Evaluation of right ventricular performance and impact of continuous positive airway pressure therapy in patients with ...

Indianola Woman Waiting For Heart Transplant Thankful For Community Support

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INDIANOLA — In this village of only around 250 people in southern Vermilion County, "when someone is going through something, we all pull together," resident Lucinda Goble said.

Goble has been friends with Kelly Manning Ingalsbe for as long as she can remember, and when she saw that Ingalsbe was offered a heart for transplant this week but that her medical team didn't think it was the best one for her, she knew she had to do something more for her lifelong friend.

"I am a strong believer in the power of prayer, and I just wanted to get more people praying about the same thing, at the same time, the same place," Goble said.

So, she posted on Facebook, with Ingalsbe being on board with it, "Ok people! Monday, July 1 at 7 p.M. At the Indianola Park, we are having a prayer vigil for Kelly Manning Ingalsbe. She has been in the hospital for more than a month waiting for a heart transplant. There is mighty power in prayer, and when God's people come together! Please share this and I hope to see you all on Monday!"

The post was also shared on the village's social-media page, stating "Let us come together as a community to send prayers and thoughts to a member of our village."

Ingalsbe, 58, is about two hours away from home at OSF St. Francis Medical Center in Peoria, but she said she feels and is grateful for the support from friends and family.

Ingalsbe had her first quadruple bypass surgery at age 38 and is now waiting for a heart transplant.

She has to stay in the hospital until her transplant, "which makes it hard," she said. "I'm missing my family."

Her sister, who staying at the hospital's Family House, takes a shuttle back and forth to the hospital to be with her.

Ingalsbe's husband, Joe, is in planting season and is busy with farming.

"Life is life and he still has to work," she said. "He makes it one day a week here."

Her sons live in Ridge Farm and Danville. She said her brother-in-law also is coming once a week to see her. Another sister died of cancer a couple decades ago.

"Life hits you all at once sometimes," Ingalsbe said. "I have strong faith in the Lord. No matter how this ends up, I'm ready."

Being in the hospital today waiting for a heart transplant goes back to those medical issues from 20 years ago.

Ingalsbe was born and raised in Georgetown and moved to Indianola, two doors down from her sister after she moved there. That was more than 28 years ago.

Ingalsbe has been married for 28 years. Her sons are Tyler Hansen, 36, of Danville and Lucas Ingalsbe, 25, of Ridge Farm.

She worked as a certified nursing assistant for many years and became a nurse in geriatrics. She's worked in home care and hospice, and dialysis with Dr. Brijnandan Sodhi in Danville.

She said it's ironic that she had to have dialysis for a month, due to an acute situation, in the same place she used to work.

"That was lucky," she said.

Ingalsbe said her medical journey started when she was 38 and started having chest pain. She initially thought she had the flu, having dizziness and vomiting, but those are also symptoms of a heart attack, too.

She said she went to work that Monday, but still wasn't feeling well. She was told to go home, so she called her mom and sister to come and get her.

She'd been vomiting for quite some time on and off and her mom and sister drove her the short distance from her workplace to the Danville hospital.

Ingalsbe said her electrocardiogram was abnormal and "that's kind of where it all started."

Further tests found she had five heart blockages, and she ended up having quadruple bypass surgery at 38.

"Basically, along the way, I've had four heart attacks and so many stents," she said, that she can't even remember the number.

She's been in different hospitals, including in Indianapolis and both in Urbana.

Finally, her OSF HealthCare cardiologist said it's time for a heart transplant.

Ingalsbe said she thought it was time for a third bypass/open-heart surgery. But the veins in her legs had already been used for previous surgeries and the ones in her arms were not sufficient enough for a bypass, she said.

"So, transplant was our next option," she said.

At first the cardiologist told her she wasn't ready for a transplant, saying her heart was not that bad. That went on for about two years, she said.

Then, at the beginning of May, she was told her ejection fraction — how hard your heart pumps, which determines how much oxygen is in the blood flowing through your body — was down to 25 percent. In 2015, her ejection fraction was 10-15 percent.

Ingalsbe said they put her on a balloon pump, and "it kind of got better on its own. It got back to normal, actually."

However, later on, they didn't put in a balloon pump, and had her on a LifeVest that would shock her if she went into cardiac arrest.

She wore the vest until a May 17 appointment. She was running a little bit behind for the appointment in Peoria and was dropped off at the front of the building and walked fast to the office. By the time she got there, she was having a chest pain and had nausea.

After another EKG, she was sent by ambulance from the doctor's office to OSF St. Francis Medical Center.

"That's how everything really got started," Ingalsbe said.

