Feb 18, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD


February 18, 2022

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only.

In This Week’s Podcast

For the week ending February 16, 2022, John Mandrola, MD comments on the following news and features stories.

I have opined that the only way to avoid post-cardiac surgery AF was not to have cardiac surgery, because for my entire career, I’ve never seen anything work.

New research into a new avenue of therapeutics via the autonomic nervous system raises hope.

JACC published a research letter on the use of spinal cord stimulation to prevent post cardiac surgery AF. The paper was presented at the virtual ACC in 2021.

A brief background: (adapted from a nice review paper in the same issue of JACC).

Autonomic control of the heart is mediated via the neurocardiac axis, and it includes reflexes at 3 levels of cardiac neural hierarchy:

  • Central (higher forebrain structures, the brainstem, and the spinal cord),

  • In the chest but not in the heart (stellate and dorsal root ganglia),

  • intrinsic cardiac: Inputs by baroreceptors and chemoreceptors, as well as the renin-angiotensin-aldosterone system, contribute to the cardiac beat-to-beat control.

Sympathetic output to the heart is directed through the middle cervical and stellate ganglia, to postganglionic sympathetic axons, to intrinsic cardiac ganglionated plexus (GP) and the atrial and ventricular myocardium.

In parallel, parasympathetic innervation is primarily mediated by branches of the vagus nerve that synapse on ganglionic parasympathetic neurons located in the GP.

Therefore, the GP, which are mainly embedded in epicardial fat pads on the posterior surface of the atria, are composed of sympathetic and parasympathetic neurons and function as “integration centers” for cardiac autonomic input and output.

In the 1990s, Douglas. Zipes was intensely interested in this area, but for whatever reason(s), it hasn’t yielded major breakthroughs, at least until, now, possibly..

It’s a small RCT done in two centers in Russia. The intervention is spinal cord stimulation.

A standard silicone insulated wire that is routinely used in spinal cord stimulation) was placed by an experienced neurosurgeon.

Under local anesthesia and fluoroscopic guidance, a trial lead was implanted using a Tuohy needle and positioned in the posterior epidural space at the C7-T4 level left to the midline.

This position was associated with the most extensive feasible coverage of the left and middle anterior thorax.

The external segment of the lead was connected to the handheld stimulator. And patients used a hand-held controller to adjust the stimulation for comfortable but consistent paresthesias.

The stimulation was started 3 days before surgery, deactivated during surgery and restarted after.

The control arm got beta blockers and standard care.

At the end of 30 days, POAF occurred in 8 (30.7%) of 26 patients in the control group vs 1 (3.8%) of 26 patients in the SCS group (P=.012, log-rank test; HR: 0.11; 95% CI: 0.01-0.90; P=.04


It now seems reasonable to try this in a bigger trial. I guess the most accurate assessment is I just don’t know if this works.

There are at least 8 RCTs in progress looking at the role of ANMT in AF prevention after heart surgery. These include low-level vagus stimulation from the ear; epicardial botulinum toxin, ganglionated plexus ablation and stellate ganglion blockade.

There are hopeful early signals but you have to have very pessimistic priors when it comes to AF after heart surgery, because nothing has worked before.

Statin Intolerance

We have all encountered this: patients who cannot take statin drugs due to side effects of one sort of another.

The EHJ has published a massive meta-analysis of 176 studies and more than 4 million patients in an effort to characterize statin intolerance.

The first author is Ibadete Bytyci, from Kosovo and the author list includes many noted experts in the field.

Four general statements about statin side effects.

We know that the rate of statin side effects is substantially higher in unblinded studies than it is in blinded RCTs.

In RCTs that are blinded, side effects on statins are essentially the same as placebo.

In the SAMSON trial, from the Imperial College London team, statins do indeed cause side effects, but these side effects are due to the act of taking the pill, not the statin chemical.

Finally, I mention an interaction with an orthopedic surgeon I had many years ago: he said, you cardiologists say someone’s body aches are due to statins, and I do an Xray and they are riddled with arthritis.

Older people, are going to have oodles of reasons for feeling achy and unwell.

The authors combined nearly every observational study and RCT published that reported statin intolerance symptoms. These range from 1990s to the present. 3 decades!

The worldwide prevalence of intolerance was 9.1%. Older age, female gender, Asian and African-American races, obesity, T2DM, alcohol use, hypothyroidism, chronic liver, and renal diseases were associated with a higher risk of SI, as were increased statin doses and the concomitant administration of antiarrhythmic agents.

One interesting secondary analysis comparing prevalence in studies of primary vs secondary prevention. They did not find a significant difference (8.2 vs. 9.1%).

In a press release the authors wrote statin intolerance is "overestimated and over-diagnosed" in most cases. They also wrote that their data means that "around 93% of patients on statin therapy can be treated effectively, with very good tolerability and without any safety issues," 


I agree with their conclusions but I don’t think this data can tell them that. Go to the main figures, the Forest plots of the trials. The results of individual trials are all over the map. Some find no intolerance, some find tons.

