of cART, especially in rural areas is scanty, HIV-DCM remains common with possibly a multifactorial pattern.

HIV-associated pulmonary hypertensionOn a global scale, the prevalence of pulmonary hypertension (PH) in HIV-infected individuals varies between 0.5% and 5.0% with HIV being recognised as an independent risk factor for the development of PH. The prevalence of HIV-associated pulmonary hypertension (HIV-PH) in developed countries with access to cART is 0.5%, while 5.5% of patients with no symptoms of PH may be at risk for PH; 1000-fold higher than in the general population.

Studies conducted in Africa found evidence of PH by echocardiographic measurements in 0.6% to 5% of HIV patients in Nigeria, Burkina Faso and Zimbabwe. Estimated survival rates in developed countries in the pre-cART era were approximately 70% at one year and 50% at three years compared to approximately 90% at one year and 70% at three years after the advent of cART. Even though this data seems convincing a direct benefit of cART on the incidence and survival of HIV-PH could not be demonstrated. cART alone

without specific treatment for PH does not result in an improved cardiac function. Also, no association between HIV-PH and CD4 count, viral load, or stage of disease could be identified.

Coronary artery diseaseOver the past decade, the association between HIV infection and coronary artery disease (CAD) and the effects of cART on the risk of CAD have been discussed with great controversy (see next paragraph). In fact, little is known about the impact of HIV infection itself on coronary arteries, but HIV infection does amplify the risk for CAD before exposure to cART. Chronic immune activation in HIV may lead to a chronic inflammatory state, endothelial dysfunction, coagulopathy and thombophilia, and/or lipid disturbance and therefore promote arteriosclerosis.

In Africa, CAD is uncommon, but dynamic socio-economic and lifestyle factors characteristic of epidemiological transition appear to have positioned the urban African community at the crossroads between historically prevalent and ‘new’ forms of heart disease, such as CAD. Data from South America also demonstrated a high prevalence of risk factors for CAD. This increasing or underlying prevalence of

modifiable cardiovascular risk factors such as hypertension and obesity in less developed countries may lead to this predicted epidemiological transition of the aetiology of heart diseases. Indeed, under consideration of the increasing proportion of patients on cART and the earlier initiation of HIV therapy in these regions altogether an increase in the proportion of aging patients and eventually rise in CVD associated morbidity and mortality can be expected. Therefore, it is extremely important to learn from regions with extensive cART experience which cardiovascular risks are associated with prolonged cART exposure to be able to prevent the extent of CVD in HIV patients now being observed in the developed world.

ConclusionIn the natural course of HIV, particularly with the outbreak of AIDS, involvement of the heart within various opportunistic infections and HIV-associated malignancies is common. Therefore, HIV infection needs to be included into differential diagnosis considerations particularly in the setting of tuberculosis-associated pericarditis. Besides cardiac involvement in various AIDS manifestations, HIV itself induced immune activation is considered to independently contribute to CVD and may partially explain the higher cardiovascular mortality in this patient group.

With regard to developing countries, dynamic socio-economic and lifestyle factors characteristic of an epidemio-logical transition appear to have po-sitioned the urban community also at risk for traditional CVD. In this context, cardiovascular risk assessment of HIV patients needs to become a critical element of care similar to developed countries. Also, access to first and sec-ond line cART with little or no impact on lipid and glucose metabolism will become of importance to reduce CVD in HIV in the future. References available on request.

In Africa, CAD is uncommon, but dynamic socio-

economic and lifestyle factors characteristic

of epidemiological transition appear to have

positioned the urban African community at

the crossroads between historically prevalent

and ‘new’ forms of heart disease, such as CAD.


Dewilde WJ, Janssen PW, Verheugt FW, et al.J Am Coll Cardiol 2014;64:1270-1280.

Study QuestionWhat is the optimal antiplatelet regimen in patients undergoing percutaneous coronary intervention (PCI) who are also taking a vitamin K antagonist (VKA) for atrial fibrillation (AF)?

MethodsThis review discusses the evidence base for the management of patients on a VKA, and who are undergoing PCI. The authors discuss the existing European and North American guidelines, and also present new information from recent studies.

ResultsThe European guidelines (2010) recommend triple therapy (aspirin + clopidogrel + VKA) in patients with AF undergoing PCI. The 2014 North American Guidelines recommend the VKA + clopidogrel (dual therapy). Data from a randomized trial (WOEST, n = 573 patients) showed that dual therapy was associated with a lower incidence of serious bleeding, transfusion requirement, and ischemic events. Data from a Danish registry of 12,165 patients with AF who experienced a myocardial infarction or underwent PCI suggested that, as compared to triple therapy, there was no increased risk of recurrent coronary events or mortality in patients

Triple Therapy for Atrial Fibrillation and Percutaneous Coronary Intervention: A Contemporary Review

taking dual therapy, and the bleeding risk was nonsignificantly lower. Preliminary studies in patients taking one of the novel oral anticoagulants (NOAC) presenting with an acute coronary syndrome have revealed more bleeding, but without a reduction in ischemic events.

