Journey of Learning


Feature Story

In this year’s ECHO (Experts’ Convergence for Health Outcomes) Summit, practicing physicians from the Philippines, Vietnam, Myanmar, Indonesia and Thailand, gathered to learn clinically pragmatic management approaches for their patients with atherosclerosis and premature vascular aging, diabetes mellitus, anxiety and depression, and osteoporosis

By Dr. Reuben Ricallo and Lyka Mae P. Chiang


The ECHO Summit, which is now on its 3rd year, is a continuing commitment of Unilab’s specialty cluster to provide a world-class continuing medical education meeting of renowned international experts, sharing their expertise on state-of-the-art global technologies and concepts as applied to research diagnostics and therapeutics. It is part of Unilab’s advocacy of ensuring that Filipino doctors are kept abreast with the evolving medical concepts and trends in clinical practice worldwide.

“The clinicians should marry the best available research evidence with their clinical experience in providing quality health care,” Herman T. Esling, general manager of Unilab’s Biofemme, said in his welcome speech.

He added that the summit follows a multi-disciplinary approach to provide a platform for interaction, learning and enhancing clinical practice, spearheaded by the three divisions under the Unilab’s specialty cluster namely LRI-Therapharma (Cardiometabolic Division), Medichem (Central Nervous System [CNS] Division), and Biofemme (Women’s Health Division).

For her part, Dr. Maria Rosario Sevilla, LRI-Therapharma medical director, described the ECHO Summit as a continuing “journey of learning”. She stressed that the summit’s format is interactive learning to maximize sharing of updates in clinical practice.

With degenerative diseases as this year’s theme, Dr. Sevilla emphasized that longevity, by itself, is really not enough. “Excellent quality of life should come hand-in-hand with prolonged years,” she said.

Giving the ASEAN audience a ‘teaser’ of the afternoon’s scientific program, she gave a bird’s eye view of what was going to be discussed. The first lecture was an exemplification that “a man is only as old as his arteries.” The stiffening of the arteries, especially if premature, leads to cardiovascular or other chronic diseases.

The second lecture would present a new perspective on diabetes management, namely, how testosterone may be useful in insulin sensitization.

The third speaker would talk about the management of anxiety and depression, which is a frequent comorbidity in cardiometabolic diseases. Unfortunately, it is frequently undiagnosed and therefore, untreated.

The fourth lecture would tackle osteoporosis, how its development may be accelerated by advancing age and the onset of menopause, and how—through lifestyle and dietary changes improving bone density—patients with this problem can have better longevity and improved quality of life.

The following are excerpts from two of the lectures delivered during the ECHO Summit.

Professor Reuven Zimlichman, MD
Professor Reuven Zimlichman, MD

Arterial Aging

Professor Reuven Zimlichman, MD

Chief of Medicine and Hypertension Institute
E. Wolfson Medical Center Head of Cardiovascular Research Institute Faculty of Medicine, Tel Aviv University, Israel

All of us will age. What happens to the cardiovascular system with aging? Is there such a thing as normal aging? Is aging a disease and what are the results of it? How can we improve patient outcomes?

About 400 years ago, Jonathan Swift said the famous phrase “every man wants to live long but no man desires to grow old.” One of the most beautiful descriptions of the state of the arteries was also written by John Wesley many years ago before medicine was so sophisticated as today. He said “In extreme old age, the arteries themselves, the grand instruments of circulation, by the continual apposition of earth, become hard, and, as it were, bony, till, having lost the power of contracting themselves, they can no longer propel the blood, even through the largest channels; in consequence of which, death naturally ensues.” Thomas Sydenham also wrote the often quoted description of vascular health: “A man is as old as his arteries.”

Now, we know that when we grow old, our arteries age and change their properties. But we know that the change is not the same in different persons, and that there are many factors that affect these changes.

Arterial stiffness

Collagen deposition in the arterial wall causes arterial stiffening. Arterial stiffness is an expression of aging of arteries and also disease of arteries. This is affected by multiple factors; to name some—hyperglycemia, dyslipidemia, hyperinsulimania, hypertension. It can manifest as hypertension, or an increase in pulse pressure, which may lead to myocardial ischemia due to increased metabolic demands.

