Acute Heart Failure Treatment Paradigm Challenged by Splanchnic Nerve-Block Studies

June 06, 2018

VIENNA — Volume overload often may not be the primary cause of congestion and symptoms in patients hospitalized with decompensated heart failure (HF). Sometimes, rather, decompensation may be triggered by redistribution of a stable fluid volume from the intra-abdominal compartment to the heart and lungs.

That process, mediated by the sympathetic nervous system, may be amenable to interventions that may seem foreign in cardiology but are established in other specialties.

That's the hypothesis behind two "first-in-human" studies that comprised 15 patients in all but still earned late-breaking-trial status here at the European Society of Cardiology Heart Failure (ESC-HF) 2018 — possibly for the challenge they present to the contemporary treatment paradigm in decompensated HF.

Their findings support adverse fluid-volume redistribution from the abdomen to the intrathoracic space as an "important component of heart failure symptoms most likely also related to episodes of decompensation," Piotr Ponikowski, MD, PhD, Medical University, Wroclaw, Poland, told theheart.org | Medscape Cardiology.

Also, therefore, the two very preliminary studies presented here suggest that therapy to reduce volume overload in decompensated HF, often loop diuretics, sometimes aims for a target that isn't there.

Perhaps fluid redistribution from the abdomen, reservoir for up to a fifth of blood volume, to the heart and lungs is a more appropriate treatment target for some patients with decompensated new or chronic HF, whether with reduced or preserved ejection fraction (HFrEF or HFpEF, respectively), Ponikowski said.

Both studies explored the potential treatment of splanchnic nerve block, which relaxes the intra-abdominal vasculature and thereby offloads intrathoracic fluid volume and alleviates congestion, according to the underlying hypothesis.

"We Actually Now Have Data…"

In a series of 10 patients with HFpEF, surgical ablation of the right greater splanchnic nerve was followed by clinically meaningful improvements in cardiac filling pressures, exercise capacity, and quality of life over 3 months, Ponikowski said when presenting the results.

The patients also showed echocardiographic signs of beneficial reverse-remodeling over 6 months, including reduced left ventricular mass and improved diastolic function.

In a separate study reported here at the ESC-HF sessions, intracardiac filling pressures, cardiac output, and self-reported dyspnea improved significantly within 90 minutes after temporary total splanchnic nerve block in five patients with decompensated chronic HF.

As reported here by Marat Fudim, MD, Duke University, Durham, North Carolina, bilateral splanchnic nerve block was achieved by fluoroscopy-guided lidocaine injections at the level of the 11th to 12th thoracic vertebrae.

If excess fluid and sodium are seen as main causes acute decompensation, it follows that diuretics and ultrafiltration would be first-line treatments, observed Fudim in an interview.

But if the volume-redistribution hypothesis is correct, at least for some patients, "the trials that show that a lot of diuresis hurts your kidneys and does not improve outcomes start making sense." The fluid volume wasn't "excess," he said. "It was just in the wrong place."

Fudim is lead author on the study's report in Circulation, published in tandem with his May 26 presentation at the ESC-HF sessions.

Splanchnic nerve block is a well-established procedure in specialties outside cardiology, especially in the anesthesiology literature, and has long been used to fight medication-refractory pain from acute pancreatitis and some cancers, observed Fudim.

Orthostatic hypotension has been a frequent side effect, which helped clue researchers in cardiology into its potential for redistributing fluid volume, he said.

Fudim was careful to say that the treatment approach is not even close to being ready for clinical practice. But with the new studies, "we actually now have data to support that there is a different mechanism of heart failure decompensation."

"A Fantastic Concept"

Observers at the ESC-HF sessions seemed willing to accept the hypothesis addressed by the two studies but hesitant to totally embrace it. They also consistently seemed impressed by its novelty and involvement of splanchnic physiology, which many remembered only from their early training.

"I think it's credible that you can move the blood to the splanchnic circulation and therefore offload the heart," said John G.F. Cleland, MD, Imperial College London, United Kingdom, as invited discussant following Fudim's presentation. The observed hemodynamic effects "are what I would expect."

He called it "a wacky idea" but said reassuringly that for him, it recalled a quote widely attributed to Albert Einstein: "If at first the idea is not absurd, then there is no hope for it."

It's "a fantastic concept" and the study was "well executed," he added. "I think we've established a scientific principle, but can you action that into a therapy?"

The results presented by Ponikowski were convincing and the new hypothesis represented "a great step ahead," said Burkert Pieske, MD, Deutsches Herzzentrum Berlin, Germany, as the formal discussant.

Moreover, "You've reminded us of a forgotten physiology," the splanchnic vasculature as a main reservoir of blood in the body, and have "addressed the unmet clinical need" of pulmonary congestion in HFpEF, a condition with few proven treatment options.

Pieske observed that "the small proof-of-concept study" was unblinded, so "we should not overinterpret the results." Future trials with sham controls would be welcome, as some of the observed results, especially in quality of life, could have been due to a placebo effect.