ConclusionThe authors favor dual therapy with a VKA and clopidogrel in patients with AF undergoing PCI since it appears to be associated with a lower risk of bleeding, but without an increase in thrombotic events.

PerspectiveMajor bleeding and transfusion requirement are associated with increased risk of death in patients undergoing PCI. The authors make a reasonable argument in favor of dual therapy in an effort to minimize the bleeding risk. In patients receiving a VKA or a NOAC who also require clopidogrel and/or aspirin, the recently updated European consensus document advocates for a lower international normalized ratio (INR) target (2.0-2.5) and the lower tested dose of the NOAC. Data from large randomized trials are required to validate these recommendations, which are primarily based on registry data.

by Debabrata Mukherjee, MD, F.A.C.C.Republished here with courtesy from the American College of Cardiology,

www.cardiosource.org/Science-And-Quality/Journal-Scan.aspx

Association of Treatment with Carvedilol vs Metoprolol Succinate and Mortality in patients with Heart FailurePasternak B, Svanstrӧm H, Melbye M, et alJAMA Intern Med 2014 ; Aug 31: (Epub ahead of print).

Study question What is the comparative clinical effectiveness of carvedilol and metoprolol succinate in patients with heart failure(HF)?

MethodsThis was a cohort study of patients with incident HF with reduced left ventricular ejection fraction (LVEF) (≤40%) who received carvedilol (n=6,026) or metropolol succinate (n=5,638) using data from a Danish national HF registry linked with health care and administrative databases. The main outcomes and measures were all-cause mortality (primary outcome) and cardiovascular mortality (secondary outcome), which were analyzed using Cox regression with adjustment for a propensity score derived from a range of clinical socioeconomic and demographic characteristics.

ResultsThe mean (standard deviation) age of the patients was 69.3 (9.1) years, 71% were men and 51% were hospitalised at index HF diagnosis. During a median (interquartile range) 2.4 (1.0-3.0) years of follow up, 875 carvedilol users and 754 metoprolol users died; the cumulative incidence of mortality was 18,3 % and 18,8% respectively. The adjusted hazard ratio for carvedilol users versus metoprolol users was 0.99 (95% confidence interval (Cl), 0.88-1.11) corresponding to an absolute risk difference of 0.07 (95% CI, - 0.84 to 0.77) deaths per 100 person-years. Estimates were consistent across subgroup analyses by sex, age, levels of LVEF, New York Heart Association classification and history of ischemic heart disease. A higher

proportion of carvedilol users achieved the recommended daily target dose (50mb; 3,124 (52%) than did metroprolol users (200mg; 689 (12%)); among patients who reached the target dose, the adjusted hazard ratio was 0.97 (95% CI 0.72-1.30). A robustness analysis with 1:1 propensity score matching confirmed the primary findings (hazard ratio, 0.97;95% CI, 0.84-1.13). The adjusted hazard ratio for cardiovascular mortality was 1.05 (95% CI, 0.88-1.26).

ConclusionsThe authors concluded that the effectiveness of carvedilol and metoprolol succinate in patients with HF is similar.

PerspectiveIn the large contemporary national cohort study of patients with HF with reduced LVEF, there was no significant difference in all-cause mortality between carvedilol and metoprolol succinate users. The primary findings were consistent through various analyses, including the secondary outcome of cardiovascular mortality, key subgroups and robustness analyses. Given the limits of the CIs, this study could rule out a relative difference in mortality of more than 12% and an absolute difference of one death or more per 100 patient-years. This suggests that any difference between carvedilol and metoprolol succinate, if it exists, is unlikely to be clinically meaningful. The data support current guideline recommendations, which do not explicitly support the use of one beta-blocker with proven mortality benefit of HF over the other and thereby regard the effectiveness of these drugs as equivalent .

by Debabrata Mukherjee, MD, F.A.C.C.Republished here with courtesy from the American College of Cardiology,


Commentary on Current Journal Articles


Congress Reportback:

European Society of Cardiology Congress

Guidelines for the Primary Prevention of Stroke: A statement for Healthcare Professionals from the American Heart Association/American Stroke Association

Meschia JF, Bushnell C, Boden-Albala B, et al.Stroke 2014; Oct 29: (Epub ahead of print)

PerspectiveThe following are 10 points for healthcare professionals to remember about these guidelines for the primary prevention of stroke:

1. The aim of this updated statement is to provide comprehensive and timely evidence-based recommendation on the prevention of stroke among individuals who have not previously experienced a stroke or transient ischemic attack.