There is a measure of this heterogeneity called I-squared. It ranges from 0-100%. When you combine studies in meta-analyses you like this to be low.

The simple point here is that the I-squared was 98-99%. I am just not sure the combination of different kinds of studies, over 30 years, tells us much that we don’t already know.

There is a huge nocebo effect with these drugs. I try to skillfully explain this to patients. If there is a strong reason to use the drug: high absolute 10-year risk plus young age, I push harder than I would if there is a low absolute risk.


Most trials of HFpEF use elevated natriuretic peptide level as an entry criteria.

In fact, a recent consensus document has proposed a new universal definition of HF, which requires elevation in NP levels or objective evidence of pulmonary or systemic congestion to meet diagnostic criteria for HF

Yet HF is a clinical syndrome. studies have reported that many patients with HFpEF have elevated filling pressures but normal NP levels.

EHJ has published a provocative paper from Mayo Clinic researchers who studied patients with HFpEF hemodynamically but normal BNP levels.

They looked back at patients referred to Rochester for unexplained dyspnea who had invasive hemodynamic assessment during rest and exercise over a 12-year period.

HFpEF was defined by signs and symptoms of HF (i.e. dyspnea or fatigue) with a left ventricular ejection fraction ≥50% and elevated wedge pressure ≥ 15 mmHg at rest and/or ≥25 mmHg during exercise, according to current guidelines.

The cutoff for BNP was 125 ng/L (or > 375 for AF).

They made three groups—

A control group with unexplained dyspnea without HFpEF,
HFpEF with normal NP,
HFpEF with high NP.

The major findings were

Compared with control patients, patients with HFpEF and normal NP had a higher left ventricular mass and worse diastolic function, but right ventricular function was preserved;

Those with HFpEF and normal NP had filling pressures that were intermediate compared with those with non-cardiac dyspnea and those with high NP HFpEF.

As you would expect, the high NP HFpEF cohort displayed the most profound cardiac functional and hemodynamic abnormalities, with notably greater prevalence of right ventricular remodeling and dysfunction, and more significant secondary mitral and tricuspid insufficiency;

Clinical outcomes such as Freedom from all-cause mortality or heart failure readmission occurred on a spectrum. Normal NP HFpEF did better than controls but worse than high BNP HFpEF.

The authors concluded that their findings provide new insight into the pathophysiology and clinical importance of the large population of patients with HFpEF and normal NP levels—and it challenges the consensus that one should require high BNP levels to diagnosis HFpEF.

Another possible conclusion the authors suggest in their discussion was that NP elevation is generally more reflective of abnormalities in biventricular (and atrial) function rather than pointing towards isolated left ventricular pathology. Recall that right heart function is one of the strongest prognosticators in HFpEF.

Why is this potentially important?

Two post-hoc analyses have shown that patients with HFpEF and lower NP levels respond more favorably to angiotensin receptor blockers and mineralocorticoid receptor antagonists as compared with patients with higher NP.

The observations from Mayo support the hypothesis that the generally poor results from HFpEF trials that enroll patients with high NP may be related to the fact that they recruit patients with more advanced stages of HFpEF, wherein abnormalities in the right heart, left atrium, and pulmonary vasculature may require alternative treatment approaches and targets.

That is in an effort to enrich trials with high-risk patients—those with high-NP, trialists may have actually selected patients too sick to respond to a simple one-drug regimen.

Finally, let me also not fail to mention the all-important clinical notion that one blood test—a biomarker—is a far cry from a clinical syndrome. BNP levels, troponins, CRP, LDL-C, are not diseases. They are biomarkers, and we would be wise to not overweight these surrogate markers.

Vitamin D:

In recent weeks, I’ve made mention of a number of nonsignificant trials looking at Vitamin D supplements.

With a little nudging, from a very smart person, I went and looked deeper into the Vitamin D story. The question at hand, is why is the hype surrounding Vitamin D so impervious to the evidence? And, perhaps more importantly, what are the implications for this lack of persuasion?

The phenomenon being that every clinic I see patients on Vitamin D, that journals keep publishing Vit D papers, researchers keep researching Vit D, and now, with the pandemic, there is outsized attention that Vitamin D may hold promise for COVID-19.

What came of my exploration is a 1200-word column. It’s up on the | Medscape Cardiology.

Here's some teasers:

Hundreds of observational studies correlate low Vit D levels w poor outcomes, of all sorts.

Hundreds of RCTs can be reduced to one sentence: Vitamin D supplements do not improve health outcomes.

Vital, D-health, The Mendelian randomization studies, the meta-analyses, systematic reviews of Vit D → essentially null.

Why then would Vit D continue to be measured, supplemented, and embraced by patients and doctors alike?

In the piece I speculate about the reasons for this. The larger message—transcends one supplement and speaks to much of what ails the translation of evidence to the bedside and the excess expectation that healthcare actually delivers health.


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