The older we are, the higher the systolic blood pressure (BP); while the diastolic BP increases initially, and at around the age of 60, it starts to decline. So a typical BP of an old person would be something like 170/60 or 160/60, characterized by a widening of the pulse pressure, which is the difference between the systolic and diastolic BPs.

Peripheral vascular resistance (PVR) may be increased even in young patients, but large artery stiffness is not yet increased. With time, PVR becomes less dominant in determination of hemodynamics, while the arterial stiffness becomes more important. So, in the elderly, we see increasing systolic BP, and decreasing diastolic BP, mainly due to increased arterial stiffness.

Now, if we can predict aging of the arteries, we can predict development of hypertension and the risk of cardiovascular events.

Pulse wave velocity

The arterial system, especially the big arteries, consists of long tubes, and by evaluating the structure of their walls, we can measure aortic stiffness. The stiffer the artery, the faster the blood flow through it, since it no longer is compliant and dilates readily as it should. So measurement of pulse wave velocity (PWV) is an excellent measure of degree of stiffness of the artery. PWV is one of the most used measurements that we do, in order to estimate how stiff the artery is. (Figure 1)

By evaluating the PWV, we can predict development of hypertension in a patient. Those with the higher quartile of PWV have higher risk of developing high BP, while those with the lowest PWV have the lowest risk.

Now, there is a feedback loop because increased BP affects hemodynamics. It increases PWV, and it causes structural changes, leading to stiffening of the artery. Of course, this is affected by multiple factors like age, diabetes, inflammation, but especially high BP. So we have a vicious cycle. The high BP increases stiffness, and the stiffness increases the BP.

Early vascular aging

Premature vascular or early vascular aging (EVA) is affected by many factors. The conventional risk factors like hypertension, diabetes, dyslipidemia, smoking, and others are well known. However, there are some poorly-identified cardiovascular risk factors which are more difficult to detect, like inflammation, and oxidative stress. These may be associated with low birth weights, genetics and by fetal programming.

Figure 1
Figure 1

So, arterial stiffness describes the degree of damage in the arterial wall, but it is also an integrator of all damages done to the arterial wall. And early arterial stiffening is defined as early vascular aging.

The systolic-diastolic hypertension is prevalent in the younger population and it becomes less and less frequent as we age. What prevails in the elderly is isolated systolic hypertension (ISH), which is only about 17 percent in young patients, but is almost 100 percent in elderly patients 80 years and older. ISH is the result of the stiffening of the arteries.

Impact on hemodynamic parameters

What happens to the various hemodynamic parameters when we age? The cardiac output decreases as we age, and in people above 70 years of age, the cardiac output decreases almost by 50 percent. The stroke volume also goes down even in apparently healthy subjects. So, a healthy elderly has a stroke volume and cardiac output which can be 50 percent of what he had when he was 20 or 30 years old. These changes develop gradually with age in a healthy subject.

What happens with the peripheral vascular resistance (PVR)? It also gradually increases over time. PWV, which is considered as the best predictor of arterial stiffness, is increasing also correspondingly. So by measuring PWV, we can understand how stiff the measured arteries are.

If the arteries are stiff, the arteries will not expand or dilate as much as a normal healthy artery does. The result is an increasing BP. And this explains why systolic BP increases gradually with age. With impaired vascular stiffness and dilation, less amount of blood can reach the peripheral circulation, resulting in decreased diastolic BP. So, diastolic BP goes down as the arteries stiffen. A person with stiff arteries has decreased cardiac output and stroke volume and increased peripheral resistance. (Figure 2)

When we measure and draw our arterial wave properties, we have two waves—the forward wave and the other is the returning wave, and they summate on each other. What happens if we are dealing with a stiff aorta? There is a tremendous increase in the systolic BP. That’s why if an 80 year old or 70 year old patient comes to our clinic with a BP of 170/60, which is typical for this age, we understand the mechanism. This patient should not be evaluated for secondary hypertension because the common denominator of endocrine hypertension or other causes of secondary hypertension is increased diastolic BP.