Also important, he said, would be the identification of patients who would be most appropriate for the intervention.

Indeed, Ponikowski said when interviewed, "We obviously need to characterize those who are most likely to respond because I am strongly against the concept — in entities like HFpEF and acute heart failure — that one size would fit all."

Volume reduction is still appropriate for patients who are symptomatic and volume overloaded, he said. But those without volume overload need something other than volume reduction.

Decompensation While Euvolemic

To that end, Ponikowski and colleagues' study deliberately entered patients with HFpEF with recent history of exertional dyspnea despite being clinically euvolemic, for whom adverse volume distribution might be more likely an issue.

The five men and five women, initially in NYHA class III with an ejection fraction of 40% or more on optimal medical therapy, underwent right-sided thoracoscopic greater-splanchnic-nerve surgical ablation and were followed for 12 months.

Nerve ablation was one-sided to preserve some sympathetic control of the splanchnic vasculature "in an emergency such as hypotension or hemorrhage," Ponikowski said.

Table 1. Hemodynamics at Baseline to 3 Months After Surgical Ablation of Right Greater Splanchnic Nerve in HFpEF

Parameters Baseline 1 Month 3 Months
Resting PCWP (mm Hg) 16.2 12.6a 13.4
Work-indexed PCWP (mm Hg/W/kg) 89 58a 56a
a P < .05 vs baseline.

PCWP = pulmonary capillary wedge pressure.

 

After 1 month, three patients had remained in NYHA class III but seven improved to class II. By 3 months and continuing at 6 months, nine were in class II and 1 was in class I.  

Their mean baseline score of 60 on the Minnesota Living With Heart Failure Questionnaire improved to 30 at 1 month and to 25 at months 3 and 6 (P < .05 for both differences vs baseline).

Their mean cardiopulmonary exercise test time improved gradually over 6 months from 4:18 at baseline to 7:14 at 6 months (P < .05). During the same period, mean peak VO2 increased by 2.5 mL/kg/min (P < .05).

Table 2. Echocardiographic Findings at Baseline to 6 Months After Surgical Ablation of Right Greater Splanchnic Nerve in HFpEF

Parameters Baseline 3 Months 6 Months
E/E' 14.6 10.7a 9.6a
LV mass (g) 261 228a 215a
a P < .05 vs baseline.

E/E' = ratio of early mitral inflow velocity to mitral annular early diastolic velocity (diastolic function).

 

In Fudim's study, the four men and one woman were several days into their hospitalization after acute management of decompensation. All had an EF less than 20%. They were required to be stable enough to lie face down for 20 to 30 minutes to allow the lidocaine injections, he said.

Right- and left-sided intracardiac pressures were seen to fall within 20 minutes of the injections, peaking at about 30 minutes and recovering to baseline after about 90 minutes.

Table 3. Hemodynamics Before and After Temporary Splanchnic Nerve Block in Acute HF

Parameters Baseline 30 Minutes (P Value vs Baseline) 90 Minutes (P Value vs Baseline)
PAP (mm Hg) 46 37 (<.01) 41 (.02)
PCWP (mm Hg) 28 21 (<.01) 24 (.01)
MAP (mm Hg) 89 72 (<.001) 80 (.01)
Cardiac index (L/min/m2) 1.92 2.54 (<.01) 1.98 (.65)
MAP = mean arterial pressure; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure.

 

Systemic vascular resistance fell over 30 minutes from 1407 dynes ⋅ sec ⋅ cm–5 at baseline to 808 dynes ⋅ sec ⋅ cm–5 (P < .001).

Mean 6-minute walk distance improved by 31.2 meters within 24 hours of the procedure, but the difference wasn't significant (P = .11). Numeric decreases in serum epinephrine, norepinephrine, and natriuretic peptides also did not reach significance.

Both Fudim and Ponikowski said they were undeterred by the statistically neutral effects of the interventions on some hemodynamic and biomarker indicators in these small proof-of-concept samples.

Ponikowski said he's confident that the hypothesis for an alternative mechanism for decompensation tested in the studies is correct. He also believes that it will somehow be applied more widely to patients with heart failure, especially if less invasive, perhaps transcatheter ablation, techniques can be developed.

Ponikowsi discloses receiving fees for consulting from Cibiem, Coridea, Axon, and RenalGuard Solutions. Fudim discloses consulting for, receiving royalties from, or having ownership or equity interest in Coridea, Axon Therapies, and Galvani. Cleland has recently disclosed serving as an advisor or consultant for Amgen, Merck Sharp & Dohme, Novartis Pharmaceuticals, Servier, and St. Jude Medical; serving as a speaker or a member of a speakers bureau for St. Jude Medical; and receiving grants from Amgen. Piesky had no disclosures.

European Society of Cardiology Heart Failure (ESC-HF) 2018. Late breaking trial I - Acute heart failure; presented May 26, 2018. Late breaking trial III - Innovative and device therapy; presented May 28, 2018.

Circulation. Published online May 25, 2018. Article.

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