She's been in the hospital over a month and was told this week that a heart was offered but her medical team declined it due to its ejection fraction only being 40 percent. Ingalsbe said the normal range is 59 percent and higher.

"If you're going to do it, you want the best outcome," she said.

Ingalsbe is small and mighty, which is in her favor, standing 4-foot-91/2 and with an ironically B positive blood type.

"Both of those are good," she said, saying that a bigger person would require a larger heart. "They say that gives me a better chance of a heart quicker."

That timeframe is unknown. It could be 24 hours to up to six months.

She said they don't anticipate it taking six months.

Ingalsbe said she appreciates all the support from home, including her longtime friend, Goble.

She said they've been friends since she moved to Indianola.

"We used to go to the same little church," Ingalsbe said.

She said friends and family also have helped with donations, financially, such as to help her sister with her meals, and nightgowns because she's tired of hospital gowns.

"I've been blessed with many contributors," Ingalsbe said.

She also appreciates the prayers.

"It's such a little community, and it's really great," she said of the planned prayer vigil.

The Hole Story: Interatrial Shunt Companies Are—Mostly—Pushing Ahead

Even since April when the RELIEVE-HF trial came out showing no benefit to an investigational interatrial shunt for heart failure (HF) patients, experts have been scratching their heads as to how best to proceed—and how cautiously—in this truly novel space.

As reported by TCTMD, RELIEVE-HF showed that implanting the Ventura shunt (V-Wave) failed to improve clinical outcomes or reduce symptoms in a wide range of HF patients and, alarmingly, raised the possibility that the shunt, designed to decrease pressure in the left atrium (LA), might actually be harmful in patients with preserved ejection fraction (HFpEF).

REDUCE-LAP-HF II, an earlier randomized trial testing a different interatrial shunt (Corvia Medical) in patients with HFpEF, also missed the mark. Here, placement of the Corvia shunt did not reduce HF events or improve health status in the overall trial. A group of HF patients did benefit, however: those without evidence of pulmonary vascular disease (PVD) identified on invasive exercise testing and without a cardiac rhythm management device. Post hoc analyses of the trial also showed favorable changes in cardiac structure and function in the responder group when compared with nonresponders. 

These mixed results, and particularly the signal of harm in RELIEVE-HF, have given pause to the several companies enrolling HFpEF patients into pivotal randomized trials, including Corvia Medical, Alleviant, and Edwards Lifesciences, among others.

James Udelson, MD (Tufts Medical Center, Boston, MA), who is involved in testing a no-implant shunt (Alleviant) in the ALLAY-HF trial, said RELIEVE-HF threw many for a loop. "The HFpEF subgroup looked pretty bad," he told TCTMD. "It was pretty stunning sitting there."

Within 24 hours or so, he said, "the dust settled." Udelson, like others, came to the conclusion that the HFpEF patients studied in RELIEVE-HF were a "pretty sick bunch" who simply were unlikely to benefit from the shunt as opposed to being harmed by the procedure.

In the HFpEF patients in RELIEVE-HF, placement of a shunt was associated with a significant 68% higher risk of all cardiovascular events and more than a threefold higher risk of all-cause mortality compared with those treated with a sham procedure. In those with HFrEF, shunt implantation was associated with a 45% lower risk of all cardiovascular events compared with the sham arm.

Given those findings, Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who presented the study at the American College of Cardiology Scientific Sessions in April, said at the time that if he were designing future trials in this space, he'd only randomize HFrEF patients.

William Abraham, MD (Ohio State University Wexner Medical Center, Columbus, OH), the chief medical officer at V-Wave, told TCTMD they are still evaluating the RELIEVE-HF findings, and that they couldn't comment about their results or future plans, including the HF patient population they envision best suited for interatrial shunting.

The RELIEVE-HF researchers are planning to publish their full results as well as a crucial "responder analysis" later this year, Stone told TCTMD.  

Responding, or Not

Nearly a dozen companies have been developing interatrial shunt devices or working on procedures to unload the LA. Since HF is characterized by increased LA pressures and pulmonary venous congestion, the working theory is that creating a small hole between the LA and right atrium (RA) might reduce LA pressures at rest and during exercise.

Corvia Medical, V-Wave, Occlutech, and Edwards Lifesciences, as well as others in early feasibility testing, have developed permanent shunts. Others, such as Alleviant, NoYA, and InterShunt, are going with the no-implant approach. Edwards Lifesciences is working on a leave-behind shunt in multiple sizes that preserves the septum and instead creates a channel between the LA and coronary sinus. Shunts vary from 4 mm to 12 mm, with some companies working across a range of sizes while others are going with a single shunt size. For example, the Corvia shunt is 8 mm, but the V-Wave and Alleviant shunts are smaller (5.1 mm and 6.0 mm, respectively).   