On the other hand, if an elderly has BP of 170/110 or higher, he or she should be evaluated for secondary hypertension, unless he’s highly stressed, since stress can induce a similar clinical picture. Because of diffuse atherosclerosis, they may develop atheroma of the renal artery resulting in renal artery stenosis. Others can have different causes of secondary hypertension like aldosteronism.

Low diastolic BP in ISH

When we give antihypertensive agents in an elderly with ISH, the diastolic BP may go down to as low as 50 mmHg. Is this dangerous? Systolic hypertension is highly correlated with stroke and other complications in the elderly. So, lowering the systolic BP is a priority. The truth is, we can do nothing with the lowering of diastolic BP, and we have to explain it to the patients. We have to evaluate the risks against the benefits for the patient by lowering both the systolic and diastolic BPs. I, personally—and many experts, too—do nothing about the lowered diastolic BP to levels like 60 mmHg. But there are exceptions like in patients with very prominent ischemic heart disease, in which cases we have to recalculate our target BPs and to consider both systolic and diastolic pressures, to prevent worsening of the ischemic condition.

Figure 2
Figure 2

The opposite of stiffness is compliance, and compliance of aorta and large arteries depends upon the stiffness and upon the age of the patient. So, in young patients, we can see that blood volume can increase considerably, but the BP will increase less in all patients. However, in the elderly, even relatively small increase in volume will cause significant increase in BP, because the artery is less compliant, less elastic.

Comparing the PWV in younger and older patients, the peak in the latter is much higher due to increased augmentation of the reflected wave amplitude. This is associated with ISH and widened pulse pressures. (Figure 3)

Using the expected changes in PWVs with age, a nomogram table of normal values for healthy subjects can be created, to assess their vascular age which may not correlate with their chronological age. For example, we may tell a patient with multiple cardiovascular risk factors, “you are 50 years old but your arteries are 65 years old.”

Figure 3
Figure 3

So we treat this patient optimally, and when we do another evaluation after 12 months, we probably can tell him, “your arteries improved; now their age is 60,” or “you are not following our orders; you do not take medications, and look, your arteries during the last year aged by another 3 or 4 years.”

So, hemodynamic patterns of hypertension and age-related vascular changes are predictable, they can be measured, and this information can help us a lot in our prognostic calculations. It can also guide us on the proper approach to treatment.

“Hemodynamic patterns of hypertension and age-related vascular changes are predictable, they can be measured, and this information can help us a lot in our prognostic calculations; it can also guide us on the proper approach to treatment”

Professor Sigfried Kasper, MD
Professor Sigfried Kasper, MD

Depression and Anxiety

Professor Sigfried Kasper, MD

Chairman, Department of Psychiatry and Psychotherapy Medical University of Vienna

If Sigmund Freud were alive, he would love this kind of talks about brain health.

Talking about depression and anxiety, we have to acknowledge they’re problems in brain medicine. But of course, nobody wants to be called psychiatrically ill because, in Europe and I think it’s pretty much the same in your country also, you are considered to be a little bit crazy, right? And when patients come with depression and anxiety saying “well doctor, I am crazy,” I tell them, “no, no, you’re not crazy; you have a mood disorder.”

If patients ask me—“Doctor, why did I get my depression?”— I tell them it’s a metabolic disorder and if I would know the cause, I would get the Nobel prize.

Anxiety and depression are not disorders with specific lesions like stroke, or multiple sclerosis; although, if these lesions involve the right hemisphere or affecting some specific parts of the brain, the likelihood that they get depression and anxieties would be higher. They may considered a “disorder of circuits,” which may be caused by genetic factors, as well as developmental factors in the environment.

Major depressive disorder (MDD) is actually the leading cause of disability both in males and females. Recurrence is also common for MDD. In that sense, depression is something like hypertension, in that we can treat depression but the bad news is that it comes back. In a large collaborative study from Brown University, the proportion of patients who had recurrence of MDD in 15 years, was 80 percent. (Mueller et al 1999)

Cortisol intoxication

Therefore, it is important that the patients take the necessary medications. Like in other medical diseases—the longer the patient is in depression, the worse is the outcome. So depression is a kind of intoxication of the brain. In depression, you have hypercortisolemia and the brain doesn’t like high cortisol level, which you’d have specifically in the morning hours. So it’s kind of hypercortisol intoxication of the brain. A conservative “wait and see” attitude, using ineffective therapies, may not be to the patient’s best interest. We need to apply promptly effective medications.

Early treatment is important. The rates of recovery diminish with the duration of MDD. In a 5-year prospective study of 431 patients done in the United States, it was shown that the longer a patient was ill, the lower his or her chances were of recovering. (Keller et al 1992)

Risk factors of recurrence

The risk factors for recurrence of MDD are: younger age at onset of index episode, severity of the index episode, number of prior episodes, psychiatric and medical comorbidities, family history of psychopathology, subsyndromal residual symptoms including depressive symptoms, anxiety, and insomnia. (Judd et al 1998; Karp et al 2004; Burcusa and Iacono 2007; Souery et al 2007)

Gender is a very critical issue. We thought that females have more depression. I do not think so, personally. I just think that males express their depression differently. Males are more aggressive and they have more anger attack, for instance. So if you put this together, then you find the same percentage in females and in males.

Somatic comorbidity is an important factor of metabolic status because if the patient has already metabolic syndrome, it doesn’t make sense to give him medication like one of the three cyclic antidepressants, where they gain even more weight.

MDD has subtypes, meaning depression with anxiety symptoms or paranoid symptoms. Then we also evaluate the severity, comorbidity, suicidality. If a patient is suicidal, you have to give him sedatives in addition to the antidepressant, and this is quite important. The patient needs to adhere to the medication; and of course, we need to listen carefully to what the patient tells us, like: “Do not give me a medication which impairs my sexual function,” “Do not give me a medication which makes me metabolic,” “Do not give me a medication with which I cannot sleep anymore.”

The dosage issue is also important; what we do in Europe right now, is to measure blood levels of the medication.

Anti-depressants

We have a large array of anti-depressants. When I started in the mid 70s in the University of Heidelberg, we only have the 3 cyclics available, which were quite effective but unfortunately, they have too many side effects. Different parts of the body were affected.

The broad spectrum anti-depressive agents with multiple actions were used in the 1950s and 60s like imipramine and amitiptyline. These were followed by more selective agents with single action in the 70s and 80s. The introduction of the selective serotonin reuptake inhibitors (SSRIs) was a big revolution in the 80s. These were followed in the 1990s and 2000 and later with novel agents affecting specific targets.

Figure 4
Figure 4

The SSRIs work by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance. They have been shown to be effective in treating MDD and generalized anxiety disorder that disrupt daily life and persists for several months.

Fluoxetine was one of the first, sertraline was introduced later. So, both of them are still standard in antidepressant treatment. Escitalopram is also a very important medication. Quetiapine is marketed as an antidepressant but it has very strong norepinephrine reuptake inhibition. Duloxetine is a dual acting antidepressant, and it has also very strong 5-HT2 blockade, which is also used as atypical antipsychotics. In Europe, non-psychiatric patients are also given quetiapine mainly for sleeping purposes.

Some newer compounds include ketamine and other drugs modulating subcortical gamma-aminobutyric acid (GABA) levels. Ketamine is an uncompetitive N-methyl-D-aspartate glutamate receptor antagonist, which induces perceptual and behavioral responses in patients with MDD. Nowadays, if you go to a psychiatric meeting, everybody talks about ketamine and GABA modulators, so it will be the future.

Suicidal patients

If the patient comes in and says “Doctor, I want to kill myself,” and he’s suicidal, you give him ketamine infusion and after 20 minutes, he says “Doctor, suicide, not good idea. Don’t want to do it anymore.” For ketamine, we use like 25mg to 50mg. Anesthesiologists give much higher dosages.

Unfortunately, ketamine has addiction problem so it cannot be widely used, but it hopefully opens up the area to new treatment modalities. (Figure 4)

Underdiagnosed

Depression is still underdiagnosed disease. Around 66 percent of the patients do not seek treatment, and those of them who seek treatment and go to primary care psychiatry, half of them are not diagnosed correctly. (Montano, 1994; Andersen, 1989)

The reason for the misdiagnosis is that it is linked to somatic symptoms, rather than the emotional or psychological symptoms like loss of pleasure and interest, and loss of drive. The somatic or physical symptoms include aches and pains (musculoskeletal pains, headache), gastrointestinal disturbances like abdominal pains, chest tightness, fatigue, low energy, changes in appetite and weight.