2. The use of a risk assessment tool such as the American Heart Association (AHA)/American College of Cardiology (ACC) cardiovascular (CV) Risk Calculator (http://my.americanheart.org/cvriskcalculator) is reasonable because these tools can help identify individuals who could benefit from therapeutic interventions and who may not be treated on the basis of any single risk factor. These calculators are useful to alert clinicians and patients of possible risk, but basing treatment decisions on the results needs to be considered in the context of the overall risk profile of the patient (Class IIa; Level of Evidence B).

3. Physical activity is recommended because it is associated with a reduction in the risk of stroke (Class I; Level of Evidence B). Healthy adults should perform at least moderate - to vigorous-intensity aerobic physical activity at least 40 minutes/day 3 to 4 days/week (Class I; Level of Evidence B).

4. Reduced intake of sodium and increased intake of potassium as indicated in the US Dietary Guidelines for Americans are recommended to lower blood pressure (Class I; Level of Evidence A). A diet that is rich in fruits and vegetables and thereby high in potassium is beneficial and may lower the risk of stroke (Class I; Level of Evidence B). A Mediterranean diet supplemented with nuts may be considered in lowering the risk of stroke (Class IIa; Level of Evidence B).

5. Regular blood pressure screening and appropriate treatment of patients with hypertension, including lifestyle modification and pharmacological therapy, are recommended (Class I; Level of Evidence A). Patients who have hypertension should be treated with antihypertensive drugs to a target blood pressure of <140/90 mm Hg (Class I; Level of Evidence A).

6. Among overweight (body mass index (BMI) =25 -29 kg/m² and obese (BMI>30kg/m²) individuals, weight reduction is recommended for reducing the risk of stroke (Class I; Level of Evidence B).

7. In addition to therapeutic lifestyle changes, treatment with an HMG coenzyme-A reductase inhibitor (statin) medication is recommended for the primary prevention of ischemic stroke in patients estimated to have a high 10-year risk for CV events as recommended in the 2013ACC/AHA Guideline on The Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (Class I; Level of Evidence A). Treatment of adults with diabetes mellitus with a statin, especially those with additional risk factors, is recommended to lower the risk of first stroke (Class I; Level of Evidence A).

8. Counselling, in combination with drug therapy using nicotine replacement, bupropion, or varencline, is recommended for active smokers to assist in quitting smoking (Class I; Level of Evidence A). Abstention from cigarette smoking is recommend for patients who have never smoked, on the basis of epidemiological studies showing a consistent and overwhelming relationship between smoking and both ischemic stroke and subarachnoid haemorrhage (Class I; Level of Evidence B).

9. For patients with nonvalvular atrial fibrillation, a CHA₂DS₂-VASc score of ≥2, and acceptably low risk for hemorrhagic complications, oral anticoagulants are recommended (Class I). Options include warfarin (international normalized ratio (INR), 2.0-3.0) Level of Evidence A), dabigatran (level of Evidence B), apixaban (Level of Evidence B), and rivaroxaban (Level of Evidence B). The selection of antithrombotic agent should be individualized on the basis of patient risk factors (particularly risk for intracranial haemorrhage), cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including the time that the INR is in therapeutic range for patients taking warfarin.

10. Patients with asymptomatic carotid stenosis should be prescribed daily aspirin and a statin. Patients should also be screened for other treatable risk factors for stroke, and appropriate medical therapies and lifestyle changes should be instituted (Class I; Level of Evidence C).

by Debabrata Mukherjee, MD, F.A.C.C. Republished here with courtesy from the American College of Cardiology,


CPD AccreditationDoctors can acquire CPD points with this newsletter by visiting www.mpconsulting.co.za and completing an online MCQ consisting of 15 questions. Should you have any queries regarding the completion of the online MCQ, please contact Inge Erasmus at 0861 111 335 or email [email protected].

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If you have any suggestions or topics you would like to see published or have articles and/or case studies for publishing, please email us at: [email protected].

SA

traeH

Congress Calendar 2015Event/

CongressDate Venue Contact

Critical Care Society of South Africa Congress

9-12 JulySun City,

South Africa

www.criticalcare.org.za

Paediatric Interventional Cath Workshop

27-31 July

Red Cross Children’s Hospital,

Cape Town

[email protected]

16th Annual SA Heart Congress 2015

25-28 October

Sun City, North West

Province

www.saheart.orgwww.eoafrica.co.za

4th Annual Perioperative Cardiothoracic Congress

11-14 November

Vineyard Hotel,

Newlands, Cape Town

www.jpc2015.co.za/

july 2015 cardiology newsletter volume 6 no 2 · 6/2/2015 · the important components of the...

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