Based on the responder group in its randomized trial, Corvia Medical launched RESPONDER-HF, a 260-patient confirmatory, randomized trial of patients with HFpEF and those with mildly reduced EF (HFmrEF) that will exclude participants with hemodynamic evidence of PVD and cardiac rhythm devices. 

Jan Komtebedde, DVM, the company's senior vice president and chief medical officer, said that considering the types of patients enrolled, there were few findings in RELIEVE-HF that took them by surprise, including the suggestion of harm in those with HFpEF. In general, though, they can't make too much of RELIEVE-HF just yet because it's not been published, and subgroup and responder analyses have not been presented. Based on what they've seen so far, Komtebedde said, Corvia has no plans to alter their inclusion/exclusion criteria. Enrollment began in April 2023.

"We have not seen any evidence that the protocol should be changed because the patients that we excluded following our pivotal trial are the patients that were included in the RELIEVE-HF trial," said Komtebedde. "That's why we expected the RELIEVE-HF [patients with HFpEF] to not have good outcomes: because there's overlap with our nonresponders."

As for the marked benefits in HFrEF patients, prior open-label studies using the Ventura shunt or the Occlutech device have not shown such benefits, said Komtebedde. Of note, in Corvia Medical's REDUCE-LAP-HF II, approximately 10% had HFmrEF, and this group clearly benefited less than those with HFpEF, he added.  

We're trying to pick out the strike zone, to find the patients most likely to respond. James Udelson

The RELIEVE-HF investigators have published their results from the open-label, roll-in cohort, which gives a sense of the types of patients randomized in the trial. As Udelson pointed out, the vast majority had NYHA class III symptoms, markedly elevated NT-proBNP levels, and evidence of more right ventricular dysfunction than in previous shunt studies. Invasive exercise hemodynamic testing was not performed in the trial.

"I think there [is] an explanation, at least in some ways, for the negative results in the HFpEF group," Udelson told TCTMD. "The HFpEF group looks very much like the nonresponders in REDUCE-LAP II. Sicker patients, higher pulmonary vascular resistance. I think we were all thinking that [RELIEVE-HF] almost validates what we're doing with these other trials. We're trying to pick out the strike zone, to find the patients most likely to respond."

The ALLAY-HF trial, said Udelson, is modelled after the REDUCE-LAP II responder group. Researchers plan to enroll 400 to 700 patients with HFpEF (left ventricular EF ≥ 40%) who have elevated pulmonary capillary wedge pressure during exercise ≥ 25 mm Hg and exercise pulmonary vascular resistance < 1.8 WU.

"Essentially, ALLAY-HF and RESPONDER-HF are studying the same type of patients," Udelson told TCTMD.

Christopher Meduri, MD (Karolinska Institute, Stockholm, Sweden), who is involved in ALLAY-HF, said that while the first two randomized, controlled trials were neutral overall, they highlighted the importance of identifying the right patient who stands to benefit from an atrial shunt.

"Corvia's responder group in REDUCE-LAP II taught us the importance of exercise phenotyping in HFpEF," he told TCTMD—an idea the investigators have been insisting on for years.

Last year, Occlutech paused enrollment in the FROST-HF, which was their sham-controlled, randomized trial, in light of the many unknowns. The company initially had plans to include patients with HFpEF and did not have exclusion criteria based on pulmonary vascular resistance during exercise. According to an Occlutech spokesperson, they are waiting to learn more about RELIEVE-HF before starting up again. 

"An in-depth understanding of [the RELIEVE-HF] data, alongside comparisons with data from other stakeholders, will inform us on how to outline the most impactful clinical development plan, including consideration of a targeted randomized controlled trial," the Occlutech spokesperson told TCTMD.

Edwards Lifesciences would not comment on whether they are making any changes to their randomized trials in light of RELIEVE-HF or REDUCE-LAP II. Earlier this year, researchers presented favourable 1-year outcomes from their early feasibility study and have since launched ALT-FLOW II, a 100-patient, sham-controlled trial that includes HFpEF and HFmrEF patients. Key exclusion criteria include patients with pulmonary vascular resistance ≥ 5.0 WU at rest and greater than mild RV dysfunction.

Other companies, including NoYA, InterShunt, NXT, Adona Medical, and D-Shant, are still in early feasibility testing or first-in-human studies.

Staying the Course

To TCTMD, Komtebedde said the development of interatrial shunting for HF is complex, with multiple variables—patient selection, shunt size, type of shunt, among others—that factor into a successful therapy for appropriate patients.