Patients with depression often present with numerous physical complaints. As the number of physical complaints increases, so does the likelihood of a mood disorder. (Kroenke, 1994)

Around 30 percent of patients with depression experience depressive physical symptoms for more than five years before correct diagnosis. (Lesse, 1993)

Very often, male depressed patients present with physical symptoms, because they think when you go to the doctor, then you have to present your body. If you present your mood, then you’re a weak man. So they come with all these physical symptoms. MDD patients presenting with depression, anxiety, pain and other somatic symptoms have the worst outcome. It’s like if the patient has hypertension, diabetes and nephropathy, a worse outcome may be expected. So the same is also true in psychiatry.

Figure 5
Figure 5

The different physical complaints are usually not linked to an identifiable organic cause. The number of unexplained physical symptoms is linked to depression. When the patient presents with physical symptoms, the likelihood that his depression gets diagnosed is very low. You have to ask the proper questions to find out if he or she has emotional or psychological symptoms suggestive of depression.

Pain, depression-anxiety interrelationship

There seems to be an interrelationship between pain, on one hand side, and anxiety-depression, on the other hand. But, if the patient starts with pain complaints, don’t tell him “You are depressed,” because the patient will tell you “No, doctor. I have pain; but I’m not depressed. I am not crazy.” Explain to him that if one has so much pain, usually this lowers also the mood. Then the patient acknowledges the impaired mood, and may realize he has other symptoms attributable to depression.

Sometimes, the patient sees that you prescribed him an antidepressant and asks you: “Doctor, I’m not depressed. Why are you giving me this medication?” Then you have to tell him the medication treats also the brain metabolism and will treat his sleep problems.

Nowadays, aside from the SSRIs, we have the so-called SNRIs (serotonin-norepinephrine reuptake inhibitors), which are potent inhibitors not only of the reuptake of serotonin but also of norepinephrine. Balanced dual inhibition of serotonin and norepinephrine reuptake can possibly offer advantages over other antidepressant drugs by treating a wider range of symptoms.

Neuropathic pain

Severe neuropathic pains can have potentially serious psychological consequences. Depression and anxiety may be found in as many as 60 percent of cases. They also complain of lack of energy, difficulty in concentration, drowsiness and poor appetite. (Figure 5)

For bothersome neuropathic pains, the dual-acting SNRIs like duloxetine or venlafaxine, may be given; pregabalin or gabapentin may also be tried. Pregabalin and gabapentin are often considered firstline treatments for various neuropathic pain syndromes, generally irrespective of cause. (Haanpää, 2015) Both pregabalin and gabapentin are antiepileptic medications that have structural resemblance to GABA, though neither agent has activity in GABA’s neuronal systems.

Usually, I tell my patients depression and anxiety are like sisters, which always go together, and they probably share also the same pathophysiology. There is an overlap of symptoms, like insomnia, cognitive problems like concentration disability, fatigue, loss of drive, and psychomotor signs, either agitation or retardation.

If depression and anxiety are both present, a worse outcome, including a higher suicide rate, may be expected. Having somatic symptoms as comorbidity is also associated with a poorer outcome. Doctors of internal medicine would say “So if we have depression and anxiety or depression and neuropathic pain or depression and some pain disease, then you have a worse outcome in your patients.”

The effect of comorbodity of depression, anxiety and somatic complaints has been shown also in the large North American study called STAR*D, which showed that the higher the anxiety/ somatization symptoms, the lower the remission rate. (Fava, 2008)

Multiple studies have also indicated that depression in patients wit comorbid anxiety symptoms have longer recovery time, greater severity in depressive illness and functional impairment, poorer prognosis, and increased risk or suicidality.

Early treatment is essential, but just remember that for a given drug, some patients are more likely to respond than others. So treatment will have to be individualized.

“As the number of physical or somatic complaints increases, so does the likelihood of a mood disorder”

July 2017 Health and Lifestyle

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