"We have excellent scientific advisors that are involved in protocol development and patient selection criteria," he said. "Based on our open label study, we thought we had the right criteria going into the pivotal trial. Lo and behold, we were wrong with respect to pacemakers and high pulmonary vascular resistance. There was no evidence these would be problematic or associated with nonresponders. And there's still things to be learned."

There's still things to be learned. Jan Komtebedde

For example, it's unclear why patients with pacemakers fared worse or if they've selected the optimal cutoff point with peak exercise pulmonary vascular resistance (< 1.75 WU). At the moment, Komtebedde said the company has no plans to study HFrEF patients in a separate randomized trial, instead choosing to focus on the responder phenotype they identified in REDUCE-LAP-HF II and are studying in RESPONDER-HF.

"That's really the top priority for our company," he said. "We hope that other companies will try to understand if patients with lower EF can benefit from a shunt."

Indeed, all of the ongoing studies will help to hone patient selection.

Based on what's known so far, Udelson said he and his coinvestigators are not too concerned about patients with HFpEF being harmed by shunt placement in the ALLAY-HF trial.

"This whole thing comes down to, whatever kind of shunt you use, you're unloading the left atrium, which is good, and you're loading the right side and pulmonary vasculature," he said. "It's all about finding who benefits from that unloading and isn't harmed by the right-sided loading. Essentially, who can handle the shunt." 

Edwin Diaz's 'sticky Hand' Ejection The Latest Example Of MLB's Arbitrary Rule

When Mets closer Edwin Diaz was ejected on Sunday night before throwing a pitch, he became the third Mets pitcher in the last year and change to fall victim to MLB's arbitrary sticky stuff rules.

The reason behind cracking down on sticky stuff is sound. The point is to prevent pitchers from using illegal substances (like spider tack) that could give them an unfair advantage -- an issue that was spiraling out of control a bit before these new rules went into effect.

But pitchers need to be able to grip the ball properly in order to be able to control where they're throwing a dangerous projectile. And the interpretation and enforcement of the rules is ridiculous.

Specifically, they are arbitrary, unscientific, and basically not challengeable -- meaning that a pitcher will face an automatic 10-game suspension because an umpire claims he did something that cannot be proven.

Any umpire on any given day can rule that any pitcher has violated the rules. But that umpire is not required to provide any actual justification for an ejection.

Speaking after the game, Diaz said that his right hand had the same three things on it as always -- rosin (a legal substance that is on the mound), sweat, and dirt -- you know, the stuff on the baseball field.

"I just said I use the same thing as always," Diaz explained. "I rub rosin, sweat, and I put my hand in the dirt a little bit because I need to have some grip on the ball. So that's what I was explaining to them, but they said it was too much stick. I understood. But at the end of the day, I was using rosin, sweat, and put my hand in the dirt.

"I was really surprised because I didn't have anything on my hand, my glove, my belt. They always check my hat, everything. And they thought that was sticky a lot. I said you could check my hand, smell my hand, and they didn't smell anything, but they threw me out of the game."

As Diaz noted, the umpires did not find anything illegal on his glove or belt. They also didn't take his glove -- giving it back to him as he exited the field.

They of course also didn't take any evidence from his hand, which could've theoretically been checked for the illegal substance umpire Vic Carapazza suggested Diaz was using.

Doing anything scientific that could prove their claims isn't part of MLB's protocol here.

New York Mets pitcher Edwin Díaz (39) is ejected during the ninth inning against the Chicago Cubs at Wrigley Field. / David Banks - USA TODAY Sports

"It definitely wasn't rosin and sweat," Carapazza told a pool reporter after the game. "We've checked thousands of these. I know what that feeling is. This was very sticky."

There are numerous problems with what Carapazza said.

The first is that because it was said through a pool reporter, it wasn't challenged with any follow-up questions.

The second is that he is making a serious claim without proof -- speaking in definitive terms about something he couldn't possibly be certain of.

And therein lies the problem with MLB's sticky stuff rules.

The same thing happened to Drew Smith last year.

And Smith, who relieved Diaz on Sunday after the closer was ejected, said after the game that he never received any clarification from the league on why he was ejected and suspended last June, and that he has done nothing differently since when it comes to what he puts on his hand before each outing.

To be clear, there are no villains here.

Carapazza believes what he is saying.

Diaz and Smith believe what they're saying.

But until MLB comes up with a better way to deal with these situations, ridiculous scenes like the one we witnessed on Sunday night are going to keep happening -- with the league penalizing players without proof and putting their teams at a significant disadvantage in the